|
Inhibitory activity against A549 cell line using MTT assay(Wild type p53)
|
Homo sapiens
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines.
Year : 2000
Volume : 43
Issue : 8
First Page : 1563
Last Page : 1572
Authors : Stanslas J, Hagan DJ, Ellis MJ, Turner C, Carmichael J, Ward W, Hammonds TR, Stevens MF.
Abstract : New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC(50) level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.
|
Cell cytotoxicity was determined against human ovarian cancer (A2780) cell line
|
Homo sapiens
|
350.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, DNA-damaging and cytotoxic properties of novel topoisomerase II-directed bisantrene analogues.
Year : 1998
Volume : 8
Issue : 2
First Page : 121
Last Page : 126
Authors : Zagotto G, Oliva A, Guano F, Menta E, Capranico G, Palumbo M.
Abstract : New bisantrene analogues were synthesized, bearing one or two 4,5-dihydro-1H-imidazol-2-yl hydrazone side chains at positions 1,4 or 9 of the anthracene ring system. A 10-azabioisostere was also prepared. The position of substituents in structurally isomeric drugs modulates topoisomerase II poisoning and specificity, along with cytotoxicity.
|
Concentration required to inhibit the cell growth by 50 % after 96 hr A2780 leukemic cells.
|
Homo sapiens
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel acridine-triazenes as prototype combilexins: synthesis, DNA binding, and biological activity.
Year : 1995
Volume : 38
Issue : 18
First Page : 3488
Last Page : 3501
Authors : McConnaughie AW, Jenkins TC.
Abstract : A series of bifunctional ligands has been developed as prototype DNA-binding combilexins using a DNA template-directed approach. These novel agents contain a 1,3-diaryltriazene linker moiety, present in the established DNA minor groove-binder berenil [1,3-bis(4'-amidinophenyl)-triazene], which is attached to an intercalating acridine chromophore by a functionalized thiazole residue. This 9-arylacridine is predicted to confer rotational freedom to the hybrid molecule and thus facilitate bifunctional interaction with double-stranded DNA through a combination of 'classical' intercalation and minor groove-binding processes. The noncovalent DNA-binding properties of these acridine-triazene combilexins, together with the component molecular fragments, have been examined by fluorescence quenching and thermal denaturation studies with calf thymus DNA and two oligonucleotides, [poly(dA-dT)]2 and [poly(dG-dC)]2. In addition, the binding behaviors of these acridine compounds are compared to those of proflavine (3,6-diaminoacridine) and its 9-phenyl derivative. The results indicate that the hybrid agents (i) are more DNA-affinic than either molecular component, (ii) retain the AT-preferential binding properties of the parent difunctionalized 1,3-diaryltriazene residues, despite weak GC-preferential behavior associated with the acridine chromophore, and (iii) have a reduced binding affinity at pH 7 that reflects the protonation status of the acridine. In contrast, the more basic proflavines show much greater binding affinity and a marked preference for GC-rich DNA sequences. In vitro cytotoxicity data with L1210 mouse leukemia and A2780 human colon cancer cell lines show that the conjugate molecules are approximately 10-40-fold more potent than the acridine or triazene subunits and have activities that compare favorably with those of other reported synthetic combilexins. Intercalative binding modes with a model d(GATACGATAC).d(GTATCGTATC) target duplex have been investigated using molecular modeling techniques. These studies provide a rational basis for the binding properties and suggest that the prototype combilexins can bind in a bimodal manner that induces little distortion of the host DNA duplex. Energy-minimized models for the possible dual interactions are discussed.
|
The compound was tested for the cytotoxicity against human leukemic CCRF-CEM cell lines
|
Homo sapiens
|
139.0
nM
|
|
Journal : J. Med. Chem.
Title : 9-substituted acridine derivatives with long half-life and potent antitumor activity: synthesis and structure-activity relationships.
Year : 1995
Volume : 38
Issue : 17
First Page : 3226
Last Page : 3235
Authors : Su TL, Chou TC, Kim JY, Huang JT, Ciszewska G, Ren WY, Otter GM, Sirotnak FM, Watanabe KA.
Abstract : A series of DNA-intercalating 9-anilinoacridines, namely 9-phenoxyacridines, 9-(phenylthio)acridines, and 9-(3',5'-disubstituted anilino)acridines, were synthesized as potential antitumor agents with inhibitory effects on DNA topoisomerase II. Unlike amsacrine (m-AMSA), these agents were designed to avoid the oxidative metabolic pathway. These acridine derivatives were, therefore, expected to have long half-life in plasma. Both 9-phenoxyacridines and 9-(phenylthio)acridines were found to have moderate cytotoxicity against mouse leukemia L1210 and human leukemic HL-60 cell growth in culture. Among 9-(3',5'-disubstituted anilino)acridines, 3-(9-acridinylamino)-5-(hydroxymethyl)aniline (AHMA) was found to be a potent topoisomerase II inhibitor and exhibited significant antitumor efficacy both in vitro and in vivo. Chemotherapy of solid-tumor-bearing mice with 10, 10, and 5 mg/kg (QD x 4, ip) AHMA, VP-16, and m-AMSA, respectively, resulted in more tumor volume reduction by AHMA than by VP-16 or m-AMSA for E0771 mammary adenocarcinoma and B-16 melanoma. For Lewis lung carcinoma, AHMA was as potent as VP-16 but more active than m-AMSA. Structure-activity relationships of AHMA derivatives are discussed.
|
Inhibitory activity of compound for AA8 cells to reduce cell density by 50% (exposed to compound for 4 hours)
|
Cricetulus griseus
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Hypoxia-selective antitumor agents. 2. Electronic effects of 4-substituents on the mechanisms of cytotoxicity and metabolic stability of nitracrine derivatives.
Year : 1989
Volume : 32
Issue : 1
First Page : 31
Last Page : 38
Authors : Wilson WR, Thompson LH, Anderson RF, Denny WA.
Abstract : The mechanism of cytotoxicity of a series of 4-substituted derivatives of 9-[[3-(dimethylamino)propyl]amino]-1-nitroacridine (nitracrine) has been studied, using a panel of DNA repair-defective mutants of the Chinese hamster ovary cell line AA8. Cell lines UV-4 and UV-5 were hypersensitive to nitracrine, with sensitivities approximately 10-fold greater than that of AA8, while EM-9 showed a hypersensitivity factor (HF) of about 2-fold. This pattern suggests the major cytotoxic lesions induced by nitracrine are bulky DNA monoadducts, rather than DNA interstrand cross-links as previously suggested. The desnitro analogue of nitracrine, which retains the intercalative potential of the latter but cannot be metabolically activated by nitro reduction, showed no hypersensitivity, indicating the specificity with which this panel of cell lines can discriminate different types of DNA damage. Several of the highly cytotoxic 4-substituted nitracrine derivatives showed HFs similar to that of the parent, but the less potent 4-dialkylamino and 4-COOMe derivatives showed much lower HFs for UV-4, suggesting that different mechanisms of cytotoxicity contribute. All compounds showed similar HFs under both aerobic and hypoxic conditions, indicating that hypoxia-selective toxicity in this series is due to a quantitative rather than qualitative change in the presence of oxygen. Rates of metabolic consumption of the compounds were measured under both aerobic and hypoxic conditions by bioassay against the sensitive UV-4 cell line. The results agreed well with previous inferences on metabolic stability derived from cell-killing kinetics and showed that electron-donating 4-substituents can be used to increase metabolic stability in vitro. Such stabilization may enhance the therapeutic utility of the nitroacridines in cancer therapy since rapid metabolism of nitracrine appears to prevent its activity against hypoxic cells in solid tumors.
|
The compound was tested for the cytotoxicity against human leukemic CEM/VBL cell lines
|
Homo sapiens
|
520.0
nM
|
|
Journal : J. Med. Chem.
Title : 9-substituted acridine derivatives with long half-life and potent antitumor activity: synthesis and structure-activity relationships.
Year : 1995
Volume : 38
Issue : 17
First Page : 3226
Last Page : 3235
Authors : Su TL, Chou TC, Kim JY, Huang JT, Ciszewska G, Ren WY, Otter GM, Sirotnak FM, Watanabe KA.
Abstract : A series of DNA-intercalating 9-anilinoacridines, namely 9-phenoxyacridines, 9-(phenylthio)acridines, and 9-(3',5'-disubstituted anilino)acridines, were synthesized as potential antitumor agents with inhibitory effects on DNA topoisomerase II. Unlike amsacrine (m-AMSA), these agents were designed to avoid the oxidative metabolic pathway. These acridine derivatives were, therefore, expected to have long half-life in plasma. Both 9-phenoxyacridines and 9-(phenylthio)acridines were found to have moderate cytotoxicity against mouse leukemia L1210 and human leukemic HL-60 cell growth in culture. Among 9-(3',5'-disubstituted anilino)acridines, 3-(9-acridinylamino)-5-(hydroxymethyl)aniline (AHMA) was found to be a potent topoisomerase II inhibitor and exhibited significant antitumor efficacy both in vitro and in vivo. Chemotherapy of solid-tumor-bearing mice with 10, 10, and 5 mg/kg (QD x 4, ip) AHMA, VP-16, and m-AMSA, respectively, resulted in more tumor volume reduction by AHMA than by VP-16 or m-AMSA for E0771 mammary adenocarcinoma and B-16 melanoma. For Lewis lung carcinoma, AHMA was as potent as VP-16 but more active than m-AMSA. Structure-activity relationships of AHMA derivatives are discussed.
|
Tested for the cytotoxicity against the repair deficient xrs-6 chinese hamster ovary cell line
|
Cricetulus griseus
|
240.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibition of topoisomerase II catalytic activity by pyridoacridine alkaloids from a Cystodytes sp. ascidian: a mechanism for the apparent intercalator-induced inhibition of topoisomerase II.
Year : 1994
Volume : 37
Issue : 22
First Page : 3819
Last Page : 3827
Authors : McDonald LA, Eldredge GS, Barrows LR, Ireland CM.
Abstract : Several new pyridoacridine alkaloids, dehydrokuanoniamine B (1), shermilamine C (2), and cystodytin J (3), in addition to the known compounds cystodytin A (4), kuanoniamine D (5), shermilamine B (6), and eilatin (7), were isolated from a Fijian Cystodytes sp. ascidian. Their structures were determined by analyses of spectroscopic data. These compounds along with a previously reported pyridoacridine, diplamine (8), showed dose-dependent inhibition of proliferation in human colon tumor (HCT) cells in vitro. All compounds inhibited the topoisomerase (TOPO) II-mediated decatenation of kinetoplast DNA (kDNA) in a dose-dependent manner. The pyridoacridines' ability to inhibit TOPO II-mediated decatenation of kDNA correlated with their cytotoxic potencies and their ability to intercalate into calf thymus DNA. These results suggest that disruption of the function of TOPO II, subsequent to intercalation, is a probable mechanism by which pyridoacridines inhibit the proliferation of HCT cells. Incorporation studies show that pyridoacridines disrupt DNA and RNA synthesis with little effect on protein synthesis. It appears that DNA is the primary cellular target of the pyridoacridine alkaloids. These results are consistent with those for known DNA intercalators.
|
The compound was tested for the cytotoxicity DC-3F cell lines
|
Cricetulus griseus
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : 9-substituted acridine derivatives with long half-life and potent antitumor activity: synthesis and structure-activity relationships.
Year : 1995
Volume : 38
Issue : 17
First Page : 3226
Last Page : 3235
Authors : Su TL, Chou TC, Kim JY, Huang JT, Ciszewska G, Ren WY, Otter GM, Sirotnak FM, Watanabe KA.
Abstract : A series of DNA-intercalating 9-anilinoacridines, namely 9-phenoxyacridines, 9-(phenylthio)acridines, and 9-(3',5'-disubstituted anilino)acridines, were synthesized as potential antitumor agents with inhibitory effects on DNA topoisomerase II. Unlike amsacrine (m-AMSA), these agents were designed to avoid the oxidative metabolic pathway. These acridine derivatives were, therefore, expected to have long half-life in plasma. Both 9-phenoxyacridines and 9-(phenylthio)acridines were found to have moderate cytotoxicity against mouse leukemia L1210 and human leukemic HL-60 cell growth in culture. Among 9-(3',5'-disubstituted anilino)acridines, 3-(9-acridinylamino)-5-(hydroxymethyl)aniline (AHMA) was found to be a potent topoisomerase II inhibitor and exhibited significant antitumor efficacy both in vitro and in vivo. Chemotherapy of solid-tumor-bearing mice with 10, 10, and 5 mg/kg (QD x 4, ip) AHMA, VP-16, and m-AMSA, respectively, resulted in more tumor volume reduction by AHMA than by VP-16 or m-AMSA for E0771 mammary adenocarcinoma and B-16 melanoma. For Lewis lung carcinoma, AHMA was as potent as VP-16 but more active than m-AMSA. Structure-activity relationships of AHMA derivatives are discussed.
|
The compound was tested for the cytotoxicity against human leukemic DC-3F/ADII cell lines, activity is expressed as IC50 values.
|
Homo sapiens
|
47.0
nM
|
|
Journal : J. Med. Chem.
Title : 9-substituted acridine derivatives with long half-life and potent antitumor activity: synthesis and structure-activity relationships.
Year : 1995
Volume : 38
Issue : 17
First Page : 3226
Last Page : 3235
Authors : Su TL, Chou TC, Kim JY, Huang JT, Ciszewska G, Ren WY, Otter GM, Sirotnak FM, Watanabe KA.
Abstract : A series of DNA-intercalating 9-anilinoacridines, namely 9-phenoxyacridines, 9-(phenylthio)acridines, and 9-(3',5'-disubstituted anilino)acridines, were synthesized as potential antitumor agents with inhibitory effects on DNA topoisomerase II. Unlike amsacrine (m-AMSA), these agents were designed to avoid the oxidative metabolic pathway. These acridine derivatives were, therefore, expected to have long half-life in plasma. Both 9-phenoxyacridines and 9-(phenylthio)acridines were found to have moderate cytotoxicity against mouse leukemia L1210 and human leukemic HL-60 cell growth in culture. Among 9-(3',5'-disubstituted anilino)acridines, 3-(9-acridinylamino)-5-(hydroxymethyl)aniline (AHMA) was found to be a potent topoisomerase II inhibitor and exhibited significant antitumor efficacy both in vitro and in vivo. Chemotherapy of solid-tumor-bearing mice with 10, 10, and 5 mg/kg (QD x 4, ip) AHMA, VP-16, and m-AMSA, respectively, resulted in more tumor volume reduction by AHMA than by VP-16 or m-AMSA for E0771 mammary adenocarcinoma and B-16 melanoma. For Lewis lung carcinoma, AHMA was as potent as VP-16 but more active than m-AMSA. Structure-activity relationships of AHMA derivatives are discussed.
|
In vitro inhibitior of human DNA topoisomerase II from HeLa cells.
|
None
|
720.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antitumor activity of 4-aminomethylthioxanthenone and 5-aminomethylbenzothiopyranoindazole derivatives.
Year : 1998
Volume : 41
Issue : 19
First Page : 3645
Last Page : 3654
Authors : Perni RB, Wentland MP, Huang JI, Powles RG, Aldous S, Klingbeil KM, Peverly AD, Robinson RG, Corbett TH, Jones JL, Mattes KC, Rake JB, Coughlin SA.
Abstract : Two new series of antitumor agents, 4-aminomethylthioxanthenones (6-50) and 5-aminomethylbenzothiopyranoindazoles (51-61), are described and compared. Nearly all members of both series display excellent in vivo activity versus murine pancreatic adenocarcinoma 03 (Panc03) although there is little to distinguish the two series from each other. In both series there is no discernible relationship between structure and in vivo efficacy. Selected analogues were evaluated in vitro; all were observed to have moderate to strong DNA binding via intercalation. However, varying degrees of in vitro P388 cytotoxicity and topoisomerase II inhibition were seen. In general, those molecules which exhibited strong topoisomerase II inhibition were significantly more cytotoxic than those which did not. In both series, those derivatives (48-50, 60, and 61) having a phenolic hydroxy substitution exhibited the most potent P388 cytotoxicity and topoisomerase II inhibition.
|
Inhibitory activity against F460pv8/eto cell line using MTT assay
|
Homo sapiens
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines.
Year : 2000
Volume : 43
Issue : 8
First Page : 1563
Last Page : 1572
Authors : Stanslas J, Hagan DJ, Ellis MJ, Turner C, Carmichael J, Ward W, Hammonds TR, Stevens MF.
Abstract : New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC(50) level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.
|
Inhibitory activity against H460pv8 cell line using MTT assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines.
Year : 2000
Volume : 43
Issue : 8
First Page : 1563
Last Page : 1572
Authors : Stanslas J, Hagan DJ, Ellis MJ, Turner C, Carmichael J, Ward W, Hammonds TR, Stevens MF.
Abstract : New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC(50) level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.
|
In vitro for the inhibition of human colon tumor (HCT-8) cells.
|
Homo sapiens
|
120.0
nM
|
|
Journal : J. Med. Chem.
Title : Potential antitumor agents. 48. 3'-Dimethylamino derivatives of amsacrine: redox chemistry and in vivo solid tumor activity.
Year : 1987
Volume : 30
Issue : 4
First Page : 652
Last Page : 658
Authors : Atwell GJ, Rewcastle GW, Baguley BC, Denny WA.
Abstract : Structure-activity relationships for a series of acridine-substituted 3'-N(CH3)2 derivatives of the clinical antileukemic drug amsacrine (1) are reported. The parent (unsubstituted) compound 3 has activity against the Lewis lung solid tumor that is superior to amsacrine (1), the new clinical amsacrine analogue 4, and the recently developed 3'-NHCH3 derivative 2. Although the compounds generally bind less well to DNA and are less dose potent in vivo than either their amsacrine (3'-OCH3) or 3'-NHCH3 analogues, they show very high levels of antitumor activity, with the 4-OCH3 derivative capable of effecting 100% cures of the Lewis lung solid tumor. The broad structure-activity relationships for acridine substitution more closely resemble those of the amsacrine than the 3'-NHCH3 series, with 4-substituted and 4,5-disubstituted compounds showing the highest activity.
|
In vitro for cytotoxicity against human colon tumor cells (HCT-8) in culture
|
Homo sapiens
|
120.0
nM
|
|
Journal : J. Med. Chem.
Title : Potential antitumor agents. 47. 3'-Methylamino analogues of amsacrine with in vivo solid tumor activity.
Year : 1986
Volume : 29
Issue : 9
First Page : 1769
Last Page : 1776
Authors : Atwell GJ, Baguley BC, Finlay GJ, Rewcastle GW, Denny WA.
Abstract : Replacement of the 3'-methoxy group of the clinical antileukemic agent amsacrine with a 3'-methylamino group provides a compound (3) with a broader spectrum of action, including in vivo activity against experimental solid tumors. The synthesis, physicochemical properties, and biological activity of a series of acridine-substituted analogues of 3 are described. The compounds show higher levels of DNA binding, water solubility, and in vivo solid tumor activity (lewis lung carcinoma) than their amsacrine counterparts. However, the structure-activity relationships for acridine substitution are different, with 3,5-disubstituted 3'-methylamino compounds showing the highest activity (compared to 4,5-disubstituted amsacrine analogues).
|
In vitro cytotoxicity against human leukemic HL-60 cell line.
|
Homo sapiens
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : 9-substituted acridine derivatives with long half-life and potent antitumor activity: synthesis and structure-activity relationships.
Year : 1995
Volume : 38
Issue : 17
First Page : 3226
Last Page : 3235
Authors : Su TL, Chou TC, Kim JY, Huang JT, Ciszewska G, Ren WY, Otter GM, Sirotnak FM, Watanabe KA.
Abstract : A series of DNA-intercalating 9-anilinoacridines, namely 9-phenoxyacridines, 9-(phenylthio)acridines, and 9-(3',5'-disubstituted anilino)acridines, were synthesized as potential antitumor agents with inhibitory effects on DNA topoisomerase II. Unlike amsacrine (m-AMSA), these agents were designed to avoid the oxidative metabolic pathway. These acridine derivatives were, therefore, expected to have long half-life in plasma. Both 9-phenoxyacridines and 9-(phenylthio)acridines were found to have moderate cytotoxicity against mouse leukemia L1210 and human leukemic HL-60 cell growth in culture. Among 9-(3',5'-disubstituted anilino)acridines, 3-(9-acridinylamino)-5-(hydroxymethyl)aniline (AHMA) was found to be a potent topoisomerase II inhibitor and exhibited significant antitumor efficacy both in vitro and in vivo. Chemotherapy of solid-tumor-bearing mice with 10, 10, and 5 mg/kg (QD x 4, ip) AHMA, VP-16, and m-AMSA, respectively, resulted in more tumor volume reduction by AHMA than by VP-16 or m-AMSA for E0771 mammary adenocarcinoma and B-16 melanoma. For Lewis lung carcinoma, AHMA was as potent as VP-16 but more active than m-AMSA. Structure-activity relationships of AHMA derivatives are discussed.
|
Cell cytotoxicity was determined against human promyelocytic leukemia (HL60) cell line
|
Homo sapiens
|
400.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, DNA-damaging and cytotoxic properties of novel topoisomerase II-directed bisantrene analogues.
Year : 1998
Volume : 8
Issue : 2
First Page : 121
Last Page : 126
Authors : Zagotto G, Oliva A, Guano F, Menta E, Capranico G, Palumbo M.
Abstract : New bisantrene analogues were synthesized, bearing one or two 4,5-dihydro-1H-imidazol-2-yl hydrazone side chains at positions 1,4 or 9 of the anthracene ring system. A 10-azabioisostere was also prepared. The position of substituents in structurally isomeric drugs modulates topoisomerase II poisoning and specificity, along with cytotoxicity.
|
Inhibitory concentration required for cytotoxicity in J774.2 murine macrophage-like cells
|
Mus musculus
|
900.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Hydroxylation at C-3 of doxorubicin alters the selected phenotype of cellular drug resistance
Year : 1995
Volume : 5
Issue : 16
First Page : 1807
Last Page : 1812
Authors : Lothstein L, Sweatman TW, Priebe W
|
Inhibitory activity against Jurkat human leukemia cells
|
Homo sapiens
|
37.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and cytotoxic activity of 7-oxo-7H-dibenz[f,ij]isoquinoline and 7-oxo-7H-benzo[e]perimidine derivatives.
Year : 2001
Volume : 44
Issue : 12
First Page : 2004
Last Page : 2014
Authors : Bu X, Deady LW, Finlay GJ, Baguley BC, Denny WA.
Abstract : A series of 7-oxo-7H-dibenz[f,ij]isoquinoline and 7-oxo-7H-benzo[e]perimidines bearing cationic side chains were prepared from aminoanthraquinones. The perimidines were prepared from 1-aminoanthraquinone by initial condensation with urea or dimethylacetamide. A series of 2-, 4-, 8-, and 11-carboxy derivatives of the dibenzisoquinolines were prepared from aminoanthraquinonecarboxylic acids. The cationic derivatives were prepared from these via amide, amine, or methylene linkers to study the effects of side chain positioning on biological activity. Within the series of carboxamide-linked compounds, the order of increasing cytotoxicity was 8- < 4- < 2- < 11-. The 2- and 4-carboxamides showed substantial growth delays against in vivo subcutaneous colon 38 tumors in mice, but the 11-carboxamide had curative activity in this refractory model and is being investigated further.
|
Inhibitory concentration against Human Jurkat leukemia (JLC) cell proliferation
|
Homo sapiens
|
37.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antitumor properties of N-[2-(dimethylamino)ethyl]carboxamide derivatives of fused tetracyclic quinolines and quinoxalines: a new class of putative topoisomerase inhibitors.
Year : 1997
Volume : 40
Issue : 13
First Page : 2040
Last Page : 2046
Authors : Deady LW, Kaye AJ, Finlay GJ, Baguley BC, Denny WA.
Abstract : A series of tetracyclic quinoline- and quinoxalinecarboxamides were prepared, and their cytotoxicities were evaluated in a series of murine human tumor cell lines. Most of the quinoline derivatives were prepared by an adaptation of the Pfitzinger synthesis, followed by thermal decarboxylation and coupling with N,N-dimethylethylenediamine via a mixed anhydride method using isobutyl chloroformate. The quinoline analogues showed cytotoxicities broadly similar to those of the known tricyclic acridine-4-carboxamide mixed topoI/II inhibitor DACA, with thieno and indeno analogues being the most active. They showed little decrease in potencies against the Jurkat human leukemia topo II-resistant lines JLA and JLC, suggesting their cytotoxicity does not result primarily from inhibition of topo II. The quinoxaline analogues had more varied IC50 values, being on average less cytotoxic than the quinoline derivatives, but appeared to have a similar mode of action. Overall, this new class of compounds appear to be mixed topo I/II inhibitors, up to 3-fold more cytotoxic than DACA in the human leukemia cell lines studied, with in vivo activity in colon 38 comparable to that of DACA and doxorubicin.
|
Inhibitory concentration required to reduce human Jurkat leukemia (JLC sensitive, wild type) cell number to 50% of control cultures
|
Homo sapiens
|
37.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for acridine-substituted analogues of the mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide.
Year : 1997
Volume : 40
Issue : 12
First Page : 1919
Last Page : 1929
Authors : Spicer JA, Gamage SA, Atwell GJ, Finlay GJ, Baguley BC, Denny WA.
Abstract : The mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) is currently in clinical trial as an anticancer drug. A series of acridine-substituted analogues were prepared, using a new synthetic route to substituted acridine-4-carboxylic acids (conversion of substituted diphenylamine diacid monoesters to the corresponding aldehydes and mild acid-catalyzed ring closure to form the acridines directly). The analogues were evaluated in a panel of cell lines which included wild-type (JLC) and mutant (JLA and JLD) forms of the human Jurkat leukemia line. The latter mutant lines are resistant to topoisomerase II targeted agents due to lower levels of the enzyme. Structure-activity studies suggest that the electronic properties of the substituents do not markedly affect cytotoxicity, but steric bulk is important, with larger groups leading to loss of activity. The compounds fell broadly into two categories. The majority had cytotoxicities similar to (or lower than) that of DACA itself and were equitoxic in all the Jurkat lines, suggesting a relatively greater effect on topoisomerase I compared with topoisomerase II. Most of the 5-substituted derivatives and the 7-Ph compound were more cytotoxic than DACA, but were less effective against JLA and JLD cell lines than in the wild-type JLC, suggesting a mode of cytotoxicity largely mediated by effects on topoisomerase II. Both DACA and selected acridine-substituted analogues were active in the relatively refractory subcutaneous colon 38 tumor model in vivo.
|
Concentration required to inhibit 50% growth of human Jurkat cells
|
Homo sapiens
|
37.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for substituted bis(acridine-4-carboxamides): a new class of anticancer agents.
Year : 1999
Volume : 42
Issue : 13
First Page : 2383
Last Page : 2393
Authors : Gamage SA, Spicer JA, Atwell GJ, Finlay GJ, Baguley BC, Denny WA.
Abstract : A series of acridine-substituted bis(acridine-4-carboxamides) linked by a (CH2)3N(Me)(CH2)3 chain have been prepared by reaction of the isolated imidazolides of the substituted acridine-4-carboxylic acids with N,N-bis(3-aminopropyl)methylamine. These dimeric analogues of the mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA), currently in clinical trial, show superior potencies to the corresponding monomeric DACA analogues in a panel of cell lines, including wild-type (JLC) and mutant (JLA and JLD) forms of human Jurkat leukemia. The latter mutant lines are resistant to topoisomerase II targeted agents because of lower levels of the enzyme. Analogues with small substituents (e.g., Me, Cl) at the acridine 5-position were clearly superior, with IC50's as low as 2 nM against the Lewis lung carcinoma and 11 nM against JLC. Larger substituents at any position caused a steady decrease in potency, likely due to lowering of DNA binding affinity. A small series of analogues of the most potent bis(5-methylDACA) compound, with second substituents (Me and Cl) in the 1- or 8- position had broadly similar potencies to the 5-Me compound, indicating that, while the 1- and 8-substituents are acceptable, they add little to the enhancing effect of the 5-methyl group. All of the compounds were at least equitoxic (some up to 4-fold more cytotoxic) against the mutant Jurkat lines than in the wild-type, consistent with a relatively greater effect on topoisomerase I compared with topoisomerase II. The bis(5-methylDACA) compound was found to inhibit the action of purified topoisomerase I in a cell-free assay. Compounds were on average 10-fold less cytotoxic in an MCF7 breast cancer line overexpressing P-glycoprotein than in the wild-type line and showed some selectivity for colon tumor lines in the NCI human tumor cell line panel. Several analogues produced significant growth delays in the relatively refractory subcutaneous colon 38 tumor model in vivo at substantially lower doses than DACA. The bis(acridine-4-carboxamides) represent a new and interesting class of potent topoisomerase inhibitors.
|
Concentration required to reduce the growth of human Jurkat cells to 50% of control cultures
|
Homo sapiens
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for the antileishmanial and antitrypanosomal activities of 1'-substituted 9-anilinoacridines.
Year : 1997
Volume : 40
Issue : 16
First Page : 2634
Last Page : 2642
Authors : Gamage SA, Figgitt DP, Wojcik SJ, Ralph RK, Ransijn A, Mauel J, Yardley V, Snowdon D, Croft SL, Denny WA.
Abstract : Members of the class of 9-anilinoacridine topoisomerase II inhibitors bearing lipophilic electron-donating 1'-anilino substituents are active against both the promastigote and amastigote forms of the parasite Leishmania major. A series of analogues of the known 1'-NHhexyl lead compound were prepared and evaluated against L. major in macrophage culture to further develop structure-activity relationships (SAR). Toxicity toward mammalian cells was measured in a human leukemia cell line, and the ratio of the two IC50 values (IC50(J)/IC50(L)) was used as a measure of the in vitro therapeutic index (IVTI). A 3,6-diNMe2 substitution pattern on the acridine greatly increased toxicity to L. major without altering mammalian toxicity, increasing IVTIs over that of the lead compound. The 2-OMe, 6-Cl acridine substitution pattern used in the antimalarial drug mepacrine also resulted in potent antileishmanial activity and high IVTIs. Earlier suggestions of the utility of 2'-OR groups in lowering mammalian cytotoxicity were not borne out in this wider study. A series of very lipophilic 1'-NRR (symmetric dialkylamino)-substituted analogues showed relatively high antileishmanial potency, but no clear trend was apparent across the series, and none were superior to the 1'-NH(CH2)5Me subclass. Subsets of the most active 1'-N(R)(CH2)5Me- and 1'-N(alkyl)2-substituted compounds against L. major were also evaluated against Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei, but no consistent SAR could be discerned in these physiologically diverse test systems. The present study has confirmed earlier conclusions that lipophilic electron-donating groups at the 1'-position of 9-anilinoacridines provide high activity against L. major, but the SAR patterns observed do not carry over to the other parasites studied.
|
Inhibition of KB cell growth in vitro
|
Homo sapiens
|
0.3
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and antitumor activity of fused tetracyclic quinoline derivatives. 1.
Year : 1989
Volume : 32
Issue : 6
First Page : 1295
Last Page : 1300
Authors : Yamato M, Takeuchi Y, Hashigaki K, Ikeda Y, Chang MR, Takeuchi K, Matsushima M, Tsuruo T, Tashiro T, Tsukagoshi S.
Abstract : Several fused tri- and tetracyclic quinolines (I and II) with [2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino or [3-(N,N-dimethylamino)propyl]amino side chains were prepared, and their DNA intercalative properties, KB cytotoxicity, antitumor activity (P388 leukemia), and ability to induce topoisomerase II dependent DNA cleavage were investigated. Some compounds having both intercalative ability and KB cytotoxicity were found to be inactive in vivo. However, a positive correlation was seen between the ability to induce topoisomerase II dependent DNA cleavage and antitumor activity in vivo. The indeno- (13a), benzofuro- (21a), and benzothieno- (22a) quinoline derivatives exhibited potent antitumor activities in vitro and in vivo, comparable to those of m-AMSA. They also intercalate DNA and induce topoisomerase II dependent DNA cleavage. Extended screening of 13a showed it to be active against solid tumors such as M5076 sarcoma, B16 melanoma, and colon 38 carcinoma.
|
Inhibitory concentration against L1210 leukemic cell proliferation over 24 hr
|
Mus musculus
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel acridine-triazenes as prototype combilexins: synthesis, DNA binding, and biological activity.
Year : 1995
Volume : 38
Issue : 18
First Page : 3488
Last Page : 3501
Authors : McConnaughie AW, Jenkins TC.
Abstract : A series of bifunctional ligands has been developed as prototype DNA-binding combilexins using a DNA template-directed approach. These novel agents contain a 1,3-diaryltriazene linker moiety, present in the established DNA minor groove-binder berenil [1,3-bis(4'-amidinophenyl)-triazene], which is attached to an intercalating acridine chromophore by a functionalized thiazole residue. This 9-arylacridine is predicted to confer rotational freedom to the hybrid molecule and thus facilitate bifunctional interaction with double-stranded DNA through a combination of 'classical' intercalation and minor groove-binding processes. The noncovalent DNA-binding properties of these acridine-triazene combilexins, together with the component molecular fragments, have been examined by fluorescence quenching and thermal denaturation studies with calf thymus DNA and two oligonucleotides, [poly(dA-dT)]2 and [poly(dG-dC)]2. In addition, the binding behaviors of these acridine compounds are compared to those of proflavine (3,6-diaminoacridine) and its 9-phenyl derivative. The results indicate that the hybrid agents (i) are more DNA-affinic than either molecular component, (ii) retain the AT-preferential binding properties of the parent difunctionalized 1,3-diaryltriazene residues, despite weak GC-preferential behavior associated with the acridine chromophore, and (iii) have a reduced binding affinity at pH 7 that reflects the protonation status of the acridine. In contrast, the more basic proflavines show much greater binding affinity and a marked preference for GC-rich DNA sequences. In vitro cytotoxicity data with L1210 mouse leukemia and A2780 human colon cancer cell lines show that the conjugate molecules are approximately 10-40-fold more potent than the acridine or triazene subunits and have activities that compare favorably with those of other reported synthetic combilexins. Intercalative binding modes with a model d(GATACGATAC).d(GTATCGTATC) target duplex have been investigated using molecular modeling techniques. These studies provide a rational basis for the binding properties and suggest that the prototype combilexins can bind in a bimodal manner that induces little distortion of the host DNA duplex. Energy-minimized models for the possible dual interactions are discussed.
|
In vitro for cytotoxicity against murine leukemia cells (L1210)
|
Mus musculus
|
33.0
nM
|
|
Journal : J. Med. Chem.
Title : Potential antitumor agents. 47. 3'-Methylamino analogues of amsacrine with in vivo solid tumor activity.
Year : 1986
Volume : 29
Issue : 9
First Page : 1769
Last Page : 1776
Authors : Atwell GJ, Baguley BC, Finlay GJ, Rewcastle GW, Denny WA.
Abstract : Replacement of the 3'-methoxy group of the clinical antileukemic agent amsacrine with a 3'-methylamino group provides a compound (3) with a broader spectrum of action, including in vivo activity against experimental solid tumors. The synthesis, physicochemical properties, and biological activity of a series of acridine-substituted analogues of 3 are described. The compounds show higher levels of DNA binding, water solubility, and in vivo solid tumor activity (lewis lung carcinoma) than their amsacrine counterparts. However, the structure-activity relationships for acridine substitution are different, with 3,5-disubstituted 3'-methylamino compounds showing the highest activity (compared to 4,5-disubstituted amsacrine analogues).
|
In vitro inhibitory activity against Murine leukemia (L1210)
|
Mus musculus
|
33.0
nM
|
|
Journal : J. Med. Chem.
Title : Potential antitumor agents. 48. 3'-Dimethylamino derivatives of amsacrine: redox chemistry and in vivo solid tumor activity.
Year : 1987
Volume : 30
Issue : 4
First Page : 652
Last Page : 658
Authors : Atwell GJ, Rewcastle GW, Baguley BC, Denny WA.
Abstract : Structure-activity relationships for a series of acridine-substituted 3'-N(CH3)2 derivatives of the clinical antileukemic drug amsacrine (1) are reported. The parent (unsubstituted) compound 3 has activity against the Lewis lung solid tumor that is superior to amsacrine (1), the new clinical amsacrine analogue 4, and the recently developed 3'-NHCH3 derivative 2. Although the compounds generally bind less well to DNA and are less dose potent in vivo than either their amsacrine (3'-OCH3) or 3'-NHCH3 analogues, they show very high levels of antitumor activity, with the 4-OCH3 derivative capable of effecting 100% cures of the Lewis lung solid tumor. The broad structure-activity relationships for acridine substitution more closely resemble those of the amsacrine than the 3'-NHCH3 series, with 4-substituted and 4,5-disubstituted compounds showing the highest activity.
|
Inhibitory activity against Lewis lung carcinoma cells
|
Mus musculus
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and cytotoxic activity of 7-oxo-7H-dibenz[f,ij]isoquinoline and 7-oxo-7H-benzo[e]perimidine derivatives.
Year : 2001
Volume : 44
Issue : 12
First Page : 2004
Last Page : 2014
Authors : Bu X, Deady LW, Finlay GJ, Baguley BC, Denny WA.
Abstract : A series of 7-oxo-7H-dibenz[f,ij]isoquinoline and 7-oxo-7H-benzo[e]perimidines bearing cationic side chains were prepared from aminoanthraquinones. The perimidines were prepared from 1-aminoanthraquinone by initial condensation with urea or dimethylacetamide. A series of 2-, 4-, 8-, and 11-carboxy derivatives of the dibenzisoquinolines were prepared from aminoanthraquinonecarboxylic acids. The cationic derivatives were prepared from these via amide, amine, or methylene linkers to study the effects of side chain positioning on biological activity. Within the series of carboxamide-linked compounds, the order of increasing cytotoxicity was 8- < 4- < 2- < 11-. The 2- and 4-carboxamides showed substantial growth delays against in vivo subcutaneous colon 38 tumors in mice, but the 11-carboxamide had curative activity in this refractory model and is being investigated further.
|
Inhibitory concentration against Murine Lewis lung carcinoma (LLC) cell proliferation
|
Mus musculus
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antitumor properties of N-[2-(dimethylamino)ethyl]carboxamide derivatives of fused tetracyclic quinolines and quinoxalines: a new class of putative topoisomerase inhibitors.
Year : 1997
Volume : 40
Issue : 13
First Page : 2040
Last Page : 2046
Authors : Deady LW, Kaye AJ, Finlay GJ, Baguley BC, Denny WA.
Abstract : A series of tetracyclic quinoline- and quinoxalinecarboxamides were prepared, and their cytotoxicities were evaluated in a series of murine human tumor cell lines. Most of the quinoline derivatives were prepared by an adaptation of the Pfitzinger synthesis, followed by thermal decarboxylation and coupling with N,N-dimethylethylenediamine via a mixed anhydride method using isobutyl chloroformate. The quinoline analogues showed cytotoxicities broadly similar to those of the known tricyclic acridine-4-carboxamide mixed topoI/II inhibitor DACA, with thieno and indeno analogues being the most active. They showed little decrease in potencies against the Jurkat human leukemia topo II-resistant lines JLA and JLC, suggesting their cytotoxicity does not result primarily from inhibition of topo II. The quinoxaline analogues had more varied IC50 values, being on average less cytotoxic than the quinoline derivatives, but appeared to have a similar mode of action. Overall, this new class of compounds appear to be mixed topo I/II inhibitors, up to 3-fold more cytotoxic than DACA in the human leukemia cell lines studied, with in vivo activity in colon 38 comparable to that of DACA and doxorubicin.
|
Inhibitory concentration required to reduce Lewis lung carcinoma cell number to 50% of control cultures
|
Mus musculus
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for acridine-substituted analogues of the mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide.
Year : 1997
Volume : 40
Issue : 12
First Page : 1919
Last Page : 1929
Authors : Spicer JA, Gamage SA, Atwell GJ, Finlay GJ, Baguley BC, Denny WA.
Abstract : The mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) is currently in clinical trial as an anticancer drug. A series of acridine-substituted analogues were prepared, using a new synthetic route to substituted acridine-4-carboxylic acids (conversion of substituted diphenylamine diacid monoesters to the corresponding aldehydes and mild acid-catalyzed ring closure to form the acridines directly). The analogues were evaluated in a panel of cell lines which included wild-type (JLC) and mutant (JLA and JLD) forms of the human Jurkat leukemia line. The latter mutant lines are resistant to topoisomerase II targeted agents due to lower levels of the enzyme. Structure-activity studies suggest that the electronic properties of the substituents do not markedly affect cytotoxicity, but steric bulk is important, with larger groups leading to loss of activity. The compounds fell broadly into two categories. The majority had cytotoxicities similar to (or lower than) that of DACA itself and were equitoxic in all the Jurkat lines, suggesting a relatively greater effect on topoisomerase I compared with topoisomerase II. Most of the 5-substituted derivatives and the 7-Ph compound were more cytotoxic than DACA, but were less effective against JLA and JLD cell lines than in the wild-type JLC, suggesting a mode of cytotoxicity largely mediated by effects on topoisomerase II. Both DACA and selected acridine-substituted analogues were active in the relatively refractory subcutaneous colon 38 tumor model in vivo.
|
Inhibitory activity against MDA-468 cell line using MTT assay (ER-, amplified EGFR, mutant p53)
|
Homo sapiens
|
490.0
nM
|
|
Journal : J. Med. Chem.
Title : Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines.
Year : 2000
Volume : 43
Issue : 8
First Page : 1563
Last Page : 1572
Authors : Stanslas J, Hagan DJ, Ellis MJ, Turner C, Carmichael J, Ward W, Hammonds TR, Stevens MF.
Abstract : New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC(50) level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.
|
Inhibitory activity against MCF-7 wt cell line using MTT assay (ER+,pgR+,wildtype p53)
|
Homo sapiens
|
75.0
nM
|
|
Journal : J. Med. Chem.
Title : Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines.
Year : 2000
Volume : 43
Issue : 8
First Page : 1563
Last Page : 1572
Authors : Stanslas J, Hagan DJ, Ellis MJ, Turner C, Carmichael J, Ward W, Hammonds TR, Stevens MF.
Abstract : New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC(50) level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.
|
Inhibitory activity of tested against Murine Lewis lung carcinoma
|
Mus musculus
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for substituted bis(acridine-4-carboxamides): a new class of anticancer agents.
Year : 1999
Volume : 42
Issue : 13
First Page : 2383
Last Page : 2393
Authors : Gamage SA, Spicer JA, Atwell GJ, Finlay GJ, Baguley BC, Denny WA.
Abstract : A series of acridine-substituted bis(acridine-4-carboxamides) linked by a (CH2)3N(Me)(CH2)3 chain have been prepared by reaction of the isolated imidazolides of the substituted acridine-4-carboxylic acids with N,N-bis(3-aminopropyl)methylamine. These dimeric analogues of the mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA), currently in clinical trial, show superior potencies to the corresponding monomeric DACA analogues in a panel of cell lines, including wild-type (JLC) and mutant (JLA and JLD) forms of human Jurkat leukemia. The latter mutant lines are resistant to topoisomerase II targeted agents because of lower levels of the enzyme. Analogues with small substituents (e.g., Me, Cl) at the acridine 5-position were clearly superior, with IC50's as low as 2 nM against the Lewis lung carcinoma and 11 nM against JLC. Larger substituents at any position caused a steady decrease in potency, likely due to lowering of DNA binding affinity. A small series of analogues of the most potent bis(5-methylDACA) compound, with second substituents (Me and Cl) in the 1- or 8- position had broadly similar potencies to the 5-Me compound, indicating that, while the 1- and 8-substituents are acceptable, they add little to the enhancing effect of the 5-methyl group. All of the compounds were at least equitoxic (some up to 4-fold more cytotoxic) against the mutant Jurkat lines than in the wild-type, consistent with a relatively greater effect on topoisomerase I compared with topoisomerase II. The bis(5-methylDACA) compound was found to inhibit the action of purified topoisomerase I in a cell-free assay. Compounds were on average 10-fold less cytotoxic in an MCF7 breast cancer line overexpressing P-glycoprotein than in the wild-type line and showed some selectivity for colon tumor lines in the NCI human tumor cell line panel. Several analogues produced significant growth delays in the relatively refractory subcutaneous colon 38 tumor model in vivo at substantially lower doses than DACA. The bis(acridine-4-carboxamides) represent a new and interesting class of potent topoisomerase inhibitors.
|
Inhibitory activity against MCF7wt cell line using MTT assay
|
Homo sapiens
|
75.0
nM
|
|
Journal : J. Med. Chem.
Title : Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines.
Year : 2000
Volume : 43
Issue : 8
First Page : 1563
Last Page : 1572
Authors : Stanslas J, Hagan DJ, Ellis MJ, Turner C, Carmichael J, Ward W, Hammonds TR, Stevens MF.
Abstract : New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC(50) level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.
|
Inhibitory activity against MDA-231 cell line using MTT assay (ER-,EGFR+,mutant p53)
|
Homo sapiens
|
140.0
nM
|
|
Journal : J. Med. Chem.
Title : Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines.
Year : 2000
Volume : 43
Issue : 8
First Page : 1563
Last Page : 1572
Authors : Stanslas J, Hagan DJ, Ellis MJ, Turner C, Carmichael J, Ward W, Hammonds TR, Stevens MF.
Abstract : New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC(50) level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.
|
Inhibitory activity against NCI-H460 cell line using MTT assay
|
Homo sapiens
|
60.0
nM
|
|
Journal : J. Med. Chem.
Title : Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines.
Year : 2000
Volume : 43
Issue : 8
First Page : 1563
Last Page : 1572
Authors : Stanslas J, Hagan DJ, Ellis MJ, Turner C, Carmichael J, Ward W, Hammonds TR, Stevens MF.
Abstract : New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC(50) level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.
|
Inhibitory activity against NCI-H460 cell line using MTT assay(Wild type p53)
|
Homo sapiens
|
60.0
nM
|
|
Journal : J. Med. Chem.
Title : Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines.
Year : 2000
Volume : 43
Issue : 8
First Page : 1563
Last Page : 1572
Authors : Stanslas J, Hagan DJ, Ellis MJ, Turner C, Carmichael J, Ward W, Hammonds TR, Stevens MF.
Abstract : New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC(50) level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.
|
Inhibitory activity against NCI-H647 cell line using MTT assay(mutant p53)
|
Homo sapiens
|
70.0
nM
|
|
Journal : J. Med. Chem.
Title : Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines.
Year : 2000
Volume : 43
Issue : 8
First Page : 1563
Last Page : 1572
Authors : Stanslas J, Hagan DJ, Ellis MJ, Turner C, Carmichael J, Ward W, Hammonds TR, Stevens MF.
Abstract : New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC(50) level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.
|
Inhibitory activity against NCI-H322 cell line using MTT assay(mutant p53)
|
Homo sapiens
|
210.0
nM
|
|
Journal : J. Med. Chem.
Title : Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines.
Year : 2000
Volume : 43
Issue : 8
First Page : 1563
Last Page : 1572
Authors : Stanslas J, Hagan DJ, Ellis MJ, Turner C, Carmichael J, Ward W, Hammonds TR, Stevens MF.
Abstract : New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC(50) level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.
|
Inhibitory activity against NCI-H358 cell line using MTT assay(mutant p53)
|
Homo sapiens
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines.
Year : 2000
Volume : 43
Issue : 8
First Page : 1563
Last Page : 1572
Authors : Stanslas J, Hagan DJ, Ellis MJ, Turner C, Carmichael J, Ward W, Hammonds TR, Stevens MF.
Abstract : New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC(50) level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.
|
In Vitro Cytotoxicity was measured by quantifying clonogenic survival in soft agar following a 1 hr transient exposure of P388 mouse leukemia cells to compound
|
Mus musculus
|
150.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cyclic variations of SR 233377 (WIN 33377) and effects on antitumor activity
Year : 1996
Volume : 6
Issue : 12
First Page : 1345
Last Page : 1350
Authors : Wentland MP, Perni RB, Huang JI, Powles RG, Aldous SC, Klingbeil KM, Danielle Peverly A, Robinson RG, Corbett TH, Jones JL, Rake JB, Coughlin SA
|
In vitro cell growth inhibitory activity against wild type P388 murine leukemia cell line (P388/W)
|
Mus musculus
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Potential antitumor agents. 59. Structure-activity relationships for 2-phenylbenzimidazole-4-carboxamides, a new class of "minimal" DNA-intercalating agents which may not act via topoisomerase II.
Year : 1990
Volume : 33
Issue : 2
First Page : 814
Last Page : 819
Authors : Denny WA, Rewcastle GW, Baguley BC.
Abstract : A series of substituted 2-phenylbenzimidazole-4-carboxamides has been synthesized and evaluated for in vitro and in vivo antitumor activity. These compounds represent the logical conclusion to our search for "minimal" DNA-intercalating agents with the lowest possible DNA-binding constants. Such "2-1" tricyclic chromophores, of lower aromaticity than the structurally similar 2-phenylquinolines, have the lowest DNA binding affinity yet seen in the broad series of tricyclic carboxamide intercalating agents. Despite very low in vitro cytotoxicities, several of the compounds had moderate levels of in vivo antileukemic effects. However, the most interesting aspect of their biological activity was the lack of cross-resistance shown to an amsacrine-resistant P388 cell line, suggesting that these compounds may not express their cytotoxicity via interaction with topoisomerase II.
|
In vitro cell growth inhibitory activity was determined against amsacrine-resistant P388 cell line (P388/A).
|
Mus musculus
|
890.0
nM
|
|
Journal : J. Med. Chem.
Title : Potential antitumor agents. 59. Structure-activity relationships for 2-phenylbenzimidazole-4-carboxamides, a new class of "minimal" DNA-intercalating agents which may not act via topoisomerase II.
Year : 1990
Volume : 33
Issue : 2
First Page : 814
Last Page : 819
Authors : Denny WA, Rewcastle GW, Baguley BC.
Abstract : A series of substituted 2-phenylbenzimidazole-4-carboxamides has been synthesized and evaluated for in vitro and in vivo antitumor activity. These compounds represent the logical conclusion to our search for "minimal" DNA-intercalating agents with the lowest possible DNA-binding constants. Such "2-1" tricyclic chromophores, of lower aromaticity than the structurally similar 2-phenylquinolines, have the lowest DNA binding affinity yet seen in the broad series of tricyclic carboxamide intercalating agents. Despite very low in vitro cytotoxicities, several of the compounds had moderate levels of in vivo antileukemic effects. However, the most interesting aspect of their biological activity was the lack of cross-resistance shown to an amsacrine-resistant P388 cell line, suggesting that these compounds may not express their cytotoxicity via interaction with topoisomerase II.
|
In vitro cytotoxicity against P388 mouse leukemia cells
|
Mus musculus
|
150.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3-benzyl-quinolones: Novel, potent inhibitors of mammalian topoisomerase II
Year : 1995
Volume : 5
Issue : 9
First Page : 1021
Last Page : 1026
Authors : Eissenstat MA, Kuo G, Weaver JD, Wentland MP, Robinson RG, Klingbeil KM, Danz DW, Corbett TH, Coughlin SA
|
In vitro cytotoxicity was evaluated following 1 hour transient exposure of P388 mouse leukemia cells to the compound
|
Mus musculus
|
150.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The antitumor activity of novel pyrazoloquinoline derivatives
Year : 1995
Volume : 5
Issue : 4
First Page : 405
Last Page : 410
Authors : Wentland MP, Aldous SC, Gruett MD, Perni RB, Powles RG, Danz DW, Klingbeil KM, Peverly A, Robinson RG, Corbett TH, Rake JB, Coughlin SA
|
In vitro cytotoxicity measured by quantifying clonogenic survival in soft agar following a 1-hour transient exposure of p388 mouse leukemia cells.
|
Mus musculus
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antitumor activity of 4-aminomethylthioxanthenone and 5-aminomethylbenzothiopyranoindazole derivatives.
Year : 1998
Volume : 41
Issue : 19
First Page : 3645
Last Page : 3654
Authors : Perni RB, Wentland MP, Huang JI, Powles RG, Aldous S, Klingbeil KM, Peverly AD, Robinson RG, Corbett TH, Jones JL, Mattes KC, Rake JB, Coughlin SA.
Abstract : Two new series of antitumor agents, 4-aminomethylthioxanthenones (6-50) and 5-aminomethylbenzothiopyranoindazoles (51-61), are described and compared. Nearly all members of both series display excellent in vivo activity versus murine pancreatic adenocarcinoma 03 (Panc03) although there is little to distinguish the two series from each other. In both series there is no discernible relationship between structure and in vivo efficacy. Selected analogues were evaluated in vitro; all were observed to have moderate to strong DNA binding via intercalation. However, varying degrees of in vitro P388 cytotoxicity and topoisomerase II inhibition were seen. In general, those molecules which exhibited strong topoisomerase II inhibition were significantly more cytotoxic than those which did not. In both series, those derivatives (48-50, 60, and 61) having a phenolic hydroxy substitution exhibited the most potent P388 cytotoxicity and topoisomerase II inhibition.
|
Inhibitory activity against P388 murine leukemia cells
|
Mus musculus
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and cytotoxic activity of 7-oxo-7H-dibenz[f,ij]isoquinoline and 7-oxo-7H-benzo[e]perimidine derivatives.
Year : 2001
Volume : 44
Issue : 12
First Page : 2004
Last Page : 2014
Authors : Bu X, Deady LW, Finlay GJ, Baguley BC, Denny WA.
Abstract : A series of 7-oxo-7H-dibenz[f,ij]isoquinoline and 7-oxo-7H-benzo[e]perimidines bearing cationic side chains were prepared from aminoanthraquinones. The perimidines were prepared from 1-aminoanthraquinone by initial condensation with urea or dimethylacetamide. A series of 2-, 4-, 8-, and 11-carboxy derivatives of the dibenzisoquinolines were prepared from aminoanthraquinonecarboxylic acids. The cationic derivatives were prepared from these via amide, amine, or methylene linkers to study the effects of side chain positioning on biological activity. Within the series of carboxamide-linked compounds, the order of increasing cytotoxicity was 8- < 4- < 2- < 11-. The 2- and 4-carboxamides showed substantial growth delays against in vivo subcutaneous colon 38 tumors in mice, but the 11-carboxamide had curative activity in this refractory model and is being investigated further.
|
Inhibitory activity against Murine p38 leukemia
|
Mus musculus
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for substituted bis(acridine-4-carboxamides): a new class of anticancer agents.
Year : 1999
Volume : 42
Issue : 13
First Page : 2383
Last Page : 2393
Authors : Gamage SA, Spicer JA, Atwell GJ, Finlay GJ, Baguley BC, Denny WA.
Abstract : A series of acridine-substituted bis(acridine-4-carboxamides) linked by a (CH2)3N(Me)(CH2)3 chain have been prepared by reaction of the isolated imidazolides of the substituted acridine-4-carboxylic acids with N,N-bis(3-aminopropyl)methylamine. These dimeric analogues of the mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA), currently in clinical trial, show superior potencies to the corresponding monomeric DACA analogues in a panel of cell lines, including wild-type (JLC) and mutant (JLA and JLD) forms of human Jurkat leukemia. The latter mutant lines are resistant to topoisomerase II targeted agents because of lower levels of the enzyme. Analogues with small substituents (e.g., Me, Cl) at the acridine 5-position were clearly superior, with IC50's as low as 2 nM against the Lewis lung carcinoma and 11 nM against JLC. Larger substituents at any position caused a steady decrease in potency, likely due to lowering of DNA binding affinity. A small series of analogues of the most potent bis(5-methylDACA) compound, with second substituents (Me and Cl) in the 1- or 8- position had broadly similar potencies to the 5-Me compound, indicating that, while the 1- and 8-substituents are acceptable, they add little to the enhancing effect of the 5-methyl group. All of the compounds were at least equitoxic (some up to 4-fold more cytotoxic) against the mutant Jurkat lines than in the wild-type, consistent with a relatively greater effect on topoisomerase I compared with topoisomerase II. The bis(5-methylDACA) compound was found to inhibit the action of purified topoisomerase I in a cell-free assay. Compounds were on average 10-fold less cytotoxic in an MCF7 breast cancer line overexpressing P-glycoprotein than in the wild-type line and showed some selectivity for colon tumor lines in the NCI human tumor cell line panel. Several analogues produced significant growth delays in the relatively refractory subcutaneous colon 38 tumor model in vivo at substantially lower doses than DACA. The bis(acridine-4-carboxamides) represent a new and interesting class of potent topoisomerase inhibitors.
|
Inhibitory concentration to reduce cell number to 50% of Murine P388 leukemia cell culture
|
Mus musculus
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antitumor properties of N-[2-(dimethylamino)ethyl]carboxamide derivatives of fused tetracyclic quinolines and quinoxalines: a new class of putative topoisomerase inhibitors.
Year : 1997
Volume : 40
Issue : 13
First Page : 2040
Last Page : 2046
Authors : Deady LW, Kaye AJ, Finlay GJ, Baguley BC, Denny WA.
Abstract : A series of tetracyclic quinoline- and quinoxalinecarboxamides were prepared, and their cytotoxicities were evaluated in a series of murine human tumor cell lines. Most of the quinoline derivatives were prepared by an adaptation of the Pfitzinger synthesis, followed by thermal decarboxylation and coupling with N,N-dimethylethylenediamine via a mixed anhydride method using isobutyl chloroformate. The quinoline analogues showed cytotoxicities broadly similar to those of the known tricyclic acridine-4-carboxamide mixed topoI/II inhibitor DACA, with thieno and indeno analogues being the most active. They showed little decrease in potencies against the Jurkat human leukemia topo II-resistant lines JLA and JLC, suggesting their cytotoxicity does not result primarily from inhibition of topo II. The quinoxaline analogues had more varied IC50 values, being on average less cytotoxic than the quinoline derivatives, but appeared to have a similar mode of action. Overall, this new class of compounds appear to be mixed topo I/II inhibitors, up to 3-fold more cytotoxic than DACA in the human leukemia cell lines studied, with in vivo activity in colon 38 comparable to that of DACA and doxorubicin.
|
Inhibitory concentration required to reduce murine p388 leukemia cell number to 50% of control cultures
|
Mus musculus
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for acridine-substituted analogues of the mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide.
Year : 1997
Volume : 40
Issue : 12
First Page : 1919
Last Page : 1929
Authors : Spicer JA, Gamage SA, Atwell GJ, Finlay GJ, Baguley BC, Denny WA.
Abstract : The mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) is currently in clinical trial as an anticancer drug. A series of acridine-substituted analogues were prepared, using a new synthetic route to substituted acridine-4-carboxylic acids (conversion of substituted diphenylamine diacid monoesters to the corresponding aldehydes and mild acid-catalyzed ring closure to form the acridines directly). The analogues were evaluated in a panel of cell lines which included wild-type (JLC) and mutant (JLA and JLD) forms of the human Jurkat leukemia line. The latter mutant lines are resistant to topoisomerase II targeted agents due to lower levels of the enzyme. Structure-activity studies suggest that the electronic properties of the substituents do not markedly affect cytotoxicity, but steric bulk is important, with larger groups leading to loss of activity. The compounds fell broadly into two categories. The majority had cytotoxicities similar to (or lower than) that of DACA itself and were equitoxic in all the Jurkat lines, suggesting a relatively greater effect on topoisomerase I compared with topoisomerase II. Most of the 5-substituted derivatives and the 7-Ph compound were more cytotoxic than DACA, but were less effective against JLA and JLD cell lines than in the wild-type JLC, suggesting a mode of cytotoxicity largely mediated by effects on topoisomerase II. Both DACA and selected acridine-substituted analogues were active in the relatively refractory subcutaneous colon 38 tumor model in vivo.
|
Inhibitory concentration IC50 against Plasmodium falciparum K1 by [3H]hypoxanthine uptake over 24 hr
|
Plasmodium falciparum
|
600.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro evaluation of 9-anilino-3,6-diaminoacridines active against a multidrug-resistant strain of the malaria parasite Plasmodium falciparum.
Year : 1994
Volume : 37
Issue : 10
First Page : 1486
Last Page : 1494
Authors : Gamage SA, Tepsiri N, Wilairat P, Wojcik SJ, Figgitt DP, Ralph RK, Denny WA.
Abstract : A series of 9-anilinoacridines have been prepared and evaluated for their activity against a multidrug-resistant K1 strain of the malaria parasite Plasmodium falciparum in erythrocyte suspensions. 3,6-Diamino substitution on the acridine ring resulted in lower mammalian cell cytotoxicity and higher antiparasitic activity than other substitution patterns, providing compounds with the highest in vitro therapeutic indices. A new synthesis of 3,6-diamino-9-anilinoacridines, via reduction of the corresponding diazides, gives much higher yields than traditional methods. Within the subset of 3,6-diamino-9-anilinoacridines, there was considerable tolerance to substitution at the 1'-anilino position. In a sharp divergence with structure-activity relationships for high mammalian cell toxicity and anticancer effects, derivatives bearing electron-withdrawing 1'-substituents (e.g., SO2-NHR and CONHR) showed the most potent antimalarial activity (IC50 values of 10-20 nM). Representative compounds were shown to be potent inhibitors of the DNA strand-passing activity of human topoisomerase II and of the DNA decatenation activity of the corresponding parasite enzyme. The 1'-SO2NH2derivative 7n completely inhibited strand passage by Jurkat topoisomerase II at 20 microM, and an increase in linear DNA (indicative of inhibition of religation) was seen at or above 1 microM. It also inhibited the decatenating activity of the parasite topoisomerase II at 6 microM and above. In contrast, the analogous compound without the 3,6-diamino substituent was inactive in both assays up to 100 microM. Overall, there was a positive relationship between the ability of the drugs to inhibit parasite growth in culture and their ability to inhibit parasite topoisomerase II activity in an isolated enzyme assay. The 1'-SO2NH2 derivative 7n showed a high IVTI (1000) and was a potent inhibitor of both P. falciparum in vitro (IC50 20 nM) and P. falciparum-derived topoisomerase II. However, the compound was inactive against Plasmodium berghei in mice; reasons may include rapid metabolic inactivation (possibly by N-acetylation) and/or poor distribution.
|
Inhibitory activity against SKBR-3 cell line using MTT assay (ER-amplified erB2,mutant p53)
|
Homo sapiens
|
60.0
nM
|
|
Journal : J. Med. Chem.
Title : Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines.
Year : 2000
Volume : 43
Issue : 8
First Page : 1563
Last Page : 1572
Authors : Stanslas J, Hagan DJ, Ellis MJ, Turner C, Carmichael J, Ward W, Hammonds TR, Stevens MF.
Abstract : New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC(50) level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.
|
Inhibitory activity against T47D cell line using MTT assay (ER+,mutant p53)
|
Homo sapiens
|
220.0
nM
|
|
Journal : J. Med. Chem.
Title : Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines.
Year : 2000
Volume : 43
Issue : 8
First Page : 1563
Last Page : 1572
Authors : Stanslas J, Hagan DJ, Ellis MJ, Turner C, Carmichael J, Ward W, Hammonds TR, Stevens MF.
Abstract : New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC(50) level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.
|
Inhibition of topoisomerase II purified from HeLa cells
|
Homo sapiens
|
720.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cyclic variations of SR 233377 (WIN 33377) and effects on antitumor activity
Year : 1996
Volume : 6
Issue : 12
First Page : 1345
Last Page : 1350
Authors : Wentland MP, Perni RB, Huang JI, Powles RG, Aldous SC, Klingbeil KM, Danielle Peverly A, Robinson RG, Corbett TH, Jones JL, Rake JB, Coughlin SA
|
Compound was tested for topoisomerase II inhibition in purified HeLa cells by SDS/K+ precipitation method
|
None
|
720.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The antitumor activity of novel pyrazoloquinoline derivatives
Year : 1995
Volume : 5
Issue : 4
First Page : 405
Last Page : 410
Authors : Wentland MP, Aldous SC, Gruett MD, Perni RB, Powles RG, Danz DW, Klingbeil KM, Peverly A, Robinson RG, Corbett TH, Rake JB, Coughlin SA
|
Inhibitory activity against HeLa cell Topoisomerase II
|
None
|
720.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3-benzyl-quinolones: Novel, potent inhibitors of mammalian topoisomerase II
Year : 1995
Volume : 5
Issue : 9
First Page : 1021
Last Page : 1026
Authors : Eissenstat MA, Kuo G, Weaver JD, Wentland MP, Robinson RG, Klingbeil KM, Danz DW, Corbett TH, Coughlin SA
|
Tested for inhibition of topoisomerase II isolated from HeLa cells by DNA-cleavage assay
|
None
|
720.0
nM
|
|
Journal : J. Med. Chem.
Title : Mammalian topoisomerase II inhibitory activity of 1-cyclopropyl-6,8- difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarb oxylic acid and related derivatives.
Year : 1993
Volume : 36
Issue : 19
First Page : 2801
Last Page : 2809
Authors : Wentland MP, Lesher GY, Reuman M, Gruett MD, Singh B, Aldous SC, Dorff PH, Rake JB, Coughlin SA.
Abstract : 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-ox o-3-quinolinecarboxylic acid (1), a previously reported potent inhibitor of bacterial DNA gyrase, was found to be interactive with mammalian topoisomerase II (topo II). In a DNA-cleavage assay using topo II isolated from HeLa cells, 1 exhibited an EC50 value of 7.6 microM (VP-16; EC50 = 0.81 microM). A series of analogues modified at the 1-, 2-, 3-, 5-, and 7-positions of 1 were subsequently made and assessed for topo II inhibition. Compound 1 was considerably more potent than derivatives where the 1-substituent was alkyl, aryl, or H, or when N-c-C3H5 was replaced with S. The descarboxyl (i.e., 3-H) analogue had potency comparable to that of 1; when both these compounds were substituted at the 2-position with methyl or phenyl, an interesting relationship between activity and the conformation of the carboxyl group emerged. Upon replacement of the 5-H of 1 with NH2 or F, sustained potency was seen. No enhancement of activity was evident upon replacing the 7-substituent of 1 with other pyridinyl groups, 4-methyl-1-piperazinyl, or pyrrolidinyl groups; however, the 7-(4-hydroxyphenyl) analogue (CP-115,953) was 6-fold more potent than 1. The topo II inhibitory properties of 1 translated to modest in vitro cytotoxicity and in vivo activity versus P388.
|
Tested for inhibitory activity against Topoisomerase II isolated from HeLa cells by using SDS-K+ precipitation method
|
None
|
720.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Relationship of structure of bridged (2,6-dimethyl-4-pyridinyl)quinolones to mammalian topoisomerase II inhibition
Year : 1993
Volume : 3
Issue : 8
First Page : 1711
Last Page : 1716
Authors : Wentland MP, Lesher GY, Reuman M, Pilling GM, Saindane MT, Perni RB, Eissenstat MA, Weaver JD, Singh B, Rake J, Coughlin SA
|
Cytotoxicity against CHO cell line xrs6
|
Cricetulus griseus
|
240.0
nM
|
|
Journal : J. Med. Chem.
Title : Topoisomerase II-mediated DNA cleavage by adocia- and xestoquinones from the Philippine sponge Xestospongia sp.
Year : 1995
Volume : 38
Issue : 22
First Page : 4503
Last Page : 4507
Authors : Concepción GP, Foderaro TA, Eldredge GS, Lobkovsky E, Clardy J, Barrows LR, Ireland CM.
Abstract : Investigation of an orange Xestospongia sp. sponge collected at Cape Bolinao in northern Luzon, Philippines, yielded the known compounds adociaquinones A and B (1, 2) and six new metabolites, secoadociaquinones A and B (3, 4), 14-methoxyxestoquinone (5), 15-methoxyxestoquinone (6), 15-chloro-14-hydroxyxestoquinone (7), and 14-chloro-15-hydroxyxestoquinone (8). All compounds showed inhibition of topoisomerase II in catalytic DNA unwinding and/or decatenation assays. Furthermore, adociaquinone B showed activity in a KSDS assay, suggesting it inhibits the enzyme by freezing the enzyme-DNA cleavable complex. Interestingly, adociaquinone B did not displace ethidium bromide from DNA or unwind supercoiled DNA, implying it does not intercalate DNA.
|
Inhibitory activity against ZR-75-1 cell line using MTT assay (ER+,pgr+,mutant p53)
|
Homo sapiens
|
180.0
nM
|
|
Journal : J. Med. Chem.
Title : Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines.
Year : 2000
Volume : 43
Issue : 8
First Page : 1563
Last Page : 1572
Authors : Stanslas J, Hagan DJ, Ellis MJ, Turner C, Carmichael J, Ward W, Hammonds TR, Stevens MF.
Abstract : New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC(50) level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.
|
Inhibitory activity in a cell-free assay of DNA cleavage mediated by purified HeLa cell topoisomerase II.
|
None
|
720.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent mammalian topoisomerase II inhibitors: 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-substituted-quinolines
Year : 1995
Volume : 5
Issue : 4
First Page : 399
Last Page : 404
Authors : Kuo G, Eissenstat MA, Wentland MP, Robinson RG, Klingbeil KM, Danz DW, Coughlin SA
|
Cytotoxicity against human HCT116 cells by XTT assay
|
Homo sapiens
|
700.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Analogs of the marine alkaloid makaluvamines: synthesis, topoisomerase II inhibition, and anticancer activity.
Year : 2007
Volume : 17
Issue : 10
First Page : 2890
Last Page : 2893
Authors : Shinkre BA, Raisch KP, Fan L, Velu SE.
Abstract : Twelve analogs of makaluvamines have been synthesized. These compounds were evaluated for their ability to inhibit the enzyme topoisomerase II. Five compounds were shown to inhibit topoisomerase catalytic activity comparable to two known topoisomerase II targeting control drugs, etoposide and m-AMSA. Their cytotoxicity against human colon cancer cell line HCT-116 and human breast cancer cell lines MCF-7 and MDA-MB-468 has been evaluated. Four makaluvamine analogs exhibited better IC(50) values against HCT-116 as compared to control drug etoposide. One analog exhibited better IC(50) value against HCT-116 as compared to m-AMSA. All 12 of the makaluvamine analogs exhibited better IC(50) values against MCF-7 and MDA-MB-468 as compared to etoposide as well as m-AMSA.
|
Cytotoxicity against human K562 cells after 5 days by XTT assay
|
Homo sapiens
|
23.0
nM
|
|
Journal : J. Nat. Prod.
Title : Curcumin induces high levels of topoisomerase I- and II-DNA complexes in K562 leukemia cells.
Year : 2007
Volume : 70
Issue : 12
First Page : 1884
Last Page : 1888
Authors : López-Lázaro M, Willmore E, Jobson A, Gilroy KL, Curtis H, Padget K, Austin CA.
Abstract : Recent data suggest that curcumin, a phytochemical with cancer chemopreventive potential, might be useful in the treatment of several solid and hematological malignancies. DNA topoisomerases (topos) are the target of several drugs commonly used in cancer chemotherapy. These drugs induce topo-DNA complexes with either topo I or topo II; then cellular processing converts these complexes into permanent DNA strand breaks that trigger cell death. Using the TARDIS in vivo assay, this study shows for the first time that curcumin induces topo I and topo II (alpha and beta)-DNA complexes in K562 leukemia cells. A comparative analysis revealed that the levels of these complexes were higher than those induced by several standard topo I and topo II inhibitors at equitoxic doses. Curcumin-induced topo I and topo II-DNA complexes were prevented by the antioxidant N-acetylcysteine; this suggests that, unlike the standard topo inhibitors, reactive oxygen species may mediate the formation of these complexes. Overall, this work shows that curcumin is capable of inducing topo-DNA complexes in cells with both topo I and topo II and increases the evidence suggesting that this dietary agent has potential to be tested in cancer chemotherapy.
|
Antiproliferative activity against human HeLa cells after 72 hrs by trypan blue test
|
Homo sapiens
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of pyrroloiminoquinone derivatives.
Year : 2008
Volume : 16
Issue : 5
First Page : 2431
Last Page : 2438
Authors : Passarella D, Belinghieri F, Scarpellini M, Pratesi G, Zunino F, Gia OM, Via LD, Santoro G, Danieli B.
Abstract : Synthesis of 10 pyrroloiminoquinone derivatives is presented. The strategy is based around the elaboration of a common intermediate by reaction with primary amines. All the compounds obtained have been subjected to antiproliferative activity with three different cell lines (NCI-H460, HeLa, and HL-60). The capacity of 4 selected compounds to affect the enzymatic activity of the nuclear enzyme DNA topoisomerase II and to form the typical DNA fragmentation which occurs in the apoptotic process is discussed here.
|
Antiproliferative activity against human HL60 cells after 72 hrs by trypan blue test
|
Homo sapiens
|
5.1
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of pyrroloiminoquinone derivatives.
Year : 2008
Volume : 16
Issue : 5
First Page : 2431
Last Page : 2438
Authors : Passarella D, Belinghieri F, Scarpellini M, Pratesi G, Zunino F, Gia OM, Via LD, Santoro G, Danieli B.
Abstract : Synthesis of 10 pyrroloiminoquinone derivatives is presented. The strategy is based around the elaboration of a common intermediate by reaction with primary amines. All the compounds obtained have been subjected to antiproliferative activity with three different cell lines (NCI-H460, HeLa, and HL-60). The capacity of 4 selected compounds to affect the enzymatic activity of the nuclear enzyme DNA topoisomerase II and to form the typical DNA fragmentation which occurs in the apoptotic process is discussed here.
|
Antiproliferative activity against human HT-29 cells after 96 hrs by MTT assay
|
Homo sapiens
|
559.0
nM
|
|
Journal : J. Nat. Prod.
Title : A mammalian cell agar-diffusion assay for the detection of toxic compounds.
Year : 1989
Volume : 52
Issue : 3
First Page : 522
Last Page : 527
Authors : Burres NS, Hunter JE, Wright AE.
Abstract : A method using murine P-388 leukemia or human HT-29 colon carcinoma cells was developed for the bioautography of potential antitumor agents. Of 18 cancer chemotherapeutic drugs and natural products tested, all were detected by toxicity at 0.01 or 1.0 micrograms with P-388 cells, and 11 of the 18 were detected at 10 micrograms or less with HT-29 cells. Bioautography of a crude extract of Pseudoplexaura wagenaari and subsequent purification yielded the known compound crassin acetate. With modification, the assay detected specifically toxic DNA-binding agents.
|
Antiproliferative activity against mouse P388 cells after 48 hrs by MTT assay
|
Mus musculus
|
229.0
nM
|
|
Journal : J. Nat. Prod.
Title : A mammalian cell agar-diffusion assay for the detection of toxic compounds.
Year : 1989
Volume : 52
Issue : 3
First Page : 522
Last Page : 527
Authors : Burres NS, Hunter JE, Wright AE.
Abstract : A method using murine P-388 leukemia or human HT-29 colon carcinoma cells was developed for the bioautography of potential antitumor agents. Of 18 cancer chemotherapeutic drugs and natural products tested, all were detected by toxicity at 0.01 or 1.0 micrograms with P-388 cells, and 11 of the 18 were detected at 10 micrograms or less with HT-29 cells. Bioautography of a crude extract of Pseudoplexaura wagenaari and subsequent purification yielded the known compound crassin acetate. With modification, the assay detected specifically toxic DNA-binding agents.
|
Cytotoxicity against human M4Beu cells by resazurin reduction test
|
Homo sapiens
|
740.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological evaluation of acridine compounds as potential agents for a combined targeted chemo-radionuclide therapy approach to melanoma.
Year : 2008
Volume : 16
Issue : 16
First Page : 7671
Last Page : 7690
Authors : Desbois N, Gardette M, Papon J, Labarre P, Maisonial A, Auzeloux P, Lartigue C, Bouchon B, Debiton E, Blache Y, Chavignon O, Teulade JC, Maublant J, Madelmont JC, Moins N, Chezal JM.
Abstract : Various iodo-acridone and acridine carboxamides have been prepared and evaluated as agents for targeted radionuclide and/or chemotherapy for melanoma, due to their structural similarity to benzamides which are known to possess specific affinity for melanin. Three of these carboxamides selected for their in vitro cytotoxic properties were radioiodinated with [(125)I]NaI at high specific activity. Biodistribution studies carried out in B16F0 murine melanoma tumour-bearing mice highlighted that acridone 8f and acridine 9d, presented high, long-lasting tumour concentrations together with an in vivo kinetic profile favourable to application in targeted radionuclide therapy.
|
Cytotoxicity against human DLD1 cells by resazurin reduction test
|
Homo sapiens
|
570.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological evaluation of acridine compounds as potential agents for a combined targeted chemo-radionuclide therapy approach to melanoma.
Year : 2008
Volume : 16
Issue : 16
First Page : 7671
Last Page : 7690
Authors : Desbois N, Gardette M, Papon J, Labarre P, Maisonial A, Auzeloux P, Lartigue C, Bouchon B, Debiton E, Blache Y, Chavignon O, Teulade JC, Maublant J, Madelmont JC, Moins N, Chezal JM.
Abstract : Various iodo-acridone and acridine carboxamides have been prepared and evaluated as agents for targeted radionuclide and/or chemotherapy for melanoma, due to their structural similarity to benzamides which are known to possess specific affinity for melanin. Three of these carboxamides selected for their in vitro cytotoxic properties were radioiodinated with [(125)I]NaI at high specific activity. Biodistribution studies carried out in B16F0 murine melanoma tumour-bearing mice highlighted that acridone 8f and acridine 9d, presented high, long-lasting tumour concentrations together with an in vivo kinetic profile favourable to application in targeted radionuclide therapy.
|
Cytotoxicity against human Jurkat cells by resazurin reduction test
|
Homo sapiens
|
80.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological evaluation of acridine compounds as potential agents for a combined targeted chemo-radionuclide therapy approach to melanoma.
Year : 2008
Volume : 16
Issue : 16
First Page : 7671
Last Page : 7690
Authors : Desbois N, Gardette M, Papon J, Labarre P, Maisonial A, Auzeloux P, Lartigue C, Bouchon B, Debiton E, Blache Y, Chavignon O, Teulade JC, Maublant J, Madelmont JC, Moins N, Chezal JM.
Abstract : Various iodo-acridone and acridine carboxamides have been prepared and evaluated as agents for targeted radionuclide and/or chemotherapy for melanoma, due to their structural similarity to benzamides which are known to possess specific affinity for melanin. Three of these carboxamides selected for their in vitro cytotoxic properties were radioiodinated with [(125)I]NaI at high specific activity. Biodistribution studies carried out in B16F0 murine melanoma tumour-bearing mice highlighted that acridone 8f and acridine 9d, presented high, long-lasting tumour concentrations together with an in vivo kinetic profile favourable to application in targeted radionuclide therapy.
|
Cytotoxicity against mouse B16F0 cells by resazurin reduction test
|
Mus musculus
|
80.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological evaluation of acridine compounds as potential agents for a combined targeted chemo-radionuclide therapy approach to melanoma.
Year : 2008
Volume : 16
Issue : 16
First Page : 7671
Last Page : 7690
Authors : Desbois N, Gardette M, Papon J, Labarre P, Maisonial A, Auzeloux P, Lartigue C, Bouchon B, Debiton E, Blache Y, Chavignon O, Teulade JC, Maublant J, Madelmont JC, Moins N, Chezal JM.
Abstract : Various iodo-acridone and acridine carboxamides have been prepared and evaluated as agents for targeted radionuclide and/or chemotherapy for melanoma, due to their structural similarity to benzamides which are known to possess specific affinity for melanin. Three of these carboxamides selected for their in vitro cytotoxic properties were radioiodinated with [(125)I]NaI at high specific activity. Biodistribution studies carried out in B16F0 murine melanoma tumour-bearing mice highlighted that acridone 8f and acridine 9d, presented high, long-lasting tumour concentrations together with an in vivo kinetic profile favourable to application in targeted radionuclide therapy.
|
Cytotoxicity against human M4Beu cells by Hoechst test
|
Homo sapiens
|
400.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological evaluation of acridine compounds as potential agents for a combined targeted chemo-radionuclide therapy approach to melanoma.
Year : 2008
Volume : 16
Issue : 16
First Page : 7671
Last Page : 7690
Authors : Desbois N, Gardette M, Papon J, Labarre P, Maisonial A, Auzeloux P, Lartigue C, Bouchon B, Debiton E, Blache Y, Chavignon O, Teulade JC, Maublant J, Madelmont JC, Moins N, Chezal JM.
Abstract : Various iodo-acridone and acridine carboxamides have been prepared and evaluated as agents for targeted radionuclide and/or chemotherapy for melanoma, due to their structural similarity to benzamides which are known to possess specific affinity for melanin. Three of these carboxamides selected for their in vitro cytotoxic properties were radioiodinated with [(125)I]NaI at high specific activity. Biodistribution studies carried out in B16F0 murine melanoma tumour-bearing mice highlighted that acridone 8f and acridine 9d, presented high, long-lasting tumour concentrations together with an in vivo kinetic profile favourable to application in targeted radionuclide therapy.
|
Cytotoxicity against mouse B16F0 cells by Hoechst test
|
Mus musculus
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological evaluation of acridine compounds as potential agents for a combined targeted chemo-radionuclide therapy approach to melanoma.
Year : 2008
Volume : 16
Issue : 16
First Page : 7671
Last Page : 7690
Authors : Desbois N, Gardette M, Papon J, Labarre P, Maisonial A, Auzeloux P, Lartigue C, Bouchon B, Debiton E, Blache Y, Chavignon O, Teulade JC, Maublant J, Madelmont JC, Moins N, Chezal JM.
Abstract : Various iodo-acridone and acridine carboxamides have been prepared and evaluated as agents for targeted radionuclide and/or chemotherapy for melanoma, due to their structural similarity to benzamides which are known to possess specific affinity for melanin. Three of these carboxamides selected for their in vitro cytotoxic properties were radioiodinated with [(125)I]NaI at high specific activity. Biodistribution studies carried out in B16F0 murine melanoma tumour-bearing mice highlighted that acridone 8f and acridine 9d, presented high, long-lasting tumour concentrations together with an in vivo kinetic profile favourable to application in targeted radionuclide therapy.
|
Cytotoxicity against human DLD1 cells by Hoechst test
|
Homo sapiens
|
80.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological evaluation of acridine compounds as potential agents for a combined targeted chemo-radionuclide therapy approach to melanoma.
Year : 2008
Volume : 16
Issue : 16
First Page : 7671
Last Page : 7690
Authors : Desbois N, Gardette M, Papon J, Labarre P, Maisonial A, Auzeloux P, Lartigue C, Bouchon B, Debiton E, Blache Y, Chavignon O, Teulade JC, Maublant J, Madelmont JC, Moins N, Chezal JM.
Abstract : Various iodo-acridone and acridine carboxamides have been prepared and evaluated as agents for targeted radionuclide and/or chemotherapy for melanoma, due to their structural similarity to benzamides which are known to possess specific affinity for melanin. Three of these carboxamides selected for their in vitro cytotoxic properties were radioiodinated with [(125)I]NaI at high specific activity. Biodistribution studies carried out in B16F0 murine melanoma tumour-bearing mice highlighted that acridone 8f and acridine 9d, presented high, long-lasting tumour concentrations together with an in vivo kinetic profile favourable to application in targeted radionuclide therapy.
|
Cytotoxicity against human Jurkat cells by Hoechst test
|
Homo sapiens
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological evaluation of acridine compounds as potential agents for a combined targeted chemo-radionuclide therapy approach to melanoma.
Year : 2008
Volume : 16
Issue : 16
First Page : 7671
Last Page : 7690
Authors : Desbois N, Gardette M, Papon J, Labarre P, Maisonial A, Auzeloux P, Lartigue C, Bouchon B, Debiton E, Blache Y, Chavignon O, Teulade JC, Maublant J, Madelmont JC, Moins N, Chezal JM.
Abstract : Various iodo-acridone and acridine carboxamides have been prepared and evaluated as agents for targeted radionuclide and/or chemotherapy for melanoma, due to their structural similarity to benzamides which are known to possess specific affinity for melanin. Three of these carboxamides selected for their in vitro cytotoxic properties were radioiodinated with [(125)I]NaI at high specific activity. Biodistribution studies carried out in B16F0 murine melanoma tumour-bearing mice highlighted that acridone 8f and acridine 9d, presented high, long-lasting tumour concentrations together with an in vivo kinetic profile favourable to application in targeted radionuclide therapy.
|
Cytotoxicity against human CCRF-CEM cells after 72 hrs
|
Homo sapiens
|
130.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : DNA threading bis(9-aminoacridine-4-carboxamides): effects of piperidine sidechains on DNA binding, cytotoxicity and cell cycle arrest.
Year : 2008
Volume : 16
Issue : 8
First Page : 4390
Last Page : 4400
Authors : He Z, Bu X, Eleftheriou A, Zihlif M, Qing Z, Stewart BW, Wakelin LP.
Abstract : We describe the synthesis of a series of DNA-threading bis(9-aminoacridine-4-carboxamides) comprising ethylpiperidino and N-methylpiperidin-4-yl sidechains, joined via neutral flexible alkyl chains, charged flexible polyamine chains and a semi-rigid charged piperazine linker. Their cytotoxicity towards human leukaemic cells gives IC(50) values ranging from 99 to 1100 nM, with the ethylpiperidino series generally being more cytotoxic than the N-methylpiperidin-4-yl series. Measurements with supercoiled DNA indicate that they bisintercalate.
|
Inhibition of human ERG potassium channel
|
Homo sapiens
|
210.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : A binary QSAR model for classification of hERG potassium channel blockers.
Year : 2008
Volume : 16
Issue : 7
First Page : 4107
Last Page : 4119
Authors : Thai KM, Ecker GF.
Abstract : Acquired long QT syndrome causes severe cardiac side effects and represents a major problem in clinical studies of drug candidates. One of the reasons for development of arrhythmias related to long QT is inhibition of the human ether-a-go-go-related-gene (hERG) potassium channel. Therefore, early prediction of hERG K(+) channel affinity of drug candidates is becoming increasingly important in the drug discovery process. Binary QSAR models with threshold values at IC(50)=1 and of 10 microM, respectively, were generated using two different sets of descriptors. One set comprising 32 P_VSA descriptors and the other one utilizing a set of descriptors identified out of a large set via a feature selection algorithm. For the full dataset, the power for classification of hERG blockers was 82-88%, which meets prior classification models. Considering the fact that 2D descriptors are fast and easy to calculate, these binary QSAR models are versatile tools for use in virtual screening protocols.
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
68.4
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Inhibition of rabbit aldehyde oxidase
|
Oryctolagus cuniculus
|
60.0
nM
|
|
Journal : J. Med. Chem.
Title : Aldehyde oxidase: an enzyme of emerging importance in drug discovery.
Year : 2010
Volume : 53
Issue : 24
First Page : 8441
Last Page : 8460
Authors : Pryde DC, Dalvie D, Hu Q, Jones P, Obach RS, Tran TD.
|
Inhibition of human ERG
|
Homo sapiens
|
208.93
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Predicting hERG activities of compounds from their 3D structures: development and evaluation of a global descriptors based QSAR model.
Year : 2011
Volume : 46
Issue : 2
First Page : 618
Last Page : 630
Authors : Sinha N, Sen S.
Abstract : A QSAR based predictive model of hERG activity in terms of 'global descriptors' has been developed and evaluated. The QSAR was developed by training 77 compounds covering a wide range of activities and was validated based on an external 'test set' of 80 compounds using neural network method. Statistical parameters and examination of enrichment factor indicated the effectiveness of the present model. Randomization test demonstrated the robustness of the model and cross-validation test further validated the QSAR. Domain of applicability test indicated to the high degree of reliability of the predicted results. Satisfactory performance in classifying compounds into 'active' and 'inactive' groups was also obtained. The cases where the QSAR failed, the possible sources of errors have been discussed.
|
Growth inhibition in human HL60 cells after 72 hrs by trypan blue assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Benzoquinazoline derivatives as new agents affecting DNA processing.
Year : 2011
Volume : 19
Issue : 3
First Page : 1197
Last Page : 1204
Authors : Marzaro G, Dalla Via L, Toninello A, Guiotto A, Chilin A.
Abstract : A new series of benzo[h]quinazoline and benzo[f]quinazoline derivatives was prepared and studied for the biological activity. The compounds carrying a dimethylaminoethyl side chain (6c, 8c and 12) inhibit cell growth. The ability to form a molecular complex with DNA and to interfere with topoII and topoI relaxation activity was evidenced for the most active 6c and 8c, along with the capacity to induce apoptosis on HeLa cells.
|
Growth inhibition in human A431 cells after 72 hrs by trypan blue assay
|
Homo sapiens
|
170.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Benzoquinazoline derivatives as new agents affecting DNA processing.
Year : 2011
Volume : 19
Issue : 3
First Page : 1197
Last Page : 1204
Authors : Marzaro G, Dalla Via L, Toninello A, Guiotto A, Chilin A.
Abstract : A new series of benzo[h]quinazoline and benzo[f]quinazoline derivatives was prepared and studied for the biological activity. The compounds carrying a dimethylaminoethyl side chain (6c, 8c and 12) inhibit cell growth. The ability to form a molecular complex with DNA and to interfere with topoII and topoI relaxation activity was evidenced for the most active 6c and 8c, along with the capacity to induce apoptosis on HeLa cells.
|
Growth inhibition in human HeLa cells after 72 hrs by trypan blue assay
|
Homo sapiens
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Benzoquinazoline derivatives as new agents affecting DNA processing.
Year : 2011
Volume : 19
Issue : 3
First Page : 1197
Last Page : 1204
Authors : Marzaro G, Dalla Via L, Toninello A, Guiotto A, Chilin A.
Abstract : A new series of benzo[h]quinazoline and benzo[f]quinazoline derivatives was prepared and studied for the biological activity. The compounds carrying a dimethylaminoethyl side chain (6c, 8c and 12) inhibit cell growth. The ability to form a molecular complex with DNA and to interfere with topoII and topoI relaxation activity was evidenced for the most active 6c and 8c, along with the capacity to induce apoptosis on HeLa cells.
|
Antiproliferative activity against human DU145 cells after 72 hrs by MTT assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and cytotoxic activity of new acridine-thiazolidine derivatives.
Year : 2012
Volume : 20
Issue : 11
First Page : 3533
Last Page : 3539
Authors : Barros FW, Silva TG, da Rocha Pitta MG, Bezerra DP, Costa-Lotufo LV, de Moraes MO, Pessoa C, de Moura MA, de Abreu FC, de Lima Mdo C, Galdino SL, Pitta Ida R, Goulart MO.
Abstract : Although their exact role in controlling tumour growth and apoptosis in humans remains undefined, acridine and thiazolidine compounds have been shown to act as tumour suppressors in most cancers. Based on this finding, a series of novel hybrid 5-acridin-9-ylmethylene-3-benzyl-thiazolidine-2,4-diones were synthesised via N-alkylation and Michael reaction. The cell viability was analysed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and DNA interaction assays were performed using electrochemical techniques.
|
Antiproliferative activity against human SF295 cells after 72 hrs by MTT assay
|
Homo sapiens
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and cytotoxic activity of new acridine-thiazolidine derivatives.
Year : 2012
Volume : 20
Issue : 11
First Page : 3533
Last Page : 3539
Authors : Barros FW, Silva TG, da Rocha Pitta MG, Bezerra DP, Costa-Lotufo LV, de Moraes MO, Pessoa C, de Moura MA, de Abreu FC, de Lima Mdo C, Galdino SL, Pitta Ida R, Goulart MO.
Abstract : Although their exact role in controlling tumour growth and apoptosis in humans remains undefined, acridine and thiazolidine compounds have been shown to act as tumour suppressors in most cancers. Based on this finding, a series of novel hybrid 5-acridin-9-ylmethylene-3-benzyl-thiazolidine-2,4-diones were synthesised via N-alkylation and Michael reaction. The cell viability was analysed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and DNA interaction assays were performed using electrochemical techniques.
|
Antiproliferative activity against human HCT15 cells after 72 hrs by MTT assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and cytotoxic activity of new acridine-thiazolidine derivatives.
Year : 2012
Volume : 20
Issue : 11
First Page : 3533
Last Page : 3539
Authors : Barros FW, Silva TG, da Rocha Pitta MG, Bezerra DP, Costa-Lotufo LV, de Moraes MO, Pessoa C, de Moura MA, de Abreu FC, de Lima Mdo C, Galdino SL, Pitta Ida R, Goulart MO.
Abstract : Although their exact role in controlling tumour growth and apoptosis in humans remains undefined, acridine and thiazolidine compounds have been shown to act as tumour suppressors in most cancers. Based on this finding, a series of novel hybrid 5-acridin-9-ylmethylene-3-benzyl-thiazolidine-2,4-diones were synthesised via N-alkylation and Michael reaction. The cell viability was analysed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and DNA interaction assays were performed using electrochemical techniques.
|
Antiproliferative activity against human SW620 cells after 72 hrs by MTT assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and cytotoxic activity of new acridine-thiazolidine derivatives.
Year : 2012
Volume : 20
Issue : 11
First Page : 3533
Last Page : 3539
Authors : Barros FW, Silva TG, da Rocha Pitta MG, Bezerra DP, Costa-Lotufo LV, de Moraes MO, Pessoa C, de Moura MA, de Abreu FC, de Lima Mdo C, Galdino SL, Pitta Ida R, Goulart MO.
Abstract : Although their exact role in controlling tumour growth and apoptosis in humans remains undefined, acridine and thiazolidine compounds have been shown to act as tumour suppressors in most cancers. Based on this finding, a series of novel hybrid 5-acridin-9-ylmethylene-3-benzyl-thiazolidine-2,4-diones were synthesised via N-alkylation and Michael reaction. The cell viability was analysed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and DNA interaction assays were performed using electrochemical techniques.
|
Antiproliferative activity against human HCT8 cells after 72 hrs by MTT assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and cytotoxic activity of new acridine-thiazolidine derivatives.
Year : 2012
Volume : 20
Issue : 11
First Page : 3533
Last Page : 3539
Authors : Barros FW, Silva TG, da Rocha Pitta MG, Bezerra DP, Costa-Lotufo LV, de Moraes MO, Pessoa C, de Moura MA, de Abreu FC, de Lima Mdo C, Galdino SL, Pitta Ida R, Goulart MO.
Abstract : Although their exact role in controlling tumour growth and apoptosis in humans remains undefined, acridine and thiazolidine compounds have been shown to act as tumour suppressors in most cancers. Based on this finding, a series of novel hybrid 5-acridin-9-ylmethylene-3-benzyl-thiazolidine-2,4-diones were synthesised via N-alkylation and Michael reaction. The cell viability was analysed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and DNA interaction assays were performed using electrochemical techniques.
|
Antiproliferative activity against human HL60 cells after 72 hrs by MTT assay
|
Homo sapiens
|
80.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and cytotoxic activity of new acridine-thiazolidine derivatives.
Year : 2012
Volume : 20
Issue : 11
First Page : 3533
Last Page : 3539
Authors : Barros FW, Silva TG, da Rocha Pitta MG, Bezerra DP, Costa-Lotufo LV, de Moraes MO, Pessoa C, de Moura MA, de Abreu FC, de Lima Mdo C, Galdino SL, Pitta Ida R, Goulart MO.
Abstract : Although their exact role in controlling tumour growth and apoptosis in humans remains undefined, acridine and thiazolidine compounds have been shown to act as tumour suppressors in most cancers. Based on this finding, a series of novel hybrid 5-acridin-9-ylmethylene-3-benzyl-thiazolidine-2,4-diones were synthesised via N-alkylation and Michael reaction. The cell viability was analysed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and DNA interaction assays were performed using electrochemical techniques.
|
Antiproliferative activity against human HeLa cells after 48 hrs by MTT assay
|
Homo sapiens
|
340.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and antiproliferative activity of 9-benzylamino-6-chloro-2-methoxy-acridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors.
Year : 2016
Volume : 116
First Page : 59
Last Page : 70
Authors : Zhang W, Zhang B, Zhang W, Yang T, Wang N, Gao C, Tan C, Liu H, Jiang Y.
Abstract : A series of 9-benzylamino acridine derivatives were synthesized as an extension of our discovery of acridine antitumor agents. Most of these acridine compounds displayed good antiproliferative activity with IC50 values in low micromole range and structure-activity relationships were studied. Topo I- and II- mediated relaxation studies suggested that all of our compounds displayed strong Topo II inhibitory activity at 100 μM, while only four exhibited moderate Topo I inhibitory activity. The typical compound 8p could penetrate A549 cancer cells efficiently. Compound 8p could intercalate within the double-stranded DNA structure and induce DNA damage. Moreover, compound 8p could induce A549 cells apoptosis through caspase-dependent intrinsic pathway and arrest A549 cells at the G2/M phase.
|
Antiproliferative activity against human HCT116 cells after 48 hrs by MTT assay
|
Homo sapiens
|
930.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and antiproliferative activity of 9-benzylamino-6-chloro-2-methoxy-acridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors.
Year : 2016
Volume : 116
First Page : 59
Last Page : 70
Authors : Zhang W, Zhang B, Zhang W, Yang T, Wang N, Gao C, Tan C, Liu H, Jiang Y.
Abstract : A series of 9-benzylamino acridine derivatives were synthesized as an extension of our discovery of acridine antitumor agents. Most of these acridine compounds displayed good antiproliferative activity with IC50 values in low micromole range and structure-activity relationships were studied. Topo I- and II- mediated relaxation studies suggested that all of our compounds displayed strong Topo II inhibitory activity at 100 μM, while only four exhibited moderate Topo I inhibitory activity. The typical compound 8p could penetrate A549 cancer cells efficiently. Compound 8p could intercalate within the double-stranded DNA structure and induce DNA damage. Moreover, compound 8p could induce A549 cells apoptosis through caspase-dependent intrinsic pathway and arrest A549 cells at the G2/M phase.
|
Antiproliferative activity against human CCRF-CEM cells after 48 hrs by MTT assay
|
Homo sapiens
|
180.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and antiproliferative activity of 9-benzylamino-6-chloro-2-methoxy-acridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors.
Year : 2016
Volume : 116
First Page : 59
Last Page : 70
Authors : Zhang W, Zhang B, Zhang W, Yang T, Wang N, Gao C, Tan C, Liu H, Jiang Y.
Abstract : A series of 9-benzylamino acridine derivatives were synthesized as an extension of our discovery of acridine antitumor agents. Most of these acridine compounds displayed good antiproliferative activity with IC50 values in low micromole range and structure-activity relationships were studied. Topo I- and II- mediated relaxation studies suggested that all of our compounds displayed strong Topo II inhibitory activity at 100 μM, while only four exhibited moderate Topo I inhibitory activity. The typical compound 8p could penetrate A549 cancer cells efficiently. Compound 8p could intercalate within the double-stranded DNA structure and induce DNA damage. Moreover, compound 8p could induce A549 cells apoptosis through caspase-dependent intrinsic pathway and arrest A549 cells at the G2/M phase.
|
Antiproliferative activity against human K562 cells after 48 hrs by MTT assay
|
Homo sapiens
|
880.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological research of novel azaacridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors.
Year : 2017
Volume : 25
Issue : 13
First Page : 3437
Last Page : 3446
Authors : Li D, Yuan Z, Chen S, Zhang C, Song L, Gao C, Chen Y, Tan C, Jiang Y.
Abstract : DNA and DNA-related enzymes are one of the most effective and common used intracellular anticancer targets in clinic and laboratory studies, however, most of DNA-targeting drugs suffered from toxic side effects. Development of new molecules with good antitumor activity and low side effects is important. Based on computer aided design and our previous studies, a series of novel azaacridine derivatives were synthesized as DNA and topoisomerases binding agents, among which compound 9 displayed the best antiproliferative activity with an IC50 value of 0.57μM against U937 cells, which was slightly better than m-AMSA. In addition, compound 9 displayed low cytotoxicity against human normal liver cells (QSG-7701), the IC50 of which was more than 3 times lower than m-AMSA. Later study indicated that all the compounds displayed topoisomerases II inhibition activity at 50μM. The representative compound 9 could bind with DNA and induce U937 apoptosis through the exogenous pathway.
|
Antiproliferative activity against human U937 cells after 48 hrs by MTT assay
|
Homo sapiens
|
610.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological research of novel azaacridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors.
Year : 2017
Volume : 25
Issue : 13
First Page : 3437
Last Page : 3446
Authors : Li D, Yuan Z, Chen S, Zhang C, Song L, Gao C, Chen Y, Tan C, Jiang Y.
Abstract : DNA and DNA-related enzymes are one of the most effective and common used intracellular anticancer targets in clinic and laboratory studies, however, most of DNA-targeting drugs suffered from toxic side effects. Development of new molecules with good antitumor activity and low side effects is important. Based on computer aided design and our previous studies, a series of novel azaacridine derivatives were synthesized as DNA and topoisomerases binding agents, among which compound 9 displayed the best antiproliferative activity with an IC50 value of 0.57μM against U937 cells, which was slightly better than m-AMSA. In addition, compound 9 displayed low cytotoxicity against human normal liver cells (QSG-7701), the IC50 of which was more than 3 times lower than m-AMSA. Later study indicated that all the compounds displayed topoisomerases II inhibition activity at 50μM. The representative compound 9 could bind with DNA and induce U937 apoptosis through the exogenous pathway.
|
Inhibition of human topoisomerase-2 at 10 uM using supercoiled pBR322 DNA as substrate after 10 to 15 mins by ethidium bromide staining based electrophoresis relative to control
|
Homo sapiens
|
56.9
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological research of novel azaacridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors.
Year : 2017
Volume : 25
Issue : 13
First Page : 3437
Last Page : 3446
Authors : Li D, Yuan Z, Chen S, Zhang C, Song L, Gao C, Chen Y, Tan C, Jiang Y.
Abstract : DNA and DNA-related enzymes are one of the most effective and common used intracellular anticancer targets in clinic and laboratory studies, however, most of DNA-targeting drugs suffered from toxic side effects. Development of new molecules with good antitumor activity and low side effects is important. Based on computer aided design and our previous studies, a series of novel azaacridine derivatives were synthesized as DNA and topoisomerases binding agents, among which compound 9 displayed the best antiproliferative activity with an IC50 value of 0.57μM against U937 cells, which was slightly better than m-AMSA. In addition, compound 9 displayed low cytotoxicity against human normal liver cells (QSG-7701), the IC50 of which was more than 3 times lower than m-AMSA. Later study indicated that all the compounds displayed topoisomerases II inhibition activity at 50μM. The representative compound 9 could bind with DNA and induce U937 apoptosis through the exogenous pathway.
|
Antiproliferative activity against human U937 cells after 48 hrs by MTT assay
|
Homo sapiens
|
610.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and anticancer evaluation of acridine hydroxamic acid derivatives as dual Topo and HDAC inhibitors.
Year : 2018
Volume : 26
Issue : 14
First Page : 3958
Last Page : 3966
Authors : Chen J, Li D, Li W, Yin J, Zhang Y, Yuan Z, Gao C, Liu F, Jiang Y.
Abstract : Multitarget inhibitors design has generated great interest in cancer treatment. Based on the synergistic effects of topoisomerase and histone deacetylase inhibitors, we designed and synthesized a new series of acridine hydroxamic acid derivatives as potential novel dual Topo and HDAC inhibitors. MTT assays indicated that all the hybrid compounds displayed good antiproliferative activities with IC50 values in low micromolar range, among which compound 8c displayed potent activity against U937 (IC50 = 0.90 μM). In addition, compound 8c also displayed the best HDAC inhibitory activity, which was several times more potent than HDAC inhibitor SAHA. Subsequent studies indicated that all the compounds displayed Topo II inhibition activity at 50 μM. Moreover, compound 8c could interact with DNA and induce U937 apoptosis. This study provides a suite of compounds for further exploration of dual Topo and HDAC inhibitors, and compound 8c can be a new dual Topo and HDAC inhibitory anticancer agent.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-4.19
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Cytotoxicity against human MCF7 cells assessed as reduction in cell viability incubated for 48 hrs by MTT assay
|
Homo sapiens
|
910.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel 4-quinoline-thiosemicarbazone derivatives: Synthesis, antiproliferative activity, in vitro and in silico biomacromolecule interaction studies and topoisomerase inhibition.
Year : 2019
Volume : 182
First Page : 111592
Last Page : 111592
Authors : Ribeiro AG, Almeida SMV, de Oliveira JF, Souza TRCL, Santos KLD, Albuquerque APB, Nogueira MCBL, Carvalho Junior LB, Moura RO, da Silva AC, Pereira VRA, Castro MCAB, Lima MDCA.
Abstract : Twelve 2-(quinolin-4-ylmethylene) hydrazinecarbothioamide derivatives were synthetized and their biological properties were investigated, among which, the ability to interact with DNA and BSA through UV-Vis absorption, fluorescence, Circular Dichroism, molecular docking and relative viscosity, antiproliferative activity against MCF-7 and T-47D mammary tumor cells and RAW-264.7 macrophages and inhibitory capacity of the enzyme topoisomerase IIα. In the binding study with DNA and BSA, all the compounds displayed affinity for interaction with both biomolecules, especially JF-92 (p-ethyl-substituted), with binding constant of 1.62 × 10<sup>6</sup> and 1.43 × 10<sup>5</sup>, respectively, and DNA binding mode by intercalation. The IC<sub>50</sub> values were obtained between 0.81 and 1.48 μM and topoisomerase inhibition results in 10 μM. Thus, we conclude that the reduction of the acridine to quinoline ring did not disrupt the antitumor action and that substitution patterns are important for biomolecule interaction affinity as they demonstrate the potential of these compounds for anticancer therapy.
|
Cytotoxicity against human T47D cells assessed as reduction in cell viability incubated for 48 hrs by MTT assay
|
Homo sapiens
|
940.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel 4-quinoline-thiosemicarbazone derivatives: Synthesis, antiproliferative activity, in vitro and in silico biomacromolecule interaction studies and topoisomerase inhibition.
Year : 2019
Volume : 182
First Page : 111592
Last Page : 111592
Authors : Ribeiro AG, Almeida SMV, de Oliveira JF, Souza TRCL, Santos KLD, Albuquerque APB, Nogueira MCBL, Carvalho Junior LB, Moura RO, da Silva AC, Pereira VRA, Castro MCAB, Lima MDCA.
Abstract : Twelve 2-(quinolin-4-ylmethylene) hydrazinecarbothioamide derivatives were synthetized and their biological properties were investigated, among which, the ability to interact with DNA and BSA through UV-Vis absorption, fluorescence, Circular Dichroism, molecular docking and relative viscosity, antiproliferative activity against MCF-7 and T-47D mammary tumor cells and RAW-264.7 macrophages and inhibitory capacity of the enzyme topoisomerase IIα. In the binding study with DNA and BSA, all the compounds displayed affinity for interaction with both biomolecules, especially JF-92 (p-ethyl-substituted), with binding constant of 1.62 × 10<sup>6</sup> and 1.43 × 10<sup>5</sup>, respectively, and DNA binding mode by intercalation. The IC<sub>50</sub> values were obtained between 0.81 and 1.48 μM and topoisomerase inhibition results in 10 μM. Thus, we conclude that the reduction of the acridine to quinoline ring did not disrupt the antitumor action and that substitution patterns are important for biomolecule interaction affinity as they demonstrate the potential of these compounds for anticancer therapy.
|
Antiproliferative against human CCRF-CEM cells incubated for 72 hrs by MTT assay
|
Homo sapiens
|
30.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological research of novel N-phenylbenzamide-4-methylamine acridine derivatives as potential topoisomerase I/II and apoptosis-inducing agents.
Year : 2019
Volume : 29
Issue : 23
First Page : 126714
Last Page : 126714
Authors : Zhang B, Dou Z, Xiong Z, Wang N, He S, Yan X, Jin H.
Abstract : A series of novel N-phenylbenzamide-4-methylamine acridine derivatives were designed and synthesized based initially on the structure of amsacrine (m-AMSA). Molecular docking suggested that the representative compound 9a had affinity for binding DNA topoisomerase (Topo) II, which was comparable with that of m-AMSA, and furthermore that 9a could have preferential interactions with Topo I. After synthesis of 9a and analogues 9b-9f, these were all tested in vitro and the synthesized compounds displayed potent antiproliferative activity against three different cancer cell lines (K562, CCRF-CEM and U937). Among them, compounds 9b, 9c and 9d exhibiting the highest activity with IC<sub>50</sub> value ranging from 0.82 to 0.91 μM against CCRF-CEM cells. In addition, 9b and 9d also showed high antiproliferative activity against U937 cells, with IC<sub>50</sub> values of 0.33 and 0.23 μM, respectively. The pharmacological mechanistic studies of these compounds were evaluated by Topo I/II inhibition, western blot assay and cell apoptosis detection. In summary, 9b effectively inhibited the activity of Topo I/II and induced DNA damage in CCRF-CEM cells and, moreover, significantly induced cell apoptosis in a concentration-dependent manner. These observations provide new information and guidance for the structural optimization of more novel acridine derivatives.
|
Antiproliferative against human K562 cells incubated for 72 hrs by MTT assay
|
Homo sapiens
|
710.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological research of novel N-phenylbenzamide-4-methylamine acridine derivatives as potential topoisomerase I/II and apoptosis-inducing agents.
Year : 2019
Volume : 29
Issue : 23
First Page : 126714
Last Page : 126714
Authors : Zhang B, Dou Z, Xiong Z, Wang N, He S, Yan X, Jin H.
Abstract : A series of novel N-phenylbenzamide-4-methylamine acridine derivatives were designed and synthesized based initially on the structure of amsacrine (m-AMSA). Molecular docking suggested that the representative compound 9a had affinity for binding DNA topoisomerase (Topo) II, which was comparable with that of m-AMSA, and furthermore that 9a could have preferential interactions with Topo I. After synthesis of 9a and analogues 9b-9f, these were all tested in vitro and the synthesized compounds displayed potent antiproliferative activity against three different cancer cell lines (K562, CCRF-CEM and U937). Among them, compounds 9b, 9c and 9d exhibiting the highest activity with IC<sub>50</sub> value ranging from 0.82 to 0.91 μM against CCRF-CEM cells. In addition, 9b and 9d also showed high antiproliferative activity against U937 cells, with IC<sub>50</sub> values of 0.33 and 0.23 μM, respectively. The pharmacological mechanistic studies of these compounds were evaluated by Topo I/II inhibition, western blot assay and cell apoptosis detection. In summary, 9b effectively inhibited the activity of Topo I/II and induced DNA damage in CCRF-CEM cells and, moreover, significantly induced cell apoptosis in a concentration-dependent manner. These observations provide new information and guidance for the structural optimization of more novel acridine derivatives.
|
Antiproliferative against human U937 cells incubated for 72 hrs by MTT assay
|
Homo sapiens
|
80.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological research of novel N-phenylbenzamide-4-methylamine acridine derivatives as potential topoisomerase I/II and apoptosis-inducing agents.
Year : 2019
Volume : 29
Issue : 23
First Page : 126714
Last Page : 126714
Authors : Zhang B, Dou Z, Xiong Z, Wang N, He S, Yan X, Jin H.
Abstract : A series of novel N-phenylbenzamide-4-methylamine acridine derivatives were designed and synthesized based initially on the structure of amsacrine (m-AMSA). Molecular docking suggested that the representative compound 9a had affinity for binding DNA topoisomerase (Topo) II, which was comparable with that of m-AMSA, and furthermore that 9a could have preferential interactions with Topo I. After synthesis of 9a and analogues 9b-9f, these were all tested in vitro and the synthesized compounds displayed potent antiproliferative activity against three different cancer cell lines (K562, CCRF-CEM and U937). Among them, compounds 9b, 9c and 9d exhibiting the highest activity with IC<sub>50</sub> value ranging from 0.82 to 0.91 μM against CCRF-CEM cells. In addition, 9b and 9d also showed high antiproliferative activity against U937 cells, with IC<sub>50</sub> values of 0.33 and 0.23 μM, respectively. The pharmacological mechanistic studies of these compounds were evaluated by Topo I/II inhibition, western blot assay and cell apoptosis detection. In summary, 9b effectively inhibited the activity of Topo I/II and induced DNA damage in CCRF-CEM cells and, moreover, significantly induced cell apoptosis in a concentration-dependent manner. These observations provide new information and guidance for the structural optimization of more novel acridine derivatives.
|
Inhibition of retinal reductase in Sprague-Dawley rat liver microsomes at 100 uM using all-trans retinaldehyde and NADPH by HPLC analysis relative to control
|
Rattus norvegicus
|
22.0
%
|
|
Title : Method for treating skin with retinoids and retinoid boosters
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
21.46
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-0.52
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-1.981
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.06
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.2
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
3.04
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
3.04
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.06
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.2
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
