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1.
Kamal A Sultana F Ramaiah MJ Srikanth YV Viswanath A Kishor C Sharma P Pushpavalli SN Addlagatta A Pal-Bhadra M 《ChemMedChem》2012,7(2):292-300
A new series of 3‐substituted 2‐phenylimidazo[2,1‐b]benzothiazoles ( 3 a – h ) were synthesized by C‐arylation of 2‐arylimidazo[2,1‐b]benzothiazoles using palladium acetate as catalyst, and the resulting compounds were evaluated for their anticancer activity. Compounds 3 a , 3 e , and 3 h exhibited good antiproliferative activity, with GI50 values in the range of 0.19–83.1 μM . Compound 3 h showed potent anticancer efficacy against 60 human cancer cell lines, with a mean GI50 value of 0.88 μM . This compound also induced cell‐cycle arrest in the G2/M phase and inhibited tubulin polymerization followed by activation of caspase‐3 and apoptosis. A high‐throughput tubulin polymerization assay showed that the level of inhibition for compound 3 h is similar to that of combretastatin A‐4. Molecular modeling studies provided a molecular basis for the favorable binding of compounds 3 a , 3 e , and 3 h to the colchicine binding pocket of tubulin. 相似文献
2.
Dr. Ahmed Kamal Vangala Santhosh Reddy Santosh Karnewar Sumit S. Chourasiya Anver Basha Shaik G. Bharath Kumar Chandan Kishor M. Kashi Reddy M. P. Narasimha Rao Dr. Ananthamurthy Nagabhushana Kallaganti V. S. Ramakrishna Dr. Anthony Addlagatta Dr. Srigiridhar Kotamraju 《ChemMedChem》2013,8(12):2015-2025
A library of imidazopyridine–oxindole conjugates was synthesised and investigated for anticancer activity against various human cancer cell lines. Some of the tested compounds, such as 10 a , 10 e , 10 f , and 10 k , exhibited promising antiproliferative activity with GI50 values ranging from 0.17 to 9.31 μM . Flow cytometric analysis showed that MCF‐7 cells treated by these compounds arrested in the G2/M phase of the cell cycle in a concentration‐dependent manner. More particularly, compound 10 f displayed a remarkable inhibitory effect on tubulin polymerisation. All the compounds depolarised mitochondrial membrane potential and caused apoptosis. These results are further supported by the decreased phosphorylation of Akt at Ser473. Studies on embryonic development revealed that the lead compounds 10 f and 10 k caused delay in the development of zebra fish embryos. Docking of compound 10 f with tubulin protein suggested that the imidazo[1,2‐a]pyridine moiety occupies the colchicine binding site of tubulin. 相似文献
3.
P. S. Srikanth V. Lakshma Nayak Korrapati Suresh Babu G. Bharath Kumar A. Ravikumar Dr. Ahmed Kamal 《ChemMedChem》2016,11(18):2050-2062
Several 2‐anilino‐3‐aroylquinolines were designed, synthesized, and screened for their cytotoxic activity against five human cancer cell lines: HeLa, DU‐145, A549, MDA‐MB‐231, and MCF‐7. Their IC50 values ranged from 0.77 to 23.6 μm . Among the series, compounds 7 f [(4‐fluorophenyl)(2‐((4‐fluorophenyl)amino)quinolin‐3‐yl)methanone] and 7 g [(4‐chlorophenyl)(2‐((4‐fluorophenyl)amino)quinolin‐3‐yl)methanone] showed remarkable antiproliferative activity against human lung cancer and prostate cancer cell lines. The IC50 values for inhibiting tubulin polymerization were 2.24 and 2.10 μm for compounds 7 f and 7 g , respectively, and were much lower than that of the reference compound E7010 [N‐(2‐(4‐hydroxyphenylamino)pyridin‐3‐yl)‐4‐methoxybenzenesulfonamide]. Furthermore, flow cytometric analysis revealed that these compounds arrest the cell cycle at the G2/M phase, leading to apoptosis. Apoptosis was also confirmed by mitochondrial membrane potential, Annexin V–FITC assay, and intracellular ROS generation. Immunohistochemistry, western blot, and tubulin polymerization assays showed that these compounds disrupt tubulin polymerization. Molecular docking studies revealed that these compounds bind efficiently to β‐tubulin at the colchicine binding site. 相似文献
4.
Design and Synthesis of Imidazo[2,1‐b]thiazole–Chalcone Conjugates: Microtubule‐Destabilizing Agents
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Dr. Ahmed Kamal Moku Balakrishna V. Lakshma Nayak Thokhir Basha Shaik Shaikh Faazil Vijaykumar D. Nimbarte 《ChemMedChem》2014,9(12):2766-2780
A series of chalcone conjugates featuring the imidazo[2,1‐b]thiazole scaffold was designed, synthesized, and evaluated for their cytotoxic activity against five human cancer cell lines (MCF‐7, A549, HeLa, DU‐145 and HT‐29). These new hybrid molecules have shown promising cytotoxic activity with IC50 values ranging from 0.64 to 30.9 μM . Among them, (E)‐3‐(6‐(4‐fluorophenyl)‐2,3‐bis(4‐methoxyphenyl)imidazo[2,1‐b]thiazol‐5‐yl)‐1‐(pyridin‐2‐yl)prop‐2‐en‐1‐one ( 11 x ) showed potent antiproliferative activity with IC50 values ranging from 0.64 to 1.44 μM in all tested cell lines. To investigate the mechanism of action, the detailed biological aspects of this promising conjugate ( 11 x ) were carried out on the A549 lung cancer cell line. The tubulin polymerization assay and immunofluoresence analysis results suggest that this conjugate effectively inhibits microtubule assembly in A549 cells. Flow cytometric analysis revealed that this conjugate induces cell‐cycle arrest in the G2/M phase and leads to apoptotic cell death. This was further confirmed by Hoechst staining, activation of caspase‐3, DNA fragmentation analysis, and Annexin V–FITC assay. Moreover, molecular docking studies indicated that this conjugate ( 11 x) interacts and binds efficiently with the tubulin protein. 相似文献
5.
Abdallah Hamze Dr. Anne Giraud Dr. Samir Messaoudi Dr. Olivier Provot Dr. Jean‐François Peyrat Prof. Jérôme Bignon Dr. Jian‐Miao Liu Dr. Joanna Wdzieczak‐Bakala Dr. Sylviane Thoret Joëlle Dubois Dr. Jean‐Daniel Brion Prof. Mouad Alami Dr. 《ChemMedChem》2009,4(11):1912-1924
The cytotoxic activities of 23 new isocombretastatin A derivatives with modifications on the B‐ring were investigated. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. Compounds isoFCA‐4 ( 2 e ), isoCA‐4 ( 2 k ) and isoNH2CA‐4 ( 2 s ) were the most cytotoxic, and strongly inhibited tubulin polymerization with IC50 values of 4, 2 and 1.5 μM , respectively. These derivatives were found to be 10‐fold more active than phenstatin and colchicine with respect to growth inhibition but displayed similar activities as tubulin polymerization inhibitors. In addition, cell cycle arrest in the G2/M phase and subsequent apoptosis was observed in three cancer cell lines when treated with these compounds. The disruptive effect of 2 e , 2 k and 2 s on the vessel‐like structures formed by human umbilical vein endothelial cells (HUVEC) suggest that these compounds may act as vascular disrupting agents. Both compounds 2 k and 2 s have the potential for further prodrug modification and development as vascular disrupting agents for treatment of solid tumors. 相似文献
6.
Dr. Wolfgang Dohle Dr. Mathew P. Leese Dr. Fabrice L. Jourdan Dr. Christopher J. Chapman Dr. Ernest Hamel Dr. Eric Ferrandis Prof. Barry V. L. Potter 《ChemMedChem》2014,9(8):1783-1793
Tetrahydroisoquinoline (THIQ)‐based “chimeric” microtubule disruptors were optimised through modification of the N‐benzyl motif, in concert with changes at C3 and C7, resulting in the identification of compounds with improved in vitro antiproliferative activities (e.g. 15 : GI50 20 nM in DU‐145). The broad anticancer activity of these novel structures was confirmed in the NCI 60‐cell line assay, with 12 e , f displaying MGM values in the 40 nM region. In addition, their profiles as inhibitors of tubulin polymerisation and colchicine binding to tubulin were confirmed. Compound 15 , for example, inhibited tubulin polymerisation with an IC50 of 1.8 μM , close to that of the clinical drug combretastatin A‐4, and also proved effective at blocking colchicine binding. Additionally, compound 20 b was identified as the only phenol in the series to date showing both better in vitro antiproliferative properties than its corresponding sulfamate and excellent antitubulin data (IC50=1.6 μM ). Compound 12 f was selected for in vivo evaluation at the NCI in the hollow fibre assay and showed very good activity and wide tissue distribution, illustrating the value of this template for further development. 相似文献
7.
Synthesis and Biological Evaluation of Benzo[b]furans as Inhibitors of Tubulin Polymerization and Inducers of Apoptosis
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Dr. Ahmed Kamal N. V. Subba Reddy V. Lakshma Nayak V. Saidi Reddy B. Prasad Vijaykumar D. Nimbarte Vunnam Srinivasulu M. V. P. S. Vishnuvardhan Prof. C. Suresh Reddy 《ChemMedChem》2014,9(1):117-128
A series of benzo[b]furans was synthesized with modification at the 5‐position of the benzene ring by introducing C‐linked substituents (aryl, alkenyl, alkynyl, etc.). These compounds were evaluated for their antiproliferative activities, inhibition of tubulin polymerization, and cell‐cycle effects. Some compounds in this series displayed excellent activity in the nanomolar range against lung cancer (A549) and renal cell carcinoma (ACHN) cancer cell lines. (6‐Methoxy‐5‐((4‐methoxyphenyl)ethynyl)‐3‐methylbenzofuran‐2‐yl)(3,4,5‐trimethoxyphenyl)methanone ( 26 ) and (E)‐3‐(6‐methoxy‐3‐methyl‐2‐(1‐(3,4,5‐trimethoxyphenyl)vinyl)benzofuran‐5‐yl)prop‐2‐en‐1‐ol ( 36 ) showed significant activity in the A549 cell line, with IC50 values of 0.08 and 0.06 μM , respectively. G2/M cell‐cycle arrest and subsequent apoptosis was observed in the A549 cell line after treatment with these compounds. The most active compound in this series, 36 , also inhibited tubulin polymerization with a value similar to that of combretastatin A‐4 (1.95 and 1.86 μM , respectively). Furthermore, detailed biological studies such as Hoechst 33258 staining, DNA fragmentation and caspase‐3 assays, and western blot analyses with the pro‐apoptotic protein Bax and the anti‐apoptotic protein Bcl‐2 also suggested that these compounds induce cell death by apoptosis. Molecular docking studies indicated that compound 36 interacts and binds efficiently with the tubulin protein. 相似文献
8.
Synthesis,Antitubulin, and Antiproliferative SAR of C3/C1‐Substituted Tetrahydroisoquinolines
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Dr. Wolfgang Dohle Dr. Mathew P. Leese Dr. Fabrice L. Jourdan Dr. Meriel R. Major Dr. Ruoli Bai Dr. Ernest Hamel Dr. Eric Ferrandis Dr. Philip G. Kasprzyk Dr. Ann Fiore Dr. Simon P. Newman Dr. Atul Purohit Prof. Barry V. L. Potter 《ChemMedChem》2014,9(2):350-370
The syntheses and antiproliferative activities of novel substituted tetrahydroisoquinoline derivatives and their sulfamates are discussed. Biasing of conformational populations through substitution on the tetrahydroisoquinoline core at C1 and C3 has a profound effect on the antiproliferative activity against various cancer cell lines. The C3 methyl‐substituted sulfamate (±)‐7‐methoxy‐2‐(3‐methoxybenzyl)‐3‐methyl‐6‐sulfamoyloxy‐1,2,3,4‐tetrahydroisoquinoline ( 6 b ), for example, was found to be ~10‐fold more potent than the corresponding non‐methylated compound 7‐methoxy‐2‐(3‐methoxybenzyl)‐6‐sulfamoyloxy‐1,2,3,4‐tetrahydroisoquinoline ( 4 b ) against DU‐145 prostate cancer cells (GI50 values: 220 nM and 2.1 μM , respectively). Such compounds were also found to be active against a drug‐resistant MCF breast cancer cell line. The position and nature of substitution of the N‐benzyl group in the C3‐substituted series was found to have a significant effect on activity. Whereas C1 methylation has little effect on activity, introduction of C1 phenyl and C3‐gem‐dimethyl substituents greatly decreases antiproliferative activity. The ability of these compounds to inhibit microtubule polymerisation and to bind tubulin in a competitive manner versus colchicine confirms the mechanism of action. The therapeutic potential of a representative compound was confirmed in an in vivo multiple myeloma xenograft study. 相似文献
9.
Chuang HY Chang JY Lai MJ Kuo CC Lee HY Hsieh HP Chen YJ Chen LT Pan WY Liou JP 《ChemMedChem》2011,6(3):450-456
A series of novel 2‐amino‐3,4,5‐trimethoxybenzophenone analogues exhibited excellent activity as tubulin polymerization inhibitors by targeting the colchicine binding site of microtubules. The lead compound 17 exhibited an IC50 value of 1.6 μM , similar to that of combretastatin A‐4 (IC50=1.9 μM ). It also displayed remarkable anti‐proliferative activity, with IC50 values ranging from 7–16 nM against a variety of human cancer cell lines and one MDR(+) cancer cell line. SAR information indicated that the introduction of an amino group at the C2 position of benzophenone ring A and the C3’ position of benzophenone ring B play important roles in maximizing activity. 相似文献
10.
Synthesis and Biological Evaluation of 1‐Methyl‐1H‐indole–Pyrazoline Hybrids as Potential Tubulin Polymerization Inhibitors
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Ya‐Liang Zhang Ya‐Juan Qin Dan‐Jie Tang Meng‐Ru Yang Bo‐Yan Li Yan‐Ting Wang Hong‐Yu Cai Prof. Bao‐Zhong Wang Prof. Dr. Hai‐Liang Zhu 《ChemMedChem》2016,11(13):1446-1458
A series of 1‐methyl‐1H‐indole–pyrazoline hybrids were designed, synthesized, and biologically evaluated as potential tubulin polymerization inhibitors. Among them, compound e19 [5‐(5‐bromo‐1‐methyl‐1H‐indol‐3‐yl)‐3‐(3,4,5‐trimethoxyphenyl)‐4,5‐dihydro‐1H‐pyrazole‐1‐carboxamide] showed the most potent inhibitory effect on tubulin assembly (IC50=2.12 μm ) and in vitro growth inhibitory activity against a panel of four human cancer cell lines (IC50 values of 0.21–0.31 μm ). Further studies confirmed that compound e19 can induce HeLa cell apoptosis, cause cell‐cycle arrest in G2/M phase, and disrupt the cellular microtubule network. These studies, along with molecular docking and 3D‐QSAR modeling, provide an important basis for further optimization of compound e19 as a potential anticancer agent. 相似文献
11.
Maria Grazia Ferlin Dr. Roberta Bortolozzi Dr. Paola Brun Dr. Ignazio Castagliuolo Prof. Ernest Hamel Dr. Giuseppe Basso Prof. Giampietro Viola Dr. 《ChemMedChem》2010,5(8):1373-1385
A series of new substituted 7‐phenyl‐3H‐pyrrolo[3,2‐f]quinolin‐9‐ones were synthesized and evaluated for their antiproliferative activity. The most active derivatives showed high selectivity against human leukemia cell lines and potently inhibited their growth, with GI50 values in the nanomolar range. The active compounds strongly blocked tubulin assembly and colchicine binding to tubulin. Their activities were equal to or greater than that of the reference compound combretastatin A‐4. Flow cytometry studies showed that the two most active compounds arrested Jurkat cells in the G2/M cell‐cycle phase in a concentration‐dependent manner. This effect was associated with apoptosis, mitochondrial depolarization, generation of reactive oxygen species, activation of caspase‐3, and cleavage of the enzyme poly(ADP‐ribose) polymerase. 相似文献
12.
Synthesis and Biological Evaluation of Imidazo[2,1‐b][1,3,4]thiadiazole‐Linked Oxindoles as Potent Tubulin Polymerization Inhibitors
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Dr. Ahmed Kamal M. P. Narasimha Rao Pompi Das P. Swapna Sowjanya Polepalli Vijaykumar D. Nimbarte Kishore Mullagiri Jeshma Kovvuri Dr. Nishant Jain 《ChemMedChem》2014,9(7):1463-1475
A series of imidazo[2,1‐b][1,3,4]thiadiazole‐linked oxindoles composed of an A, B, C and D ring system were synthesized and investigated for anti‐proliferative activity in various human cancer cell lines; test compounds were variously substituted at rings C and D. Among them, compounds 7 ((E)‐5‐fluoro‐3‐((6‐p‐tolyl‐2‐(3,4,5‐trimethoxyphenyl)‐imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one), 11 ((E)‐3‐((6‐p‐tolyl‐2‐(3,4,5‐trimethoxyphenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one), and 15 ((E)‐6‐chloro‐3‐((6‐phenyl‐2‐(3,4,5‐trimethoxyphenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one) exhibited potent anti‐proliferative activity. Treatment with these three compounds resulted in accumulation of cells in G2/M phase, inhibition of tubulin assembly, and increased cyclin‐B1 protein levels. Compound 7 displayed potent cytotoxicity, with an IC50 range of 1.1–1.6 μM , and inhibited tubulin polymerization with an IC50 value (0.15 μM ) lower than that of combretastatin A‐4 (1.16 μM ). Docking studies reveal that compounds 7 and 11 bind with αAsn101, βThr179, and βCys241 in the colchicine binding site of tubulin. 相似文献
13.
Discovery of a Nanomolar Multikinase Inhibitor (KST016366): A New Benzothiazole Derivative with Remarkable Broad‐Spectrum Antiproliferative Activity
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Ashraf Kareem El‐Damasy Dr. Nam‐Chul Cho Prof. Ghilsoo Nam Prof. Ae Nim Pae Prof. Gyochang Keum 《ChemMedChem》2016,11(15):1587-1595
Herein we report the discovery of compound 6 [KST016366; 4‐((2‐(3‐(4‐((4‐ethylpiperazin‐1‐yl)methyl)‐3‐(trifluoromethyl)phenyl)ureido)benzo[d]thiazol‐6‐yl)oxy)picolinamide] as a new potent multikinase inhibitor through minor structural modification of our previously reported RAF kinase inhibitor A . In vitro anticancer evaluation of 6 showed substantial broad‐spectrum antiproliferative activity against 60 human cancer cell lines. In particular, it showed GI50 values of 51.4 and 19 nm against leukemia K‐562 and colon carcinoma KM12 cell lines, respectively. Kinase screening of compound 6 revealed its nanomolar‐level inhibitory activity of certain oncogenic kinases implicated in both tumorigenesis and angiogenesis. Interestingly, 6 displays IC50 values of 0.82, 3.81, and 53 nm toward Tie2, TrkA, and ABL‐1 (wild‐type and T315I mutant) kinases, respectively. Moreover, 6 is orally bioavailable with a favorable in vivo pharmacokinetic profile. Compound 6 may serve as a promising candidate for further development of potent anticancer chemotherapeutics. 相似文献
14.
Prof. Dr. Hao Zhou Dr. Zhiwen Qi Dr. Danyang Liu Dr. Xingyin Xue Prof. Dr. Chengzhang Wang 《Chembiochem : a European journal of chemical biology》2023,24(18):e202300238
In the present study, a novel series of 11 urushiol-based hydroxamic acid histone deacetylase (HDAC) inhibitors was designed, synthesized, and biologically evaluated. Compounds 1 – 11 exhibited good to excellent inhibitory activities against HDAC1/2/3 (IC50: 42.09–240.17 nM) and HDAC8 (IC50: 16.11–41.15 nM) in vitro, with negligible activity against HDAC6 (>1409.59 nM). Considering HDAC8, docking experiments revealed some important features contributing to inhibitory activity. According to Western blot analysis, select compounds could notably enhance the acetylation of histone H3 and SMC3 but not-tubulin, indicating their privileged structure is appropriate for targeting class I HDACs. Furthermore, antiproliferation assays revealed that six compounds exerted greater in vitro antiproliferative activity against four human cancer cell lines (A2780, HT-29, MDA-MB-231, and HepG2, with IC50 values ranging from 2.31–5.13 μM) than suberoylanilide hydroxamic acid; administration of these compounds induced marked apoptosis in MDA-MB-231 cells, with cell cycle arrest in the G2/M phase. Collectively, specific synthesized compounds could be further optimized and biologically explored as antitumor agents. 相似文献
15.
A series of ursolic acid ((1S,2R,4aS,6aR,6aS,6bR,8aR,10S,12aR,14bS)‐10‐hydroxy‐1,2,6a,6b,9,9,12a‐heptamethyl‐2,3,4,5,6,6a,7,8,8a,10,11,12,13,14b‐tetradecahydro‐1H‐picene‐4a‐carboxylic acid) derivatives with a 12‐fluoro‐13,28β‐lactone moiety were synthesized using the electrophilic fluorination reagent Selectfluor. The antiproliferative effects of these novel compounds were evaluated in AsPC‐1 pancreatic cancer cells, and the structure–activity relationships (SARs) were evaluated. Of the compounds synthesized, ursolic acid derivatives carrying a heterocyclic ring, such as imidazole or methylimidazole, and cyanoenones were among the more potent inhibitors of AsPC‐1 pancreatic cancer cell growth. 2‐Cyano‐3‐oxo‐12α‐fluoro‐urs‐1‐en‐13,28β‐olide, compound 20 , was the most effective inhibitor with IC50 values of 0.7, 0.9 and 1.8 μM in pancreatic cancer cell lines AsPC‐1, MIA PaCa‐2 and PANC‐1, respectively. This compound also exhibited better antiproliferative activities against breast (MCF7), prostate (PC‐3), hepatocellular (Hep G2) and lung (A549) cancer cell lines, with IC50 values lower than 1 μM . The mechanism of action by which these compounds exert their biological effect was evaluated in AsPC‐1 cells using the most potent inhibitor synthesized, compound 20 . At 1 μM , the cell cycle arrested at the G1 phase with upregulation of p21waf1. Apoptosis was induced at an inhibitor concentration of 8 μM with upregulation of NOXA and downregulation of c‐FLIP. These data indicate that fluorolactone derivatives of ursolic acid have improved antiproliferative activity, acting through arrest of the cell cycle and induction of apoptosis. 相似文献
16.
A new class of nitrovinyl biphenyl compounds based on the structures of colchicines and allocolchicines were designed, synthesized, and shown to inhibit tubulin polymerization and cause mitotic arrest. A majority of these compounds were found to possess potent anticancer properties, with IC50 values in the range of 0.05–7 μM , and are equally potent with colchicine in HeLa and MCF‐7 cells. Compounds 14 e and 14 f inhibited tubulin assembly by more than 60 %, and flow cytometry studies indicated growth arrest of cells in the G2/M phase of the cell cycle in a concentration‐dependent manner. Treatment of cells with 14 f resulted in upregulation of cyclin B1 and aurora kinase B mRNA levels, corresponding to growth arrest in the G2/M phase of the cell cycle as the mode of action. 相似文献
17.
Structure–Activity Relationship of Tumor‐Selective 5‐Substituted 2‐Amino‐3‐carboxymethylthiophene Derivatives
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Dr. Joice Thomas Dr. Alenka Jejcic Peter Vervaeke Prof. Romeo Romagnoli Prof. Sandra Liekens Prof. Jan Balzarini Prof. Wim Dehaen 《ChemMedChem》2014,9(12):2744-2753
Methyl‐2‐amino‐5‐[2‐(4‐methoxyphenethyl)]thiophene‐3‐carboxylate ( 8 c ) is the prototype of a well‐defined class of tumor‐selective agents. Compound 8 c preferentially inhibited the proliferation of a number of tumor cell lines including many human T‐lymphoma/leukemia cells, but also several prostate, renal, central nervous system and liver tumor cell types. Instead, a broad variety of other tumor cell lines including B‐lymphomas and HeLa cells were not affected. The tumor selectivity (TS; selectivity index or preferential suppression of CEM lymphoma (IC50=0.90 μM ) versus HeLa tumor cell carcinoma (IC50=39 μM )) amounted up to ~43 for 8 c . At higher concentrations, the compound proved cytotoxic rather than cytostatic. The antiproliferative potency and selectivity of 8 c could be preserved by replacing the ethyl linker between the 2‐amino‐3‐carboxymethylthiophene and the substituted aryl by a thioalkyl but not by an oxyalkyl nor an aminoalkyl. Among >50 novel 8 c derivatives, the 5‐(4‐ethyl‐ and 4‐isopropylarylmethylthio)thiophene analogues, methyl‐2‐amino‐5‐((4‐ethylphenylthio)methyl)thiophene‐3‐carboxylate ( 13 m ) and methyl‐2‐amino‐5‐((4‐isopropylphenylthio)methyl)thiophene‐3‐carboxylate ( 13 n ), were more potent (IC50: 0.3–0.4 μM ) and selective (TS: 100–144) anti‐T‐lymphoma/leukemia agents than the prototype compound. 相似文献
18.
Synthesis and Biological Evaluation of Indole‐2‐carbohydrazide Derivatives as Anticancer Agents with Anti‐angiogenic and Antiproliferative Activities
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Jianqiang Zhang Tongyang Liu Mei Chen Feifei Liu Prof. Xingyuan Liu Prof. Jihong Zhang Prof. Jun Lin Prof. Yi Jin 《ChemMedChem》2018,13(12):1181-1192
A novel series of indole‐2‐carbohydrazide derivatives were synthesized, characterized, and evaluated for their antiproliferative activities against two cancer cell lines, HCT116 and SW480, and a normal human fetal lung fibroblast cell line, MRC‐5. Among this series, compound 24 f displayed potent cytotoxic activities in vitro against HCT116 and SW480 cell lines with GI50 values of 8.1 and 7.9 μm , respectively, and was inactive against MRC‐5 cells. The newly synthesized compounds were also evaluated for anti‐angiogenesis capabilities by chick chorioallantoic membrane, human umbilical vein endothelial cell (HUVEC) migration, and endothelial microtubule formation assays. Moreover, the effects of 24 f on the vascular endothelial growth factor receptor‐2 and the signaling pathway in HUVECs indicated that this compound inhibits VEGFR‐2 and its downstream related proteins. These results indicate that compound 24 f , as well as the other derivatives, are promising inhibitors of angiogenesis. 相似文献
19.
Development of Novel Selective Peptidomimetics Containing a Boronic Acid Moiety,Targeting the 20S Proteasome as Anticancer Agents
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Dr. Kety Scarbaci Dr. Valeria Troiano Dr. Roberta Ettari Dr. Andrea Pinto Dr. Nicola Micale Dr. Carmen Di Giovanni Dr. Carmen Cerchia Prof. Dr. Tanja Schirmeister Prof. Ettore Novellino Prof. Antonio Lavecchia Prof. Maria Zappalà Prof. Silvana Grasso 《ChemMedChem》2014,9(8):1801-1816
This paper describes the design, synthesis, and biological evaluation of peptidomimetic boronates as inhibitors of the 20S proteasome, a validated target in the treatment of multiple myeloma. The synthesized compounds showed a good inhibitory profile against the ChT‐L activity of 20S proteasome. Compounds bearing a β‐alanine residue at the P2 position were the most active, that is, 3‐ethylphenylamino and 4‐methoxyphenylamino (R)‐1‐{3‐[4‐(substituted)‐2‐oxopyridin‐1(2H)‐yl]propanamido}‐3‐methylbutylboronic acids ( 3 c and 3 d , respectively), and these derivatives showed inhibition constants (Ki) of 17 and 20 nM , respectively. In addition, they co‐inhibited post glutamyl peptide hydrolase activity ( 3 c , Ki=2.57 μM ; 3 d , Ki=3.81 μM ). No inhibition was recorded against the bovine pancreatic α‐chymotrypsin, which thus confirms the selectivity towards the target enzyme. Docking studies of 3 c and related inhibitors into the yeast proteasome revealed the structural basis for specificity. The evaluation of growth inhibitory effects against 60 human tumor cell lines was performed at the US National Cancer Institute. Among the selected compounds, 3 c showed 50 % growth inhibition (GI50) values at the sub‐micromolar level on all cell lines. 相似文献
20.
DNA‐modifying agents are stalwarts of chemotherapeutic cancer treatments, but require significant design improvements to improve selectivity, minimize side effects, and for their widespread use to continue. Herein we present a novel design strategy in which DNA‐modifying agents contain an oxidizable leaving group and a nitrogen mustard. The agents form strong electrophiles specifically when oxidized. Activation, measured by hydrolysis, illustrates that oxidants increase reactivity 1700‐fold. Reaction in the presence of 2′‐deoxyguanosine leads to the formation of lesions. Cytotoxicity measured in HeLa cells showed that low IC50 values require an oxidizable hydroquinone and a nitrogen mustard fragment. Cytotoxicity measurements in 15 cancer cell lines demonstrates that oxidatively activated DNA‐modifying agents are highly selective, as the analogue tested has IC50 values less than 10 μM for only three of the 15 cell lines; in contrast, cisplatin is highly toxic to 13 of the 15 cell lines. The selective cytotoxicity of oxidatively activated DNA‐damaging agents could be useful against kidney cancer cells, as the 786‐O cell line model assay resulted in an IC50 value of 5 μM . 相似文献