|
Compound was evaluated for cell growth inhibition against HL 60 cell line by irradiation in the presence of examined compound
|
Homo sapiens
|
750.0
nM
|
|
Journal : J. Med. Chem.
Title : 4'-Methyl derivatives of 5-MOP and 5-MOA: synthesis, photoreactivity, and photobiological activity.
Year : 1996
Volume : 39
Issue : 22
First Page : 4489
Last Page : 4496
Authors : Gia O, Anselmo A, Conconi MT, Antonello C, Uriarte E, Caffieri S.
Abstract : The synthesis and photobiological activity of four new 4'-methyl derivatives of 5-MOP (5-methoxypsoralen) and 5-MOA (5-methoxyangelicin), i.e., 4,4'-dimethyl-5-methoxypsoralen, 3,4'-dimethyl-5-methoxypsoralen, 4,4'-dimethyl-5-methoxyangelicin, and 3,4'-dimethyl-5-methoxyangelicin, are described. All these compounds photobind efficiently to DNA. The DNA-photobinding process was investigated using various nucleic acid structures such as double-helix DNA, bacterial DNA, and synthetic polydeoxyribonucleotides. Photoreaction experiments showed that, unlike 8-MOP (8-methoxypsoralen) and 5-MOP, both angular derivatives bind thymine and cytosine with the same efficiency. The principal nucleoside-psoralen monoadducts were isolated and characterized after enzymatic digestion or acid hydrolysis. Biological activity studies revealed a good correlation with the extent of covalent photoaddition. Moreover, the two angular derivatives and the 4,4'-dimethyl-5-methoxypsoralen were unable to induce skin erythema, in striking contrast with the reference drugs, 8-MOP and 5-MOP; only the 3,4'-dimethyl-5-methoxypsoralen caused erythema, although to a substantially lower extent than that induced by the two parent compounds.
|
The IC50-UVA is the dose of UVA light which in the presence of fixed drug concentration (20 uM) is necessary to induce a 50% inhibition of DNA synthesis by incubation at the ground state by keeping mammalian cells in the dark.
|
None
|
3.59
kJ m**-2
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of (hydroxymethyl)- and (diethylaminomethyl)benzopsoralens.
Year : 1999
Volume : 42
Issue : 15
First Page : 2936
Last Page : 2945
Authors : Chilin A, Marzano C, Guiotto A, Manzini P, Baccichetti F, Carlassare F, Bordin F.
Abstract : Some benzopsoralens, carrying a hydroxymethyl or a diethylaminomethyl group at the 3, 5, 8, and 11 positions, were prepared, and their biological activity was compared with that of 4-(hydroxymethyl)benzopsoralen (BP). 5-(Hydroxymethyl)benzopsoralen (7b), 11-(hydroxymethyl)benzopsoralen (7c), and 11-(diethylaminomethyl)benzopsoralen (8c) induced marked antiproliferative effects in mammalian cells by simple incubation in the dark; this activity appeared to be related to their ability to inhibit topoisomerase II. Benzopsoralens appeared to be more active, especially BP and 7c, upon UVA activation. Compounds carrying a methyl group at the 4 position together with a hydroxymethyl or diethylaminomethyl at the 8 position (7d and 8d, respectively) were also effective, although to a lower extent; instead, a substituent at the 3 position canceled all activity. Benzopsoralens did not induce interstrand cross-links in DNA in vitro, as seen in the induction of cytoplasmic <<petite>> mutations and double-strand breaks in yeast. This behavior is also compatible with their low mutagenic activity in E. coli WP2 and with the absence of any phototoxicity on the skin. For these features, benzopsoralens seem to be interesting potential drugs for PUVA photochemotherapy and photopheresis. The activity shown in the dark is not sufficient for their possible use as antitumor drugs, but it does offer a new model for the study of topoisomerase inhibitors.
|
The IC50-UVA is the dose of UVA light which in the presence of fixed drug concentration (20 uM) is necessary to induce a 50% inhibition of clonal growth by incubation at the ground state by keeping mammalian cells in the dark
|
None
|
1.23
kJ m**-2
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of (hydroxymethyl)- and (diethylaminomethyl)benzopsoralens.
Year : 1999
Volume : 42
Issue : 15
First Page : 2936
Last Page : 2945
Authors : Chilin A, Marzano C, Guiotto A, Manzini P, Baccichetti F, Carlassare F, Bordin F.
Abstract : Some benzopsoralens, carrying a hydroxymethyl or a diethylaminomethyl group at the 3, 5, 8, and 11 positions, were prepared, and their biological activity was compared with that of 4-(hydroxymethyl)benzopsoralen (BP). 5-(Hydroxymethyl)benzopsoralen (7b), 11-(hydroxymethyl)benzopsoralen (7c), and 11-(diethylaminomethyl)benzopsoralen (8c) induced marked antiproliferative effects in mammalian cells by simple incubation in the dark; this activity appeared to be related to their ability to inhibit topoisomerase II. Benzopsoralens appeared to be more active, especially BP and 7c, upon UVA activation. Compounds carrying a methyl group at the 4 position together with a hydroxymethyl or diethylaminomethyl at the 8 position (7d and 8d, respectively) were also effective, although to a lower extent; instead, a substituent at the 3 position canceled all activity. Benzopsoralens did not induce interstrand cross-links in DNA in vitro, as seen in the induction of cytoplasmic <<petite>> mutations and double-strand breaks in yeast. This behavior is also compatible with their low mutagenic activity in E. coli WP2 and with the absence of any phototoxicity on the skin. For these features, benzopsoralens seem to be interesting potential drugs for PUVA photochemotherapy and photopheresis. The activity shown in the dark is not sufficient for their possible use as antitumor drugs, but it does offer a new model for the study of topoisomerase inhibitors.
|
In vivo inhibition of epidermal DNA synthesis in mouse after oral administration
|
Mus musculus
|
39.1
%
|
|
Journal : J. Med. Chem.
Title : 4'-Methylangelicins: new potential agents for the photochemotherapy of psoriasis.
Year : 1983
Volume : 26
Issue : 6
First Page : 870
Last Page : 876
Authors : Dall'Acqua F, Vedaldi D, Bordin F, Baccichetti F, Carlassare F, Tamaro M, Rodighiero P, Pastorini G, Guiotto A, Recchia G, Cristofolini M.
Abstract : Three derivatives of angelicin (1) [4'-methyl-, 4,4'-dimethyl-, and 4',5-dimethylangelicin (2a-c)] have been prepared with the aim of obtaining new agents for the photochemotherapy of psoriasis. These compounds form a complex in the dark with DNA that shows an affinity for the macromolecule higher than that of the parent angelicin (1). A correlation between their octanol/water partition coefficients and the association constants of the complexes has been observed. Compounds 2a-c photobind to DNA to a much higher extent than 1 and also more effectively than 8-methoxypsoralen (8-MOP), taken as reference compound. When activated with UV-A, the three compounds strongly inactivate T2 phage and inhibit epidermal DNA synthesis in mice. Moreover, they show a mutagenic activity markedly lower than that of 8-methoxypsoralen on Escherichia coli wild-type strain. Due to its lack of skin phototoxicity, its low mutagenic activity, and its antiproliferative activity, 2c was chosen for clinical evaluation. It proved to be effective in clearing psoriasis in two patients.
|
In vivo inhibition of epidermal DNA synthesis in mouse after topical application
|
Mus musculus
|
61.0
%
|
|
Journal : J. Med. Chem.
Title : 4'-Methylangelicins: new potential agents for the photochemotherapy of psoriasis.
Year : 1983
Volume : 26
Issue : 6
First Page : 870
Last Page : 876
Authors : Dall'Acqua F, Vedaldi D, Bordin F, Baccichetti F, Carlassare F, Tamaro M, Rodighiero P, Pastorini G, Guiotto A, Recchia G, Cristofolini M.
Abstract : Three derivatives of angelicin (1) [4'-methyl-, 4,4'-dimethyl-, and 4',5-dimethylangelicin (2a-c)] have been prepared with the aim of obtaining new agents for the photochemotherapy of psoriasis. These compounds form a complex in the dark with DNA that shows an affinity for the macromolecule higher than that of the parent angelicin (1). A correlation between their octanol/water partition coefficients and the association constants of the complexes has been observed. Compounds 2a-c photobind to DNA to a much higher extent than 1 and also more effectively than 8-methoxypsoralen (8-MOP), taken as reference compound. When activated with UV-A, the three compounds strongly inactivate T2 phage and inhibit epidermal DNA synthesis in mice. Moreover, they show a mutagenic activity markedly lower than that of 8-methoxypsoralen on Escherichia coli wild-type strain. Due to its lack of skin phototoxicity, its low mutagenic activity, and its antiproliferative activity, 2c was chosen for clinical evaluation. It proved to be effective in clearing psoriasis in two patients.
|
Cytotoxicity against LoVo (human intestinal adenocarcinoma) cell line at 3.2 joule/cm**2 UVA dose
|
Homo sapiens
|
700.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and photochemotherapeutic activity of thiopyrano[2,3-e]indol-2-ones.
Year : 2005
Volume : 15
Issue : 9
First Page : 2291
Last Page : 2294
Authors : Barraja P, Sciabica L, Diana P, Lauria A, Montalbano A, Almerico AM, Dattolo G, Cirrincione G, Disarò S, Basso G, Viola G, Dall'Acqua F.
Abstract : A series of derivatives of the new ring system thiopyrano[2,3-e]indol-2-one was prepared with the aim of obtaining new photochemotherapeutic drugs. Biological screenings were performed on this new class of photoactivable drugs and a strong antiproliferative effect was observed upon irradiation with UVA light. The compound bearing a methyl substituent at the pyrrole nitrogen resulted as the most interesting showing IC50 in the nanomolar range.
|
Cytotoxicity against LoVo (human intestinal adenocarcinoma) cell line at 6.5 joule/cm**2 UVA dose
|
Homo sapiens
|
400.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and photochemotherapeutic activity of thiopyrano[2,3-e]indol-2-ones.
Year : 2005
Volume : 15
Issue : 9
First Page : 2291
Last Page : 2294
Authors : Barraja P, Sciabica L, Diana P, Lauria A, Montalbano A, Almerico AM, Dattolo G, Cirrincione G, Disarò S, Basso G, Viola G, Dall'Acqua F.
Abstract : A series of derivatives of the new ring system thiopyrano[2,3-e]indol-2-one was prepared with the aim of obtaining new photochemotherapeutic drugs. Biological screenings were performed on this new class of photoactivable drugs and a strong antiproliferative effect was observed upon irradiation with UVA light. The compound bearing a methyl substituent at the pyrrole nitrogen resulted as the most interesting showing IC50 in the nanomolar range.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of 2-aminoanthracene-induced mutation at 600 ug/plate after 72 hrs in presence of Ames S-9 fraction
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
44.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of 2-aminoanthracene-induced mutation at 300 ug/plate after 72 hrs in presence of Ames S-9 fraction
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
0.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of 2-aminoanthracene-induced mutation at 150 ug/plate after 72 hrs in presence of Ames S-9 fraction
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
0.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of acetylaminofluorene-induced mutation at 600 ug/plate after 72 hrs in presence of Ames S-9 fraction
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
39.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of acetylaminofluorene-induced mutation at 300 ug/plate after 72 hrs in presence of Ames S-9 fraction
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
21.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of acetylaminofluorene-induced mutation at 150 ug/plate after 72 hrs in presence of Ames S-9 fraction
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
0.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of benzo[a]pyrene-induced mutation at 600 ug/plate after 72 hrs in presence of Ames S-9 fraction
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
86.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of benzo[a]pyrene-induced mutation at 300 ug/plate after 72 hrs in presence of Ames S-9 fraction
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
76.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of benzo[a]pyrene-induced mutation at 150 ug/plate after 72 hrs in presence of Ames S-9 fraction
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
58.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of 2-nitroflorene-induced mutation at 600 ug/plate after 72 hrs
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
25.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of 2-nitroflorene-induced mutation at 300 ug/plate after 72 hrs
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
39.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of 2-nitroflorene-induced mutation at 150 ug/plate after 72 hrs
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
5.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Inhibition of TPA-induced EBV-early antigen activation in human Raji cells
|
Human herpesvirus 4
|
490.0
molar ratio
|
|
Journal : J. Nat. Prod.
Title : Chalcones and other compounds from the exudates of Angelica keiskei and their cancer chemopreventive effects.
Year : 2006
Volume : 69
Issue : 1
First Page : 38
Last Page : 42
Authors : Akihisa T, Tokuda H, Hasegawa D, Ukiya M, Kimura Y, Enjo F, Suzuki T, Nishino H.
Abstract : Three new chalcones, xanthoangelol I (1), xanthoangelol J (2), and deoxydihydroxanthoangelol H (3), were isolated from an ethyl acetate-soluble fraction of exudates of the stems of Angelica keiskei, and their structures were established on the basis of spectroscopic methods. Nine aromatic compounds of known structure, 4-12, and a diacetylene, 13, were also isolated and identified from this same fraction. On evaluation of these compounds for their inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, 1, 2, 4, and 9-12 showed potent inhibitory effects on EBV-EA induction. In addition, upon evaluation of the inhibitory effects against activation of (+/-)-(E)-methyl-2[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexemide (NOR 1), a nitrogen oxide (NO) donor, six compounds, namely, 1, 2, 4, 9, 11, and 12, exhibited potent inhibitory effects. Further, isobavachalcone (4) exhibited inhibitory effects on skin tumor promotion in an in vivo two-stage mouse skin carcinogenesis test using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter.
|
Photocytotoxicity against human LoVo cells treated 30 mins before 3.75 J/cm'2 UVA irradiation measured after 72 hrs by MTT assay
|
Homo sapiens
|
700.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Thiopyrano[2,3-e]indol-2-ones: angelicin heteroanalogues with potent photoantiproliferative activity.
Year : 2008
Volume : 16
Issue : 22
First Page : 9668
Last Page : 9683
Authors : Barraja P, Diana P, Montalbano A, Carbone A, Cirrincione G, Viola G, Salvador A, Vedaldi D, Dall'acqua F.
Abstract : A new class of compounds, the thiopyrano[2,3-e]indol-2-ones, bioisosters of the angular furocoumarin angelicin, was synthesized with the aim of obtaining new photochemotherapeutic agents. In particular 7,8-dimethyl-thiopyranoindolone 6c s showed a remarkable phototoxicity and a great dose UVA dependence reaching IC(50) values at submicromolar level. This latter photoinduced a massive apoptosis and a remarkable photodamage to lipids and proteins. Although it did not intercalate DNA, it was able to cause photooxidation of DNA bases.
|
Photocytotoxicity against human NCTC 2544 cells treated 30 mins before 3.75 J/cm'2 UVA irradiation measured after 72 hrs by MTT assay
|
Homo sapiens
|
900.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Thiopyrano[2,3-e]indol-2-ones: angelicin heteroanalogues with potent photoantiproliferative activity.
Year : 2008
Volume : 16
Issue : 22
First Page : 9668
Last Page : 9683
Authors : Barraja P, Diana P, Montalbano A, Carbone A, Cirrincione G, Viola G, Salvador A, Vedaldi D, Dall'acqua F.
Abstract : A new class of compounds, the thiopyrano[2,3-e]indol-2-ones, bioisosters of the angular furocoumarin angelicin, was synthesized with the aim of obtaining new photochemotherapeutic agents. In particular 7,8-dimethyl-thiopyranoindolone 6c s showed a remarkable phototoxicity and a great dose UVA dependence reaching IC(50) values at submicromolar level. This latter photoinduced a massive apoptosis and a remarkable photodamage to lipids and proteins. Although it did not intercalate DNA, it was able to cause photooxidation of DNA bases.
|
Phototoxicity against human LoVo cells exposed to irradiation with 3.75 J/cm'2 UVA light prior to 72 hrs drug exposure by MTT assay
|
Homo sapiens
|
700.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyrano[2,3-e]isoindol-2-ones, new angelicin heteroanalogues.
Year : 2009
Volume : 19
Issue : 6
First Page : 1711
Last Page : 1714
Authors : Barraja P, Spanò V, Patrizia D, Carbone A, Cirrincione G, Vedaldi D, Salvador A, Viola G, Dall'acqua F.
Abstract : A convenient synthesis of the pyrano[2,3-e]isoindol-2-one ring system, an heteroanalogue of angelicin, is reported. Our synthetic approach consists of the annelation of the pyran ring on the isoindole moiety using 5-dialkylamino- or 5-hydroxymethylene intermediates as building blocks. The photoantiproliferative activity of the new derivatives was studied. Some of them bearing the benzyl group at the 8 position were active with IC(50) in the micromolar range. Cell cytotoxicity involves apoptosis, alteration of cell cycle profile and membrane photodamage.
|
Antitumor activity against human HeLa cells after 72 hrs by MTS assay
|
Homo sapiens
|
7.6
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and antitumor activity of some new xanthotoxin derivatives.
Year : 2009
Volume : 44
Issue : 7
First Page : 2967
Last Page : 2974
Authors : Abdel Hafez OM, Amin KM, Abdel-Latif NA, Mohamed TK, Ahmed EY, Maher T.
Abstract : The condensation of 4-amino-9-methoxy psoralene (4-aminoxanthotoxin) with some aromatic aldehydes led to the formation of 4-arylimine xanthotoxin derivatives 2a-h, which were cyclized with mercaptoacetic acid to afford the thiazolidinone derivatives 3a-h. On the other hand, the reaction of aminoxanthotoxin 1 with some anhydrides afforded 4-imidione derivatives 3a-d. When 1 reacted with some isothiocyanates, the thiourea derivatives 5a-c were obtained but the thiourea derivative 6 was obtained when 1 reacted with ammonium thiocyanate. The thiourea derivative 6 was cyclized by the reaction with monochloroacetic acid in the presence of sodium acetate to give aminothiazolidinone derivative 7, but when the same reaction is carried out in the presence of pyridine, the thioxoimidazolidinone 8 was formed. The condensation of xanthotoxin sulphonamide with aromatic aldehydes gave the aryliminosulphonyl derivatives 9a-e. Xanthotoxin sulphonyl hydrazine condensed with some anhydride afforded sulphonic acid imide derivatives 10a-c. The antitumor and cytotoxic activities of 9 synthesized derivatives were tested, five compounds were found to be active, they inhibited the growth of HeLa cells.
|
Mechanism based inhibition of human cytochrome P450 2A6 measured by coumarin 7-hydroxylation using a recombinant system
|
Homo sapiens
|
800.0
nM
|
|
Journal : Curr. Drug Metab.
Title : Cytochrome p450 enzymes mechanism based inhibitors: common sub-structures and reactivity.
Year : 2005
Volume : 6
Issue : 1
First Page : 413
Last Page : 454
Authors : Fontana E, Dansette PM, Poli SM.
Abstract : The inhibition of human cytochrome P450s (CYPs) is one of the most common mechanisms which can lead to drug-drug interactions. The inhibition of CYPs can be reversible (competitive or non-competitive) or irreversible. Irreversible inhibition usually derives from activation of a drug by CYPs into a reactive metabolite, which tightly binds to the enzyme active site, leading to a long lasting inactivation. This process is called "mechanism based inhibition" or "suicide inhibition". The irreversible inactivation usually implies the formation of a covalent bond between the metabolite and the enzyme, which can lead to hapten formation and can in some cases trigger an autoimmune-response. For these reasons it is of utmost importance to study the mechanism of the CYP inhibition of new potential drugs as early as possible during the drug discovery process. The literature on CYPs is vast and covers numerous aspects of their biology and biochemistry, however to our knowledge there is no general and systematic review focusing on mechanism-based inhibitors; we have reviewed the literature and compiled all the available data on chemical entities, which are known to be CYP suicide inhibitors. Each compound is reported together with its chemical structure, the CYP isoform and the parameters describing the inactivation. Literature references are reported together with their PMID (PubMed ID number) to allow a fast retrieval of the papers. This review offers a quick reference to help predict liabilities of new chemical entities without carrying out extensive in vitro work, and will hopefully help in designing safer drugs.
|
DRUGMATRIX: CYP450, 1A2 enzyme inhibition (substrate: 3-Cyano-7-ethoxycoumarin)
|
None
|
40.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Inhibition of recombinant human BACE1 using Rh-EVNLDAEFK as substrate at 500 uM after 60 mins by fluorescence quenching assay
|
Homo sapiens
|
-4.9
%
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationships for naturally occurring coumarins as β-secretase inhibitor.
Year : 2012
Volume : 20
Issue : 2
First Page : 784
Last Page : 788
Authors : Marumoto S, Miyazawa M.
Abstract : The present study was demonstrated to evaluate the effects of naturally occurring coumarins (NOCs) including simple coumarins, furanocoumarins, and pyranocoumarins on the inhibition of β-secretase (BACE1) activity. Of 41 NOCs examined, some furanocoumarins inhibited BACE1 activity, but simple coumarins and pyranocoumarins did not affect. The most potent inhibitor was 5-geranyloxy-8-methoxypsoralen (31), which has an IC(50) value of 9.9 μM. Other furanocoumarin derivatives, for example, 8-geranyloxy-5-methoxypsoralen (35), 8-geranyloxypsoralen (24), and bergamottin (18) inhibited BACE1 activity, with the IC(50) values <25.0 μM. Analyses of the inhibition mechanism by Dixon plots and Cornish-Bowden plots showed that compounds 18, 31 and 35 were mixed-type inhibitor. The kinetics of inhibition of BACE1 by coumarins 24 was non-competitive inhibitors.
|
Inhibition of electric eel AChE at 2 mg/ml by Ellman's method
|
Electrophorus electricus
|
4.4
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Inhibition of horse BChE at 2 mg/ml by Ellman's method
|
Equus caballus
|
8.34
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
38.1
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
8.9
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
-1.6
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Antioxidant activity assessed as inhibition of AAPH-induced linoleic acid lipid peroxidation at 100 uM by spectrophotometric analysis
|
None
|
5.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Syntheses and evaluation of the antioxidant activity of novel methoxypsoralen derivatives.
Year : 2013
Volume : 60
First Page : 155
Last Page : 169
Authors : Bariamis SE, Marin M, Athanassopoulos CM, Kontogiorgis C, Tsimali Z, Papaioannou D, Sindona G, Romeo G, Avgoustakis K, Hadjipavlou-Litina D.
Abstract : A series of 5- and 8-methoxypsoralen (MOP) analogs, suitable for structure-antioxidative/anti-inflammatory activity relationship studies, were synthesized using as key-reactions the selective monobromination of MOPs with N-bromosaccharin and either a Heck reaction or a Suzuki coupling or a Suzuki coupling followed by a Wittig reaction to install side-chains of the acrylate- or benzoate- or cinnamate-type, respectively. The 8-MOP analogs 19 and 24, incorporating at position 5 of the psoralen nucleus a butyl acrylate or a tert-butyl cinnamate moiety, were the most powerful inhibitors of soybean LOX and inhibited effectively lipid peroxidation. Analog 19 was a more potent anti-inflammatory agent than the reference compound indomethacin and of comparable cytocompatibility to 8-MOP whereas analog 24 was a weaker inhibitor of inflammation than indomethacin and significantly more cytotoxic than 8-MOP. The results of the biological tests are discussed in terms of structural characteristics.
|
Inhibition of acetylcholinesterase (unknown origin) using acetylcholine iodide as substrate preincubated for 15 mins prior to substrate addition by spectrophotometric analysis
|
Homo sapiens
|
760.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New bioactive dihydrofuranocoumarins from the roots of the Tunisian Ferula lutea (Poir.) Maire.
Year : 2013
Volume : 23
Issue : 14
First Page : 4248
Last Page : 4252
Authors : Ben Salem S, Jabrane A, Harzallah-Skhiri F, Ben Jannet H.
Abstract : A phytochemical investigation of the roots of Ferula lutea (Poir.) Maire led to the isolation of new dihydrofuranocoumarins as two inseparable isomers, (-)-5-hydroxyprantschimgin 1 and (-)-5-hydroxydeltoin 2, together with eight known compounds, (-)-prantschimgin 3, (-)-deltoin 4, psoralen 5, xanthotoxin 6, umbelliferone 7, caffeic acid 8, β-sitosterol 9 and stigmasterol 10. Their structures were elucidated on the basis of extensive spectroscopic methods, including 1D and 2D NMR experiments and mass spectroscopy analysis, as well as by comparison with literature data. The anti-acetylcholinesterase and cytotoxic effects of the isolates and antioxidant activities of the mixture (1+2) were also evaluated in this work. Results showed that the mixture (1+2) has the most cytotoxic activity with IC50 values 0.29±0.05 and 1.61±0.57μM against the cell lines HT-29 and HCT 116, respectively. The greatest acetylcholinesterase inhibitory activity (IC50=0.76±0.03) was exhibited by the xanthotoxin 6. In addition, the mixture (1+2) was investigated for its antioxidant activity and showed IC50 values 18.56, 13.06, 7.59, and 4.81μM towards DPPH free radical scavenging, ABTS radical monocation, singlet oxygen and hydrogen peroxide, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
102.46
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
107.28
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of PTP1B (unknown origin) at 20 ug/ml using pNPP substrate measured after 3 mins by colorimetric assay
|
Homo sapiens
|
50.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : PTP1B inhibitors from stems of Angelica keiskei (Ashitaba).
Year : 2015
Volume : 25
Issue : 10
First Page : 2028
Last Page : 2032
Authors : Li JL, Gao LX, Meng FW, Tang CL, Zhang RJ, Li JY, Luo C, Li J, Zhao WM.
Abstract : Three new chalcones, xanthoangelols K-M (1-3), together with 19 known compounds were isolated from the stems of Angelica keiskei Koidzumi, a well-known rejuvenated and anti-diabetic plant originated from Japan. The structures of compounds 1-3 were elucidated on the basis of spectroscopic data and Mosher's method. All compounds were evaluated for their inhibitory activity against protein tyrosine phosphatase 1B (PTP1B). Among them, six chalcones, xanthoangelol K (1), xanthoangelol (4), xanthoangelol F (5), 4-hydroxyderricin (6), xanthoangelol D (7), xanthoangelol E (8), and a coumarin, methoxsalen (17), showed strong PTP1B inhibitory effect with IC50 values of 0.82, 1.97, 1.67, 2.47, 3.97, 1.43, and 2.53μg/mL, respectively. A kinetic study revealed that compound 1 inhibited PTP1B with characteristics typical of a competitive inhibitor. Molecular docking simulations elucidated that ring B of 1 may anchor in a pocket of PTP1B and the molecule is stabilized by hydrogen bonds with Arg47, Asp48, and π-π interaction with Phe182 of PTP1B.
|
Mixed inhibition of CYP2A13 (unknown origin)
|
Homo sapiens
|
40.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Evaluation of inhibition selectivity for human cytochrome P450 2A enzymes.
Year : 2012
Volume : 40
Issue : 9
First Page : 1797
Last Page : 1802
Authors : Stephens ES, Walsh AA, Scott EE.
Abstract : Cytochrome P450 (P450) enzymes are mixed-function oxidases that catalyze the metabolism of xenobiotics and endogenous biochemicals. Selective inhibitors are needed to accurately distinguish the contributions of individual P450 enzymes in the metabolism of drugs and the activation of procarcinogens in human tissues, but very frequently these enzymes have substantial overlapping selectivity. We evaluated a chemically diverse set of nine previously identified CYP2A6 inhibitors to determine which are able to discriminate between human CYP2A enzymes CYP2A6 and the 94%-identical CYP2A13 enzyme. Inhibitor binding to recombinant purified enzyme was evaluated, and affinities were determined. K(i) values were determined for inhibition of p-nitrophenol 2-hydroxylation, a reaction accomplished by CYP2A13 and CYP2A6 with more similar catalytic efficiencies (k(cat)/K(m) 0.19 and 0.12 μM⁻¹ · min⁻¹, respectively) than hydroxylation of the classic substrate coumarin (0.11 and 0.53 μM⁻¹ · min⁻¹, respectively). Of the nine compounds assayed, only tranylcypromine and (R)-(+)-menthofuran had a greater than 10-fold preference for CYP2A6 inhibition versus CYP2A13 inhibition. Most compounds evaluated [tryptamine, 4-dimethylaminobenzaldehyde, phenethyl isothiocyanate, β-nicotyrine, (S)-nicotine, and pilocarpine] demonstrated only moderate or no preference for inhibition of one CYP2A enzyme over the other. However, 8-methoxypsoralen has a 6-fold lower K(i) for CYP2A13 than for CYP2A6. This information is useful to inform reinterpretation of previous data with these inhibitors and to guide future studies seeking to determine which human CYP2A enzyme is responsible for the in vivo metabolism of compounds in human tissues expressing both enzymes.
|
Mixed inhibition of CYP2A6 (unknown origin)
|
Homo sapiens
|
250.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Evaluation of inhibition selectivity for human cytochrome P450 2A enzymes.
Year : 2012
Volume : 40
Issue : 9
First Page : 1797
Last Page : 1802
Authors : Stephens ES, Walsh AA, Scott EE.
Abstract : Cytochrome P450 (P450) enzymes are mixed-function oxidases that catalyze the metabolism of xenobiotics and endogenous biochemicals. Selective inhibitors are needed to accurately distinguish the contributions of individual P450 enzymes in the metabolism of drugs and the activation of procarcinogens in human tissues, but very frequently these enzymes have substantial overlapping selectivity. We evaluated a chemically diverse set of nine previously identified CYP2A6 inhibitors to determine which are able to discriminate between human CYP2A enzymes CYP2A6 and the 94%-identical CYP2A13 enzyme. Inhibitor binding to recombinant purified enzyme was evaluated, and affinities were determined. K(i) values were determined for inhibition of p-nitrophenol 2-hydroxylation, a reaction accomplished by CYP2A13 and CYP2A6 with more similar catalytic efficiencies (k(cat)/K(m) 0.19 and 0.12 μM⁻¹ · min⁻¹, respectively) than hydroxylation of the classic substrate coumarin (0.11 and 0.53 μM⁻¹ · min⁻¹, respectively). Of the nine compounds assayed, only tranylcypromine and (R)-(+)-menthofuran had a greater than 10-fold preference for CYP2A6 inhibition versus CYP2A13 inhibition. Most compounds evaluated [tryptamine, 4-dimethylaminobenzaldehyde, phenethyl isothiocyanate, β-nicotyrine, (S)-nicotine, and pilocarpine] demonstrated only moderate or no preference for inhibition of one CYP2A enzyme over the other. However, 8-methoxypsoralen has a 6-fold lower K(i) for CYP2A13 than for CYP2A6. This information is useful to inform reinterpretation of previous data with these inhibitors and to guide future studies seeking to determine which human CYP2A enzyme is responsible for the in vivo metabolism of compounds in human tissues expressing both enzymes.
|
Anti-proliferative activity against human L02 cells after 48 hrs by MTT assay
|
Homo sapiens
|
3.3
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design and synthesis of new triazoles linked to xanthotoxin for potent and highly selective anti-gastric cancer agents.
Year : 2017
Volume : 27
Issue : 21
First Page : 4871
Last Page : 4875
Authors : Shen QK, Liu CF, Zhang HJ, Tian YS, Quan ZS.
Abstract : Two series of xanthotoxin-triazole derivatives were designed, synthesized, and studied for their antiproliferative properties. The in vitro cytotoxicity of the compounds in the AGS cancer cell line and the L02 normal cell line was evaluated via MTT assay. Among the synthesized compounds, 9-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-7H-furo[3,2-g]chromen-7-one (6p) was found to have the greatest antiproliferative activity against AGS cells (IC50=7.5μM) and showed better activity than the lead compound (xanthotoxin, IC50>100μM) and the reference drug (5-fluorouracil, IC50=29.6μM) did. The IC50 value of 6p in L02 cells was 13.3 times higher than that in the AGS cells. Therefore, the compound exhibited better therapeutic activity and specificity compared with the positive control 5-fluorouracil. Cell cycle analysis revealed that compound 6p inhibited cell growth via the induction of S/G2 phase arrest in AGS cells. Compound 6p was identified as a promising lead compound for the further development and identification of 1,2,3-triazole-based anticancer agents.
|
Inhibition of recombinant human CYP1A1 expressed in baker's yeast-derived microsomes (Sacchrosomes) at 10 uM using 7-ethoxyresorufin substrate by EROD assay relative to control
|
Homo sapiens
|
84.0
%
|
|
Journal : MedChemComm
Title : Identification of karanjin isolated from the Indian beech tree as a potent CYP1 enzyme inhibitor with cellular efficacy <i>via</i> screening of a natural product repository.
Year : 2018
Volume : 9
Issue : 2
First Page : 371
Last Page : 382
Authors : Joshi P, Sonawane VR, Williams IS, McCann GJP, Gatchie L, Sharma R, Satti N, Chaudhuri B, Bharate SB.
Abstract : CYP1A1 is thought to mediate carcinogenesis in oral, lung and epithelial cancers. In order to identify a CYP1A1 inhibitor from an edible plant, 394 natural products in the IIIM's natural product repository were screened, at 10 μM concentration, using CYP1A1-Sacchrosomes™ (<i>i.e.</i> microsomal enzyme isolated from recombinant baker's yeast). Twenty-seven natural products were identified that inhibited 40-97% of CYP1A1's 7-ethoxyresorufin-<i>O</i>-deethylase activity. The IC<sub>50</sub> values of the 'hits', belonging to different chemical scaffolds, were determined. Their selectivity was studied against a panel of 8 CYP-Sacchrosomes™. In order to assess cellular efficacy, the 'hits' were screened for their capability to inhibit CYP enzymes expressed within live recombinant human embryonic kidney (HEK293) cells from plasmids encoding specific CYP genes (1A2, 1B1, 2C9, 2C19, 2D6, 3A4). Isopimpinellin (IN-475; IC<sub>50</sub>, 20 nM) and karanjin (IN-195; IC<sub>50</sub>, 30 nM) showed the most potent inhibition of CYP1A1 in human cells. Isopimpinellin is found in celery, parsnip, fruits and in the rind and pulp of limes whereas different parts of the Indian beech tree, which contain karanjin, have been used in traditional medicine. Both isopimpinellin and karanjin negate the cellular toxicity of CYP1A1-mediated benzo[<i>a</i>]pyrene. Molecular docking and molecular dynamic simulations with CYP isoforms rationalize the observed trends in the potency and selectivity of isopimpinellin and karanjin.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
13.34
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-6.11
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
4.76
%
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
9.19
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
12.61
%
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
9.57
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
12.68
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
-3.39
%
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
5.22
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-9.6
%
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-0.09
%
|
|
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media using NBS plates, by Resazurin F(560/590)
|
Staphylococcus aureus subsp. aureus
|
3.08
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by Resazurin F(560/590)
|
Acinetobacter baumannii
|
-6.09
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by Resazurin F(560/590)
|
Escherichia coli
|
2.12
%
|
|
|
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
|
5.62
%
|
|
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.
|
Phototoxicity against mouse PAM212 cells assessed as cell growth inhibition preincubated for 30 mins followed by 1.28 J/cm2 UV light exposure and measured after 5 days by coulter counting method
|
Mus musculus
|
100.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthetically modified methoxsalen for enhanced cytotoxicity in light and dark reactions.
Year : 2019
Volume : 29
Issue : 4
First Page : 619
Last Page : 622
Authors : Guillon CD, Jan YH, Foster N, Ressner J, Heck DE, Laskin JD, Heindel ND.
Abstract : Linear furocoumarins, also known as psoralens, are clinically useful photo-activated pharmaceuticals employed to address hyperproliferative skin diseases. Seven diverse cytotoxic pharmacophores have been synthetically attached to 8-methoxypsoralen via a 5-amino functionality. The resulting unique set of compounds was evaluated for dark and light toxicity against PAM212 keratinocytes in culture.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
14.31
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
15.15
%
|
|
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
|
0.12
%
|
|
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
|
0.42
%
|
|
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
|
0.42
%
|
|
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
|
0.12
%
|
|
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.
