|
Cytotoxicity against human HT-29 cells
|
Homo sapiens
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Anti-microtubule 'plinabulin' chemical probe KPU-244-B3 labeled both alpha- and beta-tubulin.
Year : 2010
Volume : 18
Issue : 9
First Page : 3169
Last Page : 3174
Authors : Yamazaki Y, Sumikura M, Hidaka K, Yasui H, Kiso Y, Yakushiji F, Hayashi Y.
Abstract : Plinabulin (1, NPI-2358), a potent microtubule-targeting agent derived from the natural diketopiperazine 'phenylahistin' with a colchicine-like tubulin depolymerization activity, is an anticancer agent undergoing Phase II clinical trials in four countries including the United States. In order to understand the precise binding mode of plinabulin with tubulin, a new bioactive biotin-tagged photoaffinity probe 4 (KPU-244-B3) was designed and synthesized. Probe 4 showed significant binding affinity to tubulin in a binding assay, and selectively bound to tubulin in an HT-1080 cell lysate without photo-irradiation. In a tubulin photoaffinity labeling study, probe 4 labeled both alpha- and beta-tubulin subunits and these interactions were competitively inhibited by plinabulin during photo-irradiation. These results suggest that plinabulin binds in the boundary region between alpha- and beta-tubulin near the colchicine binding site, and not inside the colchicine binding cavity.
|
Cytotoxicity against human HT-29 cells after 72 hrs by XTT/PMS method
|
Homo sapiens
|
13.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Tubulin photoaffinity labeling study with a plinabulin chemical probe possessing a biotin tag at the oxazole.
Year : 2011
Volume : 19
Issue : 1
First Page : 595
Last Page : 602
Authors : Yamazaki Y, Kido Y, Hidaka K, Yasui H, Kiso Y, Yakushiji F, Hayashi Y.
Abstract : A new bioactive photoaffinity probe KPU-252-B1 (4) possessing a biotin tag on the oxazole ring of a potent plinabulin derivative KPU-244 (2) was synthesized via the Cu(I)-catalyzed Huisgen's cycloaddition reaction to understand the precise binding mode of the diketopiperazine-based anti-microtubule agent plinabulin on tubulin. Probe 4 showed significant binding affinity toward tubulin and cytotoxicity against an HT-29 cells. A photoaffinity labeling study suggested that probe 4 specifically recognizes tubulin at a binding site that binds plinabulin or colchicine, most likely near or at the colchicine binding site, which is located at the interfacial region formed by α-and β-tubulin association. The results also demonstrated that probe 4 may serve as a useful plinabulin chemical probe to investigate the molecular mechanism by which anti-microtubule diketopiperazine derivatives operate.
|
Cytotoxicity against human HT-29 cells
|
Homo sapiens
|
18.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Highlights of marine invertebrate-derived biosynthetic products: their biomedical potential and possible production by microbial associants.
Year : 2011
Volume : 19
Issue : 22
First Page : 6658
Last Page : 6674
Authors : Radjasa OK, Vaske YM, Navarro G, Vervoort HC, Tenney K, Linington RG, Crews P.
Abstract : Coral reefs are among the most productive marine ecosystems and are the source of a large group of structurally unique biosynthetic products. Annual reviews of marine natural products continue to illustrate that the most prolific source of bioactive compounds consist of coral reef invertebrates-sponges, ascidians, mollusks, and bryozoans. This account examines recent milestone developments pertaining to compounds from invertebrates designated as therapeutic leads for biomedical discovery. The focus is on the secondary metabolites, their inspirational structural scaffolds and the possible role of micro-organism associants in their biosynthesis. Also important are the increasing concerns regarding the collection of reef invertebrates for the discovery process. The case examples considered here will be useful to insure that future research to unearth bioactive invertebrate-derived compounds will be carried out in a sustainable and environmentally conscious fashion. Our account begins with some observations pertaining to the natural history of these organisms. Many still believe that a serious obstacle to the ultimate development of a marine natural product isolated from coral reef invertebrates is the problem of compound supply. Recent achievements through total synthesis can now be drawn on to forcefully cast this myth aside. The tools of semisynthesis of complex natural products or insights from SAR efforts to simplify an active pharmacophore are at hand and demand discussion. Equally exciting is the prospect that invertebrate-associated micro-organisms may represent the next frontier to accelerate the development of high priority therapeutic candidates. Currently in the United States there are two FDA approved marine-derived therapeutic drugs and two others that are often cited as being marine-inspired. This record will be examined first followed by an analysis of a dozen of our favorite examples of coral reef invertebrate natural products having therapeutic potential. The record of using complex scaffolds of marine invertebrate products as the starting point for development will be reviewed by considering eight case examples. The potential promise of developing invertebrate-derived micro-organisms as the starting point for further exploration of therapeutically relevant structures is considered. Also significant is the circumstance that there are some 14 sponge-derived compounds that are available to facilitate fundamental biological investigations.
|
Cytotoxicity against human HT-29 cells after 48 hrs using resazurin by microplate fluorometer analysis
|
Homo sapiens
|
14.9
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship study of antimicrotubule agents phenylahistin derivatives with a didehydropiperazine-2,5-dione structure.
Year : 2012
Volume : 55
Issue : 3
First Page : 1056
Last Page : 1071
Authors : Yamazaki Y, Tanaka K, Nicholson B, Deyanat-Yazdi G, Potts B, Yoshida T, Oda A, Kitagawa T, Orikasa S, Kiso Y, Yasui H, Akamatsu M, Chinen T, Usui T, Shinozaki Y, Yakushiji F, Miller BR, Neuteboom S, Palladino M, Kanoh K, Lloyd GK, Hayashi Y.
Abstract : Plinabulin (11, NPI-2358) is a potent microtubule-targeting agent derived from the natural diketopiperazine "phenylahistin" (1) with a colchicine-like tubulin depolymerization activity. Compound 11 was recently developed as VDA and is now under phase II clinical trials as an anticancer drug. To develop more potent antimicrotubule and cytotoxic derivatives based on the didehydro-DKP skeleton, we performed further modification on the tert-butyl or phenyl groups of 11, and evaluated their cytotoxic and tubulin-binding activities. In the SAR study, we developed more potent derivatives 33 with 2,5-difluorophenyl and 50 with a benzophenone in place of the phenyl group. The anti-HuVEC activity of 33 and 50 exhibited a lowest effective concentration of 2 and 1 nM for microtubule depolymerization, respectively. The values of 33 and 50 were 5 and 10 times more potent than that of CA-4, respectively. These derivatives could be a valuable second-generation derivative with both vascular disrupting and cytotoxic activities.
|
Cytotoxicity against HUVEC after 48 hrs using resazurin by microplate fluorometer analysis
|
Homo sapiens
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship study of antimicrotubule agents phenylahistin derivatives with a didehydropiperazine-2,5-dione structure.
Year : 2012
Volume : 55
Issue : 3
First Page : 1056
Last Page : 1071
Authors : Yamazaki Y, Tanaka K, Nicholson B, Deyanat-Yazdi G, Potts B, Yoshida T, Oda A, Kitagawa T, Orikasa S, Kiso Y, Yasui H, Akamatsu M, Chinen T, Usui T, Shinozaki Y, Yakushiji F, Miller BR, Neuteboom S, Palladino M, Kanoh K, Lloyd GK, Hayashi Y.
Abstract : Plinabulin (11, NPI-2358) is a potent microtubule-targeting agent derived from the natural diketopiperazine "phenylahistin" (1) with a colchicine-like tubulin depolymerization activity. Compound 11 was recently developed as VDA and is now under phase II clinical trials as an anticancer drug. To develop more potent antimicrotubule and cytotoxic derivatives based on the didehydro-DKP skeleton, we performed further modification on the tert-butyl or phenyl groups of 11, and evaluated their cytotoxic and tubulin-binding activities. In the SAR study, we developed more potent derivatives 33 with 2,5-difluorophenyl and 50 with a benzophenone in place of the phenyl group. The anti-HuVEC activity of 33 and 50 exhibited a lowest effective concentration of 2 and 1 nM for microtubule depolymerization, respectively. The values of 33 and 50 were 5 and 10 times more potent than that of CA-4, respectively. These derivatives could be a valuable second-generation derivative with both vascular disrupting and cytotoxic activities.
|
Cytotoxicity against human HT-29 cells after 48 hrs by resazurin assay
|
Homo sapiens
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and structure-activity relationships of benzophenone-bearing diketopiperazine-type anti-microtubule agents.
Year : 2012
Volume : 20
Issue : 14
First Page : 4279
Last Page : 4289
Authors : Yamazaki Y, Sumikura M, Masuda Y, Hayashi Y, Yasui H, Kiso Y, Chinen T, Usui T, Yakushiji F, Potts B, Neuteboom S, Palladino M, Lloyd GK, Hayashi Y.
Abstract : KPU-105 (4), a potent anti-microtubule agent that contains a benzophenone was derived from the diketopiperazine-type vascular disrupting agent (VDA) plinabulin 3, which displays colchicine-like tubulin depolymerization activity. To develop derivatives with more potent anti-microtubule and cytotoxic activities, we further modified the benzophenone moiety of 4. Accordingly, we obtained a 4-fluorobenzophenone derivative 16j that inhibited tumor cell growth in vitro with a subnanomolar IC(50) value against HT-29 cells (IC(50)=0.5 nM). Next, the effect of 16j on mitotic spindles was evaluated in HeLa cells. Treatment with 3nM of 16j partially disrupted the interphase microtubule network. By contrast, treatment with the same concentration of CA-4 barely affected the microtubule network, indicating that 16j exhibited more potent anti-mitotic effects than did CA-4.
|
Cytotoxicity against human NCI-H1975 cells assessed as reduction in cell viability after 72 hrs by CCK8 assay
|
Homo sapiens
|
11.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design and synthesis of novel soluble 2,5-diketopiperazine derivatives as potential anticancer agents.
Year : 2014
Volume : 83
First Page : 236
Last Page : 244
Authors : Liao S, Qin X, Li D, Tu Z, Li J, Zhou X, Wang J, Yang B, Lin X, Liu J, Yang X, Liu Y.
Abstract : Non-protected 2,5-diketopiperazine derivatives have poor solubility thus with negative impact on their bioavailability. In the present study, twenty-one novel soluble mono-protected, and three non-protected 2,5-diketopiperazine derivatives were designed and synthesized. Their anticancer activity to ten cell lines were evaluated by using CCK8 assay, and the results showed that about half of the mono-protected derivatives had broad-spectrum anticancer activity. Among allyl-protected derivatives, compound 4m had strong activity to all the cell lines (IC50 = 0.5-4.5 μM), especially to the cancer cell lines U937 (IC50 = 0.5 μM) and K562 (IC50 = 0.9 μM). Compound 4m could become a lead compound for further development for anticancer agents.
|
Cytotoxicity against human BGC823 cells assessed as reduction in cell viability after 72 hrs by CCK8 assay
|
Homo sapiens
|
9.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design and synthesis of novel soluble 2,5-diketopiperazine derivatives as potential anticancer agents.
Year : 2014
Volume : 83
First Page : 236
Last Page : 244
Authors : Liao S, Qin X, Li D, Tu Z, Li J, Zhou X, Wang J, Yang B, Lin X, Liu J, Yang X, Liu Y.
Abstract : Non-protected 2,5-diketopiperazine derivatives have poor solubility thus with negative impact on their bioavailability. In the present study, twenty-one novel soluble mono-protected, and three non-protected 2,5-diketopiperazine derivatives were designed and synthesized. Their anticancer activity to ten cell lines were evaluated by using CCK8 assay, and the results showed that about half of the mono-protected derivatives had broad-spectrum anticancer activity. Among allyl-protected derivatives, compound 4m had strong activity to all the cell lines (IC50 = 0.5-4.5 μM), especially to the cancer cell lines U937 (IC50 = 0.5 μM) and K562 (IC50 = 0.9 μM). Compound 4m could become a lead compound for further development for anticancer agents.
|
Cytotoxicity against human HeLa cells assessed as reduction in cell viability after 72 hrs by CCK8 assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design and synthesis of novel soluble 2,5-diketopiperazine derivatives as potential anticancer agents.
Year : 2014
Volume : 83
First Page : 236
Last Page : 244
Authors : Liao S, Qin X, Li D, Tu Z, Li J, Zhou X, Wang J, Yang B, Lin X, Liu J, Yang X, Liu Y.
Abstract : Non-protected 2,5-diketopiperazine derivatives have poor solubility thus with negative impact on their bioavailability. In the present study, twenty-one novel soluble mono-protected, and three non-protected 2,5-diketopiperazine derivatives were designed and synthesized. Their anticancer activity to ten cell lines were evaluated by using CCK8 assay, and the results showed that about half of the mono-protected derivatives had broad-spectrum anticancer activity. Among allyl-protected derivatives, compound 4m had strong activity to all the cell lines (IC50 = 0.5-4.5 μM), especially to the cancer cell lines U937 (IC50 = 0.5 μM) and K562 (IC50 = 0.9 μM). Compound 4m could become a lead compound for further development for anticancer agents.
|
Cytotoxicity against human HuH7 cells assessed as reduction in cell viability after 72 hrs by CCK8 assay
|
Homo sapiens
|
31.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design and synthesis of novel soluble 2,5-diketopiperazine derivatives as potential anticancer agents.
Year : 2014
Volume : 83
First Page : 236
Last Page : 244
Authors : Liao S, Qin X, Li D, Tu Z, Li J, Zhou X, Wang J, Yang B, Lin X, Liu J, Yang X, Liu Y.
Abstract : Non-protected 2,5-diketopiperazine derivatives have poor solubility thus with negative impact on their bioavailability. In the present study, twenty-one novel soluble mono-protected, and three non-protected 2,5-diketopiperazine derivatives were designed and synthesized. Their anticancer activity to ten cell lines were evaluated by using CCK8 assay, and the results showed that about half of the mono-protected derivatives had broad-spectrum anticancer activity. Among allyl-protected derivatives, compound 4m had strong activity to all the cell lines (IC50 = 0.5-4.5 μM), especially to the cancer cell lines U937 (IC50 = 0.5 μM) and K562 (IC50 = 0.9 μM). Compound 4m could become a lead compound for further development for anticancer agents.
|
Cytotoxicity against human MCF7 cells assessed as reduction in cell viability after 72 hrs by CCK8 assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design and synthesis of novel soluble 2,5-diketopiperazine derivatives as potential anticancer agents.
Year : 2014
Volume : 83
First Page : 236
Last Page : 244
Authors : Liao S, Qin X, Li D, Tu Z, Li J, Zhou X, Wang J, Yang B, Lin X, Liu J, Yang X, Liu Y.
Abstract : Non-protected 2,5-diketopiperazine derivatives have poor solubility thus with negative impact on their bioavailability. In the present study, twenty-one novel soluble mono-protected, and three non-protected 2,5-diketopiperazine derivatives were designed and synthesized. Their anticancer activity to ten cell lines were evaluated by using CCK8 assay, and the results showed that about half of the mono-protected derivatives had broad-spectrum anticancer activity. Among allyl-protected derivatives, compound 4m had strong activity to all the cell lines (IC50 = 0.5-4.5 μM), especially to the cancer cell lines U937 (IC50 = 0.5 μM) and K562 (IC50 = 0.9 μM). Compound 4m could become a lead compound for further development for anticancer agents.
|
Cytotoxicity against human A549 cells assessed as reduction in cell viability after 72 hrs by CCK8 assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design and synthesis of novel soluble 2,5-diketopiperazine derivatives as potential anticancer agents.
Year : 2014
Volume : 83
First Page : 236
Last Page : 244
Authors : Liao S, Qin X, Li D, Tu Z, Li J, Zhou X, Wang J, Yang B, Lin X, Liu J, Yang X, Liu Y.
Abstract : Non-protected 2,5-diketopiperazine derivatives have poor solubility thus with negative impact on their bioavailability. In the present study, twenty-one novel soluble mono-protected, and three non-protected 2,5-diketopiperazine derivatives were designed and synthesized. Their anticancer activity to ten cell lines were evaluated by using CCK8 assay, and the results showed that about half of the mono-protected derivatives had broad-spectrum anticancer activity. Among allyl-protected derivatives, compound 4m had strong activity to all the cell lines (IC50 = 0.5-4.5 μM), especially to the cancer cell lines U937 (IC50 = 0.5 μM) and K562 (IC50 = 0.9 μM). Compound 4m could become a lead compound for further development for anticancer agents.
|
Cytotoxicity against human HL60 cells assessed as reduction in cell viability after 72 hrs by CCK8 assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design and synthesis of novel soluble 2,5-diketopiperazine derivatives as potential anticancer agents.
Year : 2014
Volume : 83
First Page : 236
Last Page : 244
Authors : Liao S, Qin X, Li D, Tu Z, Li J, Zhou X, Wang J, Yang B, Lin X, Liu J, Yang X, Liu Y.
Abstract : Non-protected 2,5-diketopiperazine derivatives have poor solubility thus with negative impact on their bioavailability. In the present study, twenty-one novel soluble mono-protected, and three non-protected 2,5-diketopiperazine derivatives were designed and synthesized. Their anticancer activity to ten cell lines were evaluated by using CCK8 assay, and the results showed that about half of the mono-protected derivatives had broad-spectrum anticancer activity. Among allyl-protected derivatives, compound 4m had strong activity to all the cell lines (IC50 = 0.5-4.5 μM), especially to the cancer cell lines U937 (IC50 = 0.5 μM) and K562 (IC50 = 0.9 μM). Compound 4m could become a lead compound for further development for anticancer agents.
|
Cytotoxicity against human K562 cells assessed as reduction in cell viability after 72 hrs by CCK8 assay
|
Homo sapiens
|
8.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design and synthesis of novel soluble 2,5-diketopiperazine derivatives as potential anticancer agents.
Year : 2014
Volume : 83
First Page : 236
Last Page : 244
Authors : Liao S, Qin X, Li D, Tu Z, Li J, Zhou X, Wang J, Yang B, Lin X, Liu J, Yang X, Liu Y.
Abstract : Non-protected 2,5-diketopiperazine derivatives have poor solubility thus with negative impact on their bioavailability. In the present study, twenty-one novel soluble mono-protected, and three non-protected 2,5-diketopiperazine derivatives were designed and synthesized. Their anticancer activity to ten cell lines were evaluated by using CCK8 assay, and the results showed that about half of the mono-protected derivatives had broad-spectrum anticancer activity. Among allyl-protected derivatives, compound 4m had strong activity to all the cell lines (IC50 = 0.5-4.5 μM), especially to the cancer cell lines U937 (IC50 = 0.5 μM) and K562 (IC50 = 0.9 μM). Compound 4m could become a lead compound for further development for anticancer agents.
|
Cytotoxicity against human U937 cells assessed as reduction in cell viability after 72 hrs by CCK8 assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design and synthesis of novel soluble 2,5-diketopiperazine derivatives as potential anticancer agents.
Year : 2014
Volume : 83
First Page : 236
Last Page : 244
Authors : Liao S, Qin X, Li D, Tu Z, Li J, Zhou X, Wang J, Yang B, Lin X, Liu J, Yang X, Liu Y.
Abstract : Non-protected 2,5-diketopiperazine derivatives have poor solubility thus with negative impact on their bioavailability. In the present study, twenty-one novel soluble mono-protected, and three non-protected 2,5-diketopiperazine derivatives were designed and synthesized. Their anticancer activity to ten cell lines were evaluated by using CCK8 assay, and the results showed that about half of the mono-protected derivatives had broad-spectrum anticancer activity. Among allyl-protected derivatives, compound 4m had strong activity to all the cell lines (IC50 = 0.5-4.5 μM), especially to the cancer cell lines U937 (IC50 = 0.5 μM) and K562 (IC50 = 0.9 μM). Compound 4m could become a lead compound for further development for anticancer agents.
|
Cytotoxicity against human HeLa cells after 48 hrs by WST8 assay
|
Homo sapiens
|
20.6
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Development of a new benzophenone-diketopiperazine-type potent antimicrotubule agent possessing a 2-pyridine structure.
Year : 2014
Volume : 5
Issue : 10
First Page : 1094
Last Page : 1098
Authors : Hayashi Y, Takeno H, Chinen T, Muguruma K, Okuyama K, Taguchi A, Takayama K, Yakushiji F, Miura M, Usui T, Hayashi Y.
Abstract : A new benzophenone-diketopiperazine-type potent antimicrotubule agent was developed by modifying the structure of the clinical candidate plinabulin (1). Although the right-hand imidazole ring with a branched alkyl chain at the 5-position in 1 was critical for the potency of the antimicrotubule activity, we successfully substituted this moiety with a simpler 2-pyridyl structure by converting the left-hand ring from a phenyl to a benzophenone structure without decreasing the potency. The resultant compound 6b (KPU-300) exhibited a potent cytotoxicity, with an IC50 value of 7.0 nM against HT-29 cells, by strongly binding to tubulin (K d = 1.3 μM) and inducing microtubule depolymerization.
|
Cytotoxicity against human A549 cells after 48 hrs by WST8 assay
|
Homo sapiens
|
35.7
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Development of a new benzophenone-diketopiperazine-type potent antimicrotubule agent possessing a 2-pyridine structure.
Year : 2014
Volume : 5
Issue : 10
First Page : 1094
Last Page : 1098
Authors : Hayashi Y, Takeno H, Chinen T, Muguruma K, Okuyama K, Taguchi A, Takayama K, Yakushiji F, Miura M, Usui T, Hayashi Y.
Abstract : A new benzophenone-diketopiperazine-type potent antimicrotubule agent was developed by modifying the structure of the clinical candidate plinabulin (1). Although the right-hand imidazole ring with a branched alkyl chain at the 5-position in 1 was critical for the potency of the antimicrotubule activity, we successfully substituted this moiety with a simpler 2-pyridyl structure by converting the left-hand ring from a phenyl to a benzophenone structure without decreasing the potency. The resultant compound 6b (KPU-300) exhibited a potent cytotoxicity, with an IC50 value of 7.0 nM against HT-29 cells, by strongly binding to tubulin (K d = 1.3 μM) and inducing microtubule depolymerization.
|
Cytotoxicity against human HT-29 cells assessed as reduction in cell viability measured after 48 hrs by resazurin dye-based fluorometric analysis
|
Homo sapiens
|
9.8
nM
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Cytotoxicity against human PC3 cells assessed as reduction in cell viability measured after 48 hrs by resazurin dye-based fluorometric analysis
|
Homo sapiens
|
1.0
nM
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Cytotoxicity against mouse P388 cells assessed as reduction in cell viability measured after 48 hrs by resazurin dye-based fluorometric analysis
|
Mus musculus
|
31.8
nM
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Cytotoxicity against human HT-29 cells assessed as reduction in cell viability measured after 48 hrs by resazurin dye-based fluorometric analysis relative to control
|
Homo sapiens
|
82.5
%
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Cytotoxicity against human MDA-MB-231 cells assessed as reduction in cell viability measured after 48 hrs by resazurin dye-based fluorometric analysis
|
Homo sapiens
|
13.8
nM
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Cytotoxicity against human MDA-MB-231 cells assessed as reduction in cell viability measured after 48 hrs by resazurin dye-based fluorometric analysis relative to control
|
Homo sapiens
|
56.7
%
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Cytotoxicity against human NCI-H292 cells assessed as reduction in cell viability measured after 48 hrs by resazurin dye-based fluorometric analysis
|
Homo sapiens
|
17.5
nM
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Cytotoxicity against human NCI-H292 cells assessed as reduction in cell viability measured after 48 hrs by resazurin dye-based fluorometric analysis relative to control
|
Homo sapiens
|
65.0
%
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Cytotoxicity against human OVCAR3 cells assessed as reduction in cell viability measured after 48 hrs by resazurin dye-based fluorometric analysis relative to control
|
Homo sapiens
|
45.8
%
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Cytotoxicity against mouse B16F10 cells assessed as reduction in cell viability measured after 48 hrs by resazurin dye-based fluorometric analysis
|
Mus musculus
|
37.1
nM
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Cytotoxicity against mouse B16F10 cells assessed as reduction in cell viability measured after 48 hrs by resazurin dye-based fluorometric analysis relative to control
|
Mus musculus
|
71.8
%
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Cytotoxicity against human CCD-27Sk cells assessed as reduction in cell viability measured after 48 hrs by resazurin dye-based fluorometric analysis
|
Homo sapiens
|
9.2
nM
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Cytotoxicity against human CCD-27Sk cells assessed as reduction in cell viability measured after 48 hrs by resazurin dye-based fluorometric analysis relative to control
|
Homo sapiens
|
64.3
%
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Antiproliferative activity against taxol-sensitive human MES-SA cells expressing MDR1 mRNA and P-gp
|
Homo sapiens
|
8.5
nM
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Antiproliferative activity against taxol-sensitive human MES-SA cells pretreated with p-gp inhibitor cyclosporinA followed by compound addition
|
Homo sapiens
|
31.0
nM
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Antiproliferative activity against taxol-resistant human MES-SA/Dx5 cells expressing MDR1 mRNA and P-gp
|
Homo sapiens
|
10.5
nM
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Antiproliferative activity against taxol-resistant human MES-SA/Dx5 cells expressing MDR1 mRNA and P-gp pretreated with p-gp inhibitor cyclosporinA followed by compound addition
|
Homo sapiens
|
37.8
nM
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Antiproliferative activity against human mitoxantrone-sensitive HL60 cells
|
Homo sapiens
|
6.4
nM
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Antiproliferative activity against human mitoxantrone-resistant HL60/MX2 cells
|
Homo sapiens
|
8.17
nM
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Antiproliferative activity against human taxol-sensitive MCF7 cells
|
Homo sapiens
|
39.6
nM
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Cytotoxicity against human Jurkat cells
|
Homo sapiens
|
11.0
nM
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Inhibition of human CDK1/human cyclinB at 10 uM in presence of ATP
|
Homo sapiens
|
50.0
%
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Inhibition of human c-RAF at 10 uM in presence of ATP
|
Homo sapiens
|
50.0
%
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Inhibition of rat JNK3 at 10 uM in presence of ATP
|
Rattus norvegicus
|
50.0
%
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Inhibition of mouse Lyn at 10 uM in presence of ATP
|
Mus musculus
|
50.0
%
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Inhibition of bovine brain microtubule polymerization assessed as decrease in microtubule length at 1.25 uM by TEM analysis relative to control
|
Bos taurus
|
70.0
%
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Antimitotic activity in human MCF7 cells assessed as mitotic index measured after 20 hrs by DAPI-staining based fluorescence microscopic analysis
|
Homo sapiens
|
17.4
nM
|
|
Title : Analogs of dehydrophenylahistins and their therapeutic use
Year : 2007
|
Cytotoxicity against human NCI-H460 cells assessed as decrease in cell viability after 72 hrs by MTT assay
|
Homo sapiens
|
33.9
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Development of MBRI-001, a deuterium-substituted plinabulin derivative as a potent anti-cancer agent.
Year : 2017
Volume : 27
Issue : 6
First Page : 1416
Last Page : 1419
Authors : Ding Z, Cheng H, Wang S, Hou Y, Zhao J, Guan H, Li W.
Abstract : Plinabulin, a drug targeting microtubule of cancer cells, has been currently tried in its phase III clinical study. However, low efficacy caused by poor pharmacokinetic (PK) properties has been considered to be the main obstacle to approved by the Food and Drug Administration. Herein, we introduced a deuterium atom as an isostere in its structure to become a new compound named (MBRI-001, No. 9 in a series of deuterium-substituted compounds). The structure of MBRI-001 was characterized by HRMS, NMR, IR and a single crystal analysis. MBRI-001 exhibited better pharmacokinetic characteristics than that of plinabulin. Additionally, its antitumor activity is in a low nanomolar level for a variety of cancer cell lines and high activity against human NCI-H460 xenograted in mice intravenous administration. Importantly, continuous administration of MBRI-001 exhibited lower toxicity compared to docetaxel. We thus suggest that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
Cytotoxicity against human NCI-H446 cells assessed as decrease in cell viability after 72 hrs by MTT assay
|
Homo sapiens
|
44.2
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Development of MBRI-001, a deuterium-substituted plinabulin derivative as a potent anti-cancer agent.
Year : 2017
Volume : 27
Issue : 6
First Page : 1416
Last Page : 1419
Authors : Ding Z, Cheng H, Wang S, Hou Y, Zhao J, Guan H, Li W.
Abstract : Plinabulin, a drug targeting microtubule of cancer cells, has been currently tried in its phase III clinical study. However, low efficacy caused by poor pharmacokinetic (PK) properties has been considered to be the main obstacle to approved by the Food and Drug Administration. Herein, we introduced a deuterium atom as an isostere in its structure to become a new compound named (MBRI-001, No. 9 in a series of deuterium-substituted compounds). The structure of MBRI-001 was characterized by HRMS, NMR, IR and a single crystal analysis. MBRI-001 exhibited better pharmacokinetic characteristics than that of plinabulin. Additionally, its antitumor activity is in a low nanomolar level for a variety of cancer cell lines and high activity against human NCI-H460 xenograted in mice intravenous administration. Importantly, continuous administration of MBRI-001 exhibited lower toxicity compared to docetaxel. We thus suggest that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
Cytotoxicity against human Jurkat cells assessed as decrease in cell viability after 72 hrs by MTT assay
|
Homo sapiens
|
3.3
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Development of MBRI-001, a deuterium-substituted plinabulin derivative as a potent anti-cancer agent.
Year : 2017
Volume : 27
Issue : 6
First Page : 1416
Last Page : 1419
Authors : Ding Z, Cheng H, Wang S, Hou Y, Zhao J, Guan H, Li W.
Abstract : Plinabulin, a drug targeting microtubule of cancer cells, has been currently tried in its phase III clinical study. However, low efficacy caused by poor pharmacokinetic (PK) properties has been considered to be the main obstacle to approved by the Food and Drug Administration. Herein, we introduced a deuterium atom as an isostere in its structure to become a new compound named (MBRI-001, No. 9 in a series of deuterium-substituted compounds). The structure of MBRI-001 was characterized by HRMS, NMR, IR and a single crystal analysis. MBRI-001 exhibited better pharmacokinetic characteristics than that of plinabulin. Additionally, its antitumor activity is in a low nanomolar level for a variety of cancer cell lines and high activity against human NCI-H460 xenograted in mice intravenous administration. Importantly, continuous administration of MBRI-001 exhibited lower toxicity compared to docetaxel. We thus suggest that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
Antiproliferative activity against human BxPC3 cells after 72 hrs by sulforhodamine B assay
|
Homo sapiens
|
4.28
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of anti-pancreatic cancer activity of plinabulin derivatives based on the co-crystal structure.
Year : 2018
Volume : 26
Issue : 8
First Page : 2061
Last Page : 2072
Authors : Fu Z, Hou Y, Ji C, Ma M, Tian Z, Deng M, Zhong L, Chu Y, Li W.
Abstract : Based on the co-crystal structures of tubulin with plinabulin and Compound 1 (a derivative of plinabulin), a total of 18 novel plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human pancreatic cancer BxPC-3 cell lines. Two novel Compounds 13d and 13e exhibited potent activities with IC50 at 1.56 and 1.72 nM, respectively. The tubulin polymerization assay indicated that these derivatives could inhibit microtubule polymerization. Furthermore, the interaction between tubulin and these compounds were elucidated by molecular docking. The binding modes of Compounds 13d and 13e were similar to the co-crystal structure of Compound 1. H-π interaction was observed between the aromatic hydrogen of thiophene moiety with Phe20, which could enhance their binding affinities.
|
Inhibition of tubulin polymerization (unknown origin) at 5 uM after 1 min in presence of GTP by fluorescence-based assay relative to control
|
Homo sapiens
|
18.34
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of anti-pancreatic cancer activity of plinabulin derivatives based on the co-crystal structure.
Year : 2018
Volume : 26
Issue : 8
First Page : 2061
Last Page : 2072
Authors : Fu Z, Hou Y, Ji C, Ma M, Tian Z, Deng M, Zhong L, Chu Y, Li W.
Abstract : Based on the co-crystal structures of tubulin with plinabulin and Compound 1 (a derivative of plinabulin), a total of 18 novel plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human pancreatic cancer BxPC-3 cell lines. Two novel Compounds 13d and 13e exhibited potent activities with IC50 at 1.56 and 1.72 nM, respectively. The tubulin polymerization assay indicated that these derivatives could inhibit microtubule polymerization. Furthermore, the interaction between tubulin and these compounds were elucidated by molecular docking. The binding modes of Compounds 13d and 13e were similar to the co-crystal structure of Compound 1. H-π interaction was observed between the aromatic hydrogen of thiophene moiety with Phe20, which could enhance their binding affinities.
|
Inhibition of CYP2C9 in human liver microsomes preincubated for 10 mins followed by NADPH addition measured after 10 mins by LC-MS/MS analysis
|
Homo sapiens
|
530.0
nM
|
|
Journal : Bioorg Med Chem
Title : In vitro and in vivo pharmacokinetic and pharmacodynamic study of MBRI-001, a deuterium-substituted plinabulin derivative as a potent anti-cancer agent.
Year : 2018
Volume : 26
Issue : 16
First Page : 4687
Last Page : 4692
Authors : Ma M, Zhao J, Cheng H, Deng M, Ding Z, Hou Y, Li F, Dou G, Li W.
Abstract : MBRI-001 was demonstrated preliminary better pharmacokinetics and antitumor effects than that of plinabulin in vivo. In this approach, we further carried out systematic pharmacokinetic and pharmacodynamic study of MBRI-001 in vitro and in vivo. MBRI-001 was tested stable in rat plasma and more stable in liver microsomes than plinabulin in vitro. In vivo, MBRI-001 could be distributed rapidly and widely in various tissues, especially the concentration of MBRI-001 in lung was remarkably higher than other tissues. Excretion study indicated that MBRI-001 might been decomposed and excreted as metabolites. Additionally, the combination treatment of MBRI-001 and gefitinib revealed better antitumor inhibition rate than monotherapy in vivo. Therefore, we suggest that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
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
|
21.75
%
|
|
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.
|
Inhibition of tubulin (unknown origin) polymerization at 5 uM
|
Homo sapiens
|
27.85
%
|
|
Journal : Bioorg Med Chem
Title : Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.
Year : 2019
Volume : 27
Issue : 9
First Page : 1836
Last Page : 1844
Authors : Ma M, Ding Z, Wang S, Ma L, Wang Y, Zhong L, Li Z, Yang J, Li W.
Abstract : MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
Cytotoxicity in human A549 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay
|
Homo sapiens
|
3.5
nM
|
|
Journal : Bioorg Med Chem
Title : Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.
Year : 2019
Volume : 27
Issue : 9
First Page : 1836
Last Page : 1844
Authors : Ma M, Ding Z, Wang S, Ma L, Wang Y, Zhong L, Li Z, Yang J, Li W.
Abstract : MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
Cytotoxicity in human NCI-H1975 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay
|
Homo sapiens
|
10.2
nM
|
|
Journal : Bioorg Med Chem
Title : Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.
Year : 2019
Volume : 27
Issue : 9
First Page : 1836
Last Page : 1844
Authors : Ma M, Ding Z, Wang S, Ma L, Wang Y, Zhong L, Li Z, Yang J, Li W.
Abstract : MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
Antiproliferative activity in human A549 cells assessed as inhibition of cell proliferation at 1.5625 nM incubated for 72 hrs by MTT assay
|
Homo sapiens
|
23.29
%
|
|
Journal : Bioorg Med Chem
Title : Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.
Year : 2019
Volume : 27
Issue : 9
First Page : 1836
Last Page : 1844
Authors : Ma M, Ding Z, Wang S, Ma L, Wang Y, Zhong L, Li Z, Yang J, Li W.
Abstract : MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
Antiproliferative activity in human A549 cells assessed as inhibition of cell proliferation at 3.125 nM incubated for 72 hrs by MTT assay
|
Homo sapiens
|
42.53
%
|
|
Journal : Bioorg Med Chem
Title : Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.
Year : 2019
Volume : 27
Issue : 9
First Page : 1836
Last Page : 1844
Authors : Ma M, Ding Z, Wang S, Ma L, Wang Y, Zhong L, Li Z, Yang J, Li W.
Abstract : MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
Antiproliferative activity in human A549 cells assessed as inhibition of cell proliferation at 6.25 nM incubated for 72 hrs by MTT assay
|
Homo sapiens
|
87.95
%
|
|
Journal : Bioorg Med Chem
Title : Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.
Year : 2019
Volume : 27
Issue : 9
First Page : 1836
Last Page : 1844
Authors : Ma M, Ding Z, Wang S, Ma L, Wang Y, Zhong L, Li Z, Yang J, Li W.
Abstract : MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
Antiproliferative activity in human A549 cells assessed as inhibition of cell proliferation at 12.5 nM incubated for 72 hrs by MTT assay
|
Homo sapiens
|
85.07
%
|
|
Journal : Bioorg Med Chem
Title : Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.
Year : 2019
Volume : 27
Issue : 9
First Page : 1836
Last Page : 1844
Authors : Ma M, Ding Z, Wang S, Ma L, Wang Y, Zhong L, Li Z, Yang J, Li W.
Abstract : MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
Antiproliferative activity in human A549 cells assessed as inhibition of cell proliferation at 25 nM incubated for 72 hrs by MTT assay
|
Homo sapiens
|
88.39
%
|
|
Journal : Bioorg Med Chem
Title : Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.
Year : 2019
Volume : 27
Issue : 9
First Page : 1836
Last Page : 1844
Authors : Ma M, Ding Z, Wang S, Ma L, Wang Y, Zhong L, Li Z, Yang J, Li W.
Abstract : MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
Antiproliferative activity in human A549 cells assessed as inhibition of cell proliferation at 50 nM incubated for 72 hrs by MTT assay
|
Homo sapiens
|
86.61
%
|
|
Journal : Bioorg Med Chem
Title : Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.
Year : 2019
Volume : 27
Issue : 9
First Page : 1836
Last Page : 1844
Authors : Ma M, Ding Z, Wang S, Ma L, Wang Y, Zhong L, Li Z, Yang J, Li W.
Abstract : MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
Antiproliferative activity in human NCI-H1975 cells assessed as inhibition of cell proliferation at 1.5625 nM incubated for 72 hrs by MTT assay
|
Homo sapiens
|
1.03
%
|
|
Journal : Bioorg Med Chem
Title : Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.
Year : 2019
Volume : 27
Issue : 9
First Page : 1836
Last Page : 1844
Authors : Ma M, Ding Z, Wang S, Ma L, Wang Y, Zhong L, Li Z, Yang J, Li W.
Abstract : MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
Antiproliferative activity in human NCI-H1975 cells assessed as inhibition of cell proliferation at 3.125 nM incubated for 72 hrs by MTT assay
|
Homo sapiens
|
3.89
%
|
|
Journal : Bioorg Med Chem
Title : Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.
Year : 2019
Volume : 27
Issue : 9
First Page : 1836
Last Page : 1844
Authors : Ma M, Ding Z, Wang S, Ma L, Wang Y, Zhong L, Li Z, Yang J, Li W.
Abstract : MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
Antiproliferative activity in human NCI-H1975 cells assessed as inhibition of cell proliferation at 6.25 nM incubated for 72 hrs by MTT assay
|
Homo sapiens
|
13.27
%
|
|
Journal : Bioorg Med Chem
Title : Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.
Year : 2019
Volume : 27
Issue : 9
First Page : 1836
Last Page : 1844
Authors : Ma M, Ding Z, Wang S, Ma L, Wang Y, Zhong L, Li Z, Yang J, Li W.
Abstract : MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
Antiproliferative activity in human NCI-H1975 cells assessed as inhibition of cell proliferation at 12.5 nM incubated for 72 hrs by MTT assay
|
Homo sapiens
|
61.08
%
|
|
Journal : Bioorg Med Chem
Title : Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.
Year : 2019
Volume : 27
Issue : 9
First Page : 1836
Last Page : 1844
Authors : Ma M, Ding Z, Wang S, Ma L, Wang Y, Zhong L, Li Z, Yang J, Li W.
Abstract : MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
Antiproliferative activity in human NCI-H1975 cells assessed as inhibition of cell proliferation at 25 nM incubated for 72 hrs by MTT assay
|
Homo sapiens
|
86.28
%
|
|
Journal : Bioorg Med Chem
Title : Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.
Year : 2019
Volume : 27
Issue : 9
First Page : 1836
Last Page : 1844
Authors : Ma M, Ding Z, Wang S, Ma L, Wang Y, Zhong L, Li Z, Yang J, Li W.
Abstract : MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
Antiproliferative activity in human NCI-H1975 cells assessed as inhibition of cell proliferation at 50 nM incubated for 72 hrs by MTT assay
|
Homo sapiens
|
88.69
%
|
|
Journal : Bioorg Med Chem
Title : Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.
Year : 2019
Volume : 27
Issue : 9
First Page : 1836
Last Page : 1844
Authors : Ma M, Ding Z, Wang S, Ma L, Wang Y, Zhong L, Li Z, Yang J, Li W.
Abstract : MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
21.87
%
|
|
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
|
-0.16
%
|
|
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
|
-0.16
%
|
|
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.
|
Antiproliferative activity against human NCI-H460 cells assessed as reduction in cell viability after 72 hrs by SRB assay
|
Homo sapiens
|
26.2
nM
|
|
Journal : Bioorg Med Chem
Title : Development of novel phenoxy-diketopiperazine-type plinabulin derivatives as potent antimicrotubule agents based on the co-crystal structure.
Year : 2020
Volume : 28
Issue : 1
First Page : 115186
Last Page : 115186
Authors : Ding Z, Ma M, Zhong C, Wang S, Fu Z, Hou Y, Liu Y, Zhong L, Chu Y, Li F, Song C, Wang Y, Yang J, Li W.
Abstract : The co-crystal structure of Compound 6b with tubulin was prepared and solved for indicating the binding mode and for further optimization. Based on the co-crystal structures of tubulin with plinabulin and Compound 6b, a total of 27 novel A/B/C-rings plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human lung cancer NCI-H460 cell line. The optimum phenoxy-diketopiperazine-type Compound 6o exhibited high potent cytotoxicity (IC<sub>50</sub> = 4.0 nM) through SAR study of three series of derivatives, which was more potent than plinabulin (IC<sub>50</sub> = 26.2 nM) and similar to Compound 6b (IC<sub>50</sub> = 3.8 nM) against human lung cancer NCI-H460 cell line. Subsequently, the Compound 6o was evaluated against other four human cancer cell lines. Both tubulin polymerization assay and immunofluorescence assay showed that Compound 6o could inhibit microtubule polymerization efficiently. Furthermore, theoretical calculation of the physical properties and molecular docking were elucidated for these plinabulin derivatives. The binding mode of Compound 6o was similar to Compound 6b based on the result of molecular docking. The theoretical calculated LogPo/w and PCaco of Compound 6o were better than Compound 6b, which could enhance its cytostatic activity. Therefore, Compound 6o might be developed as a novel potent anti-microtubule agent.
|
Antiproliferative activity against human HepG2 cells assessed as reduction in cell viability after 72 hrs by SRB assay
|
Homo sapiens
|
4.8
nM
|
|
Journal : Bioorg Med Chem
Title : Development of novel phenoxy-diketopiperazine-type plinabulin derivatives as potent antimicrotubule agents based on the co-crystal structure.
Year : 2020
Volume : 28
Issue : 1
First Page : 115186
Last Page : 115186
Authors : Ding Z, Ma M, Zhong C, Wang S, Fu Z, Hou Y, Liu Y, Zhong L, Chu Y, Li F, Song C, Wang Y, Yang J, Li W.
Abstract : The co-crystal structure of Compound 6b with tubulin was prepared and solved for indicating the binding mode and for further optimization. Based on the co-crystal structures of tubulin with plinabulin and Compound 6b, a total of 27 novel A/B/C-rings plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human lung cancer NCI-H460 cell line. The optimum phenoxy-diketopiperazine-type Compound 6o exhibited high potent cytotoxicity (IC<sub>50</sub> = 4.0 nM) through SAR study of three series of derivatives, which was more potent than plinabulin (IC<sub>50</sub> = 26.2 nM) and similar to Compound 6b (IC<sub>50</sub> = 3.8 nM) against human lung cancer NCI-H460 cell line. Subsequently, the Compound 6o was evaluated against other four human cancer cell lines. Both tubulin polymerization assay and immunofluorescence assay showed that Compound 6o could inhibit microtubule polymerization efficiently. Furthermore, theoretical calculation of the physical properties and molecular docking were elucidated for these plinabulin derivatives. The binding mode of Compound 6o was similar to Compound 6b based on the result of molecular docking. The theoretical calculated LogPo/w and PCaco of Compound 6o were better than Compound 6b, which could enhance its cytostatic activity. Therefore, Compound 6o might be developed as a novel potent anti-microtubule agent.
|
Antiproliferative activity against human HCT116 cells assessed as reduction in cell viability after 72 hrs by SRB assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : Bioorg Med Chem
Title : Development of novel phenoxy-diketopiperazine-type plinabulin derivatives as potent antimicrotubule agents based on the co-crystal structure.
Year : 2020
Volume : 28
Issue : 1
First Page : 115186
Last Page : 115186
Authors : Ding Z, Ma M, Zhong C, Wang S, Fu Z, Hou Y, Liu Y, Zhong L, Chu Y, Li F, Song C, Wang Y, Yang J, Li W.
Abstract : The co-crystal structure of Compound 6b with tubulin was prepared and solved for indicating the binding mode and for further optimization. Based on the co-crystal structures of tubulin with plinabulin and Compound 6b, a total of 27 novel A/B/C-rings plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human lung cancer NCI-H460 cell line. The optimum phenoxy-diketopiperazine-type Compound 6o exhibited high potent cytotoxicity (IC<sub>50</sub> = 4.0 nM) through SAR study of three series of derivatives, which was more potent than plinabulin (IC<sub>50</sub> = 26.2 nM) and similar to Compound 6b (IC<sub>50</sub> = 3.8 nM) against human lung cancer NCI-H460 cell line. Subsequently, the Compound 6o was evaluated against other four human cancer cell lines. Both tubulin polymerization assay and immunofluorescence assay showed that Compound 6o could inhibit microtubule polymerization efficiently. Furthermore, theoretical calculation of the physical properties and molecular docking were elucidated for these plinabulin derivatives. The binding mode of Compound 6o was similar to Compound 6b based on the result of molecular docking. The theoretical calculated LogPo/w and PCaco of Compound 6o were better than Compound 6b, which could enhance its cytostatic activity. Therefore, Compound 6o might be developed as a novel potent anti-microtubule agent.
|
Antiproliferative activity against human MCF7 cells assessed as reduction in cell viability after 72 hrs by SRB assay
|
Homo sapiens
|
29.8
nM
|
|
Journal : Bioorg Med Chem
Title : Development of novel phenoxy-diketopiperazine-type plinabulin derivatives as potent antimicrotubule agents based on the co-crystal structure.
Year : 2020
Volume : 28
Issue : 1
First Page : 115186
Last Page : 115186
Authors : Ding Z, Ma M, Zhong C, Wang S, Fu Z, Hou Y, Liu Y, Zhong L, Chu Y, Li F, Song C, Wang Y, Yang J, Li W.
Abstract : The co-crystal structure of Compound 6b with tubulin was prepared and solved for indicating the binding mode and for further optimization. Based on the co-crystal structures of tubulin with plinabulin and Compound 6b, a total of 27 novel A/B/C-rings plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human lung cancer NCI-H460 cell line. The optimum phenoxy-diketopiperazine-type Compound 6o exhibited high potent cytotoxicity (IC<sub>50</sub> = 4.0 nM) through SAR study of three series of derivatives, which was more potent than plinabulin (IC<sub>50</sub> = 26.2 nM) and similar to Compound 6b (IC<sub>50</sub> = 3.8 nM) against human lung cancer NCI-H460 cell line. Subsequently, the Compound 6o was evaluated against other four human cancer cell lines. Both tubulin polymerization assay and immunofluorescence assay showed that Compound 6o could inhibit microtubule polymerization efficiently. Furthermore, theoretical calculation of the physical properties and molecular docking were elucidated for these plinabulin derivatives. The binding mode of Compound 6o was similar to Compound 6b based on the result of molecular docking. The theoretical calculated LogPo/w and PCaco of Compound 6o were better than Compound 6b, which could enhance its cytostatic activity. Therefore, Compound 6o might be developed as a novel potent anti-microtubule agent.
|
Antiproliferative activity against human HeLa cells assessed as reduction in cell viability after 72 hrs by SRB assay
|
Homo sapiens
|
9.0
nM
|
|
Journal : Bioorg Med Chem
Title : Development of novel phenoxy-diketopiperazine-type plinabulin derivatives as potent antimicrotubule agents based on the co-crystal structure.
Year : 2020
Volume : 28
Issue : 1
First Page : 115186
Last Page : 115186
Authors : Ding Z, Ma M, Zhong C, Wang S, Fu Z, Hou Y, Liu Y, Zhong L, Chu Y, Li F, Song C, Wang Y, Yang J, Li W.
Abstract : The co-crystal structure of Compound 6b with tubulin was prepared and solved for indicating the binding mode and for further optimization. Based on the co-crystal structures of tubulin with plinabulin and Compound 6b, a total of 27 novel A/B/C-rings plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human lung cancer NCI-H460 cell line. The optimum phenoxy-diketopiperazine-type Compound 6o exhibited high potent cytotoxicity (IC<sub>50</sub> = 4.0 nM) through SAR study of three series of derivatives, which was more potent than plinabulin (IC<sub>50</sub> = 26.2 nM) and similar to Compound 6b (IC<sub>50</sub> = 3.8 nM) against human lung cancer NCI-H460 cell line. Subsequently, the Compound 6o was evaluated against other four human cancer cell lines. Both tubulin polymerization assay and immunofluorescence assay showed that Compound 6o could inhibit microtubule polymerization efficiently. Furthermore, theoretical calculation of the physical properties and molecular docking were elucidated for these plinabulin derivatives. The binding mode of Compound 6o was similar to Compound 6b based on the result of molecular docking. The theoretical calculated LogPo/w and PCaco of Compound 6o were better than Compound 6b, which could enhance its cytostatic activity. Therefore, Compound 6o might be developed as a novel potent anti-microtubule agent.
|
Inhibition of porcine brain tubulin polymerization at 5 uM by fluorescence analysis relative to control
|
Sus scrofa
|
13.52
%
|
|
Journal : Bioorg Med Chem
Title : Development of novel phenoxy-diketopiperazine-type plinabulin derivatives as potent antimicrotubule agents based on the co-crystal structure.
Year : 2020
Volume : 28
Issue : 1
First Page : 115186
Last Page : 115186
Authors : Ding Z, Ma M, Zhong C, Wang S, Fu Z, Hou Y, Liu Y, Zhong L, Chu Y, Li F, Song C, Wang Y, Yang J, Li W.
Abstract : The co-crystal structure of Compound 6b with tubulin was prepared and solved for indicating the binding mode and for further optimization. Based on the co-crystal structures of tubulin with plinabulin and Compound 6b, a total of 27 novel A/B/C-rings plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human lung cancer NCI-H460 cell line. The optimum phenoxy-diketopiperazine-type Compound 6o exhibited high potent cytotoxicity (IC<sub>50</sub> = 4.0 nM) through SAR study of three series of derivatives, which was more potent than plinabulin (IC<sub>50</sub> = 26.2 nM) and similar to Compound 6b (IC<sub>50</sub> = 3.8 nM) against human lung cancer NCI-H460 cell line. Subsequently, the Compound 6o was evaluated against other four human cancer cell lines. Both tubulin polymerization assay and immunofluorescence assay showed that Compound 6o could inhibit microtubule polymerization efficiently. Furthermore, theoretical calculation of the physical properties and molecular docking were elucidated for these plinabulin derivatives. The binding mode of Compound 6o was similar to Compound 6b based on the result of molecular docking. The theoretical calculated LogPo/w and PCaco of Compound 6o were better than Compound 6b, which could enhance its cytostatic activity. Therefore, Compound 6o might be developed as a novel potent anti-microtubule agent.
|
Cytotoxicity against human NCI-H460 cells assessed as reduction in cell viability after 72 hrs by MTT assay
|
Homo sapiens
|
26.2
nM
|
|
Journal : Bioorg Med Chem
Title : Structure-based design and synthesis of novel furan-diketopiperazine-type derivatives as potent microtubule inhibitors for treating cancer.
Year : 2020
Volume : 28
Issue : 10
First Page : 115435
Last Page : 115435
Authors : Ding Z, Li F, Zhong C, Li F, Liu Y, Wang S, Zhao J, Li W.
Abstract : Plinabulin, a synthetic analog of the marine natural product "diketopiperazine phenylahistin," displayed depolymerization effects on microtubules and targeted the colchicine site, which has been moved into phase III clinical trials for the treatment of non-small cell lung cancer (NSCLC) and the prevention of chemotherapy-induced neutropenia (CIN). To develop more potent anti-microtubule and cytotoxic derivatives, the co-crystal complexes of plinabulin derivatives were summarized and analyzed. We performed further modifications of the tert-butyl moiety or C-ring of imidazole-type derivatives to build a library of molecules through the introduction of different groups for novel skeletons. Our structure-activity relationship study indicated that compounds 17o (IC<sub>50</sub> = 14.0 nM, NCI-H460) and 17p (IC<sub>50</sub> = 2.9 nM, NCI-H460) with furan groups exhibited potent cytotoxic activities at the nanomolar level against various human cancer cell lines. In particular, the 5-methyl or methoxymethyl substituent of furan group could replace the alkyl group of imidazole at the 5-position to maintain cytotoxic activity, contradicting previous reports that the tert-butyl moiety at the 5-position of imidazole was essential for the activity of such compounds. Immunofluorescence assay indicated that compounds 17o and 17p could efficiently inhibit microtubule polymerization. Overall, the novel furan-diketopiperazine-type derivatives could be considered as a potential scaffold for the development of anti-cancer drugs.
|
Cytotoxicity against human BxPC3 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay
|
Homo sapiens
|
5.8
nM
|
|
Journal : Bioorg Med Chem
Title : Structure-based design and synthesis of novel furan-diketopiperazine-type derivatives as potent microtubule inhibitors for treating cancer.
Year : 2020
Volume : 28
Issue : 10
First Page : 115435
Last Page : 115435
Authors : Ding Z, Li F, Zhong C, Li F, Liu Y, Wang S, Zhao J, Li W.
Abstract : Plinabulin, a synthetic analog of the marine natural product "diketopiperazine phenylahistin," displayed depolymerization effects on microtubules and targeted the colchicine site, which has been moved into phase III clinical trials for the treatment of non-small cell lung cancer (NSCLC) and the prevention of chemotherapy-induced neutropenia (CIN). To develop more potent anti-microtubule and cytotoxic derivatives, the co-crystal complexes of plinabulin derivatives were summarized and analyzed. We performed further modifications of the tert-butyl moiety or C-ring of imidazole-type derivatives to build a library of molecules through the introduction of different groups for novel skeletons. Our structure-activity relationship study indicated that compounds 17o (IC<sub>50</sub> = 14.0 nM, NCI-H460) and 17p (IC<sub>50</sub> = 2.9 nM, NCI-H460) with furan groups exhibited potent cytotoxic activities at the nanomolar level against various human cancer cell lines. In particular, the 5-methyl or methoxymethyl substituent of furan group could replace the alkyl group of imidazole at the 5-position to maintain cytotoxic activity, contradicting previous reports that the tert-butyl moiety at the 5-position of imidazole was essential for the activity of such compounds. Immunofluorescence assay indicated that compounds 17o and 17p could efficiently inhibit microtubule polymerization. Overall, the novel furan-diketopiperazine-type derivatives could be considered as a potential scaffold for the development of anti-cancer drugs.
|
Cytotoxicity against human HT-29 cells assessed as reduction in cell viability after 72 hrs by MTT assay
|
Homo sapiens
|
6.6
nM
|
|
Journal : Bioorg Med Chem
Title : Structure-based design and synthesis of novel furan-diketopiperazine-type derivatives as potent microtubule inhibitors for treating cancer.
Year : 2020
Volume : 28
Issue : 10
First Page : 115435
Last Page : 115435
Authors : Ding Z, Li F, Zhong C, Li F, Liu Y, Wang S, Zhao J, Li W.
Abstract : Plinabulin, a synthetic analog of the marine natural product "diketopiperazine phenylahistin," displayed depolymerization effects on microtubules and targeted the colchicine site, which has been moved into phase III clinical trials for the treatment of non-small cell lung cancer (NSCLC) and the prevention of chemotherapy-induced neutropenia (CIN). To develop more potent anti-microtubule and cytotoxic derivatives, the co-crystal complexes of plinabulin derivatives were summarized and analyzed. We performed further modifications of the tert-butyl moiety or C-ring of imidazole-type derivatives to build a library of molecules through the introduction of different groups for novel skeletons. Our structure-activity relationship study indicated that compounds 17o (IC<sub>50</sub> = 14.0 nM, NCI-H460) and 17p (IC<sub>50</sub> = 2.9 nM, NCI-H460) with furan groups exhibited potent cytotoxic activities at the nanomolar level against various human cancer cell lines. In particular, the 5-methyl or methoxymethyl substituent of furan group could replace the alkyl group of imidazole at the 5-position to maintain cytotoxic activity, contradicting previous reports that the tert-butyl moiety at the 5-position of imidazole was essential for the activity of such compounds. Immunofluorescence assay indicated that compounds 17o and 17p could efficiently inhibit microtubule polymerization. Overall, the novel furan-diketopiperazine-type derivatives could be considered as a potential scaffold for the development of anti-cancer drugs.
|
Cytotoxicity against human U-937 cells assessed as reduction in cell viability measured after 72 hrs by CCK8 assay
|
Homo sapiens
|
6.8
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and cytotoxic activities of novel 2,5-diketopiperazine derivatives.
Year : 2016
Volume : 121
First Page : 500
Last Page : 509
Authors : Liao SR,Qin XC,Wang Z,Li D,Xu L,Li JS,Tu ZC,Liu Y
Abstract : A series of novel N-1-monoallylated 2,5-diketopiperazine derivatives were designed, synthesized, and evaluated as cytotoxic agents against eight cancer cell lines by using CCK8 assay. These derivatives were substituted with methoxyphenyl groups at C-6 position, and various long alkyl side chains at C-3-position of the 2,5-diketopiperazine ring. The cytotoxic results showed that 4-methoxyphenyl group was better than 2-methoxyphenyl group as optimal substitutive group, while 3-methoxyphenyl group was not a suitable one. When the number (n value) of the methylene groups for the long alkyl side chain was 3 (compounds 1c and 3c), the derivatives had the strongest cytotoxicities. Compound 3c substituted with 4-methoxyphenyl group and pentylidene side chain exhibited strong activity (IC50 = 0.36-1.9 μM) against all cancer cell lines, and could obviously induce apoptosis of cancer cell line U937 at 1.0 μM after 48 h treatment.
|
Cytotoxicity against human K562 cells assessed as reduction in cell viability measured after 72 hrs by CCK8 assay
|
Homo sapiens
|
6.3
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and cytotoxic activities of novel 2,5-diketopiperazine derivatives.
Year : 2016
Volume : 121
First Page : 500
Last Page : 509
Authors : Liao SR,Qin XC,Wang Z,Li D,Xu L,Li JS,Tu ZC,Liu Y
Abstract : A series of novel N-1-monoallylated 2,5-diketopiperazine derivatives were designed, synthesized, and evaluated as cytotoxic agents against eight cancer cell lines by using CCK8 assay. These derivatives were substituted with methoxyphenyl groups at C-6 position, and various long alkyl side chains at C-3-position of the 2,5-diketopiperazine ring. The cytotoxic results showed that 4-methoxyphenyl group was better than 2-methoxyphenyl group as optimal substitutive group, while 3-methoxyphenyl group was not a suitable one. When the number (n value) of the methylene groups for the long alkyl side chain was 3 (compounds 1c and 3c), the derivatives had the strongest cytotoxicities. Compound 3c substituted with 4-methoxyphenyl group and pentylidene side chain exhibited strong activity (IC50 = 0.36-1.9 μM) against all cancer cell lines, and could obviously induce apoptosis of cancer cell line U937 at 1.0 μM after 48 h treatment.
|
Cytotoxicity against human HL-60 cells assessed as reduction in cell viability measured after 72 hrs by CCK8 assay
|
Homo sapiens
|
14.8
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and cytotoxic activities of novel 2,5-diketopiperazine derivatives.
Year : 2016
Volume : 121
First Page : 500
Last Page : 509
Authors : Liao SR,Qin XC,Wang Z,Li D,Xu L,Li JS,Tu ZC,Liu Y
Abstract : A series of novel N-1-monoallylated 2,5-diketopiperazine derivatives were designed, synthesized, and evaluated as cytotoxic agents against eight cancer cell lines by using CCK8 assay. These derivatives were substituted with methoxyphenyl groups at C-6 position, and various long alkyl side chains at C-3-position of the 2,5-diketopiperazine ring. The cytotoxic results showed that 4-methoxyphenyl group was better than 2-methoxyphenyl group as optimal substitutive group, while 3-methoxyphenyl group was not a suitable one. When the number (n value) of the methylene groups for the long alkyl side chain was 3 (compounds 1c and 3c), the derivatives had the strongest cytotoxicities. Compound 3c substituted with 4-methoxyphenyl group and pentylidene side chain exhibited strong activity (IC50 = 0.36-1.9 μM) against all cancer cell lines, and could obviously induce apoptosis of cancer cell line U937 at 1.0 μM after 48 h treatment.
|
Cytotoxicity against human A549 cells assessed as reduction in cell viability measured after 72 hrs by CCK8 assay
|
Homo sapiens
|
5.5
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and cytotoxic activities of novel 2,5-diketopiperazine derivatives.
Year : 2016
Volume : 121
First Page : 500
Last Page : 509
Authors : Liao SR,Qin XC,Wang Z,Li D,Xu L,Li JS,Tu ZC,Liu Y
Abstract : A series of novel N-1-monoallylated 2,5-diketopiperazine derivatives were designed, synthesized, and evaluated as cytotoxic agents against eight cancer cell lines by using CCK8 assay. These derivatives were substituted with methoxyphenyl groups at C-6 position, and various long alkyl side chains at C-3-position of the 2,5-diketopiperazine ring. The cytotoxic results showed that 4-methoxyphenyl group was better than 2-methoxyphenyl group as optimal substitutive group, while 3-methoxyphenyl group was not a suitable one. When the number (n value) of the methylene groups for the long alkyl side chain was 3 (compounds 1c and 3c), the derivatives had the strongest cytotoxicities. Compound 3c substituted with 4-methoxyphenyl group and pentylidene side chain exhibited strong activity (IC50 = 0.36-1.9 μM) against all cancer cell lines, and could obviously induce apoptosis of cancer cell line U937 at 1.0 μM after 48 h treatment.
|
Cytotoxicity against human MCF7 cells assessed as reduction in cell viability measured after 72 hrs by CCK8 assay
|
Homo sapiens
|
12.6
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and cytotoxic activities of novel 2,5-diketopiperazine derivatives.
Year : 2016
Volume : 121
First Page : 500
Last Page : 509
Authors : Liao SR,Qin XC,Wang Z,Li D,Xu L,Li JS,Tu ZC,Liu Y
Abstract : A series of novel N-1-monoallylated 2,5-diketopiperazine derivatives were designed, synthesized, and evaluated as cytotoxic agents against eight cancer cell lines by using CCK8 assay. These derivatives were substituted with methoxyphenyl groups at C-6 position, and various long alkyl side chains at C-3-position of the 2,5-diketopiperazine ring. The cytotoxic results showed that 4-methoxyphenyl group was better than 2-methoxyphenyl group as optimal substitutive group, while 3-methoxyphenyl group was not a suitable one. When the number (n value) of the methylene groups for the long alkyl side chain was 3 (compounds 1c and 3c), the derivatives had the strongest cytotoxicities. Compound 3c substituted with 4-methoxyphenyl group and pentylidene side chain exhibited strong activity (IC50 = 0.36-1.9 μM) against all cancer cell lines, and could obviously induce apoptosis of cancer cell line U937 at 1.0 μM after 48 h treatment.
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Cytotoxicity against human HeLa cells assessed as reduction in cell viability measured after 72 hrs by CCK8 assay
|
Homo sapiens
|
8.4
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and cytotoxic activities of novel 2,5-diketopiperazine derivatives.
Year : 2016
Volume : 121
First Page : 500
Last Page : 509
Authors : Liao SR,Qin XC,Wang Z,Li D,Xu L,Li JS,Tu ZC,Liu Y
Abstract : A series of novel N-1-monoallylated 2,5-diketopiperazine derivatives were designed, synthesized, and evaluated as cytotoxic agents against eight cancer cell lines by using CCK8 assay. These derivatives were substituted with methoxyphenyl groups at C-6 position, and various long alkyl side chains at C-3-position of the 2,5-diketopiperazine ring. The cytotoxic results showed that 4-methoxyphenyl group was better than 2-methoxyphenyl group as optimal substitutive group, while 3-methoxyphenyl group was not a suitable one. When the number (n value) of the methylene groups for the long alkyl side chain was 3 (compounds 1c and 3c), the derivatives had the strongest cytotoxicities. Compound 3c substituted with 4-methoxyphenyl group and pentylidene side chain exhibited strong activity (IC50 = 0.36-1.9 μM) against all cancer cell lines, and could obviously induce apoptosis of cancer cell line U937 at 1.0 μM after 48 h treatment.
|
Cytotoxicity against human DU-145 cells assessed as reduction in cell viability measured after 72 hrs by CCK8 assay
|
Homo sapiens
|
14.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and cytotoxic activities of novel 2,5-diketopiperazine derivatives.
Year : 2016
Volume : 121
First Page : 500
Last Page : 509
Authors : Liao SR,Qin XC,Wang Z,Li D,Xu L,Li JS,Tu ZC,Liu Y
Abstract : A series of novel N-1-monoallylated 2,5-diketopiperazine derivatives were designed, synthesized, and evaluated as cytotoxic agents against eight cancer cell lines by using CCK8 assay. These derivatives were substituted with methoxyphenyl groups at C-6 position, and various long alkyl side chains at C-3-position of the 2,5-diketopiperazine ring. The cytotoxic results showed that 4-methoxyphenyl group was better than 2-methoxyphenyl group as optimal substitutive group, while 3-methoxyphenyl group was not a suitable one. When the number (n value) of the methylene groups for the long alkyl side chain was 3 (compounds 1c and 3c), the derivatives had the strongest cytotoxicities. Compound 3c substituted with 4-methoxyphenyl group and pentylidene side chain exhibited strong activity (IC50 = 0.36-1.9 μM) against all cancer cell lines, and could obviously induce apoptosis of cancer cell line U937 at 1.0 μM after 48 h treatment.
|
Cytotoxicity against human HT-29 cells assessed as reduction in cell viability measured after 72 hrs by CCK8 assay
|
Homo sapiens
|
13.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and cytotoxic activities of novel 2,5-diketopiperazine derivatives.
Year : 2016
Volume : 121
First Page : 500
Last Page : 509
Authors : Liao SR,Qin XC,Wang Z,Li D,Xu L,Li JS,Tu ZC,Liu Y
Abstract : A series of novel N-1-monoallylated 2,5-diketopiperazine derivatives were designed, synthesized, and evaluated as cytotoxic agents against eight cancer cell lines by using CCK8 assay. These derivatives were substituted with methoxyphenyl groups at C-6 position, and various long alkyl side chains at C-3-position of the 2,5-diketopiperazine ring. The cytotoxic results showed that 4-methoxyphenyl group was better than 2-methoxyphenyl group as optimal substitutive group, while 3-methoxyphenyl group was not a suitable one. When the number (n value) of the methylene groups for the long alkyl side chain was 3 (compounds 1c and 3c), the derivatives had the strongest cytotoxicities. Compound 3c substituted with 4-methoxyphenyl group and pentylidene side chain exhibited strong activity (IC50 = 0.36-1.9 μM) against all cancer cell lines, and could obviously induce apoptosis of cancer cell line U937 at 1.0 μM after 48 h treatment.
