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1.
Design,Synthesis, and in vitro Biological Evaluation of 3,5‐Dimethylisoxazole Derivatives as BRD4 Inhibitors 下载免费PDF全文
Xiangyang Li Jian Zhang Dr. Leilei Zhao Yifei Yang Prof. Huibin Zhang Prof. Jinpei Zhou 《ChemMedChem》2018,13(13):1363-1368
BRD4 has been identified as a potential target for blocking proliferation in a variety of cancer cell lines. In this study, 3,5‐dimethylisoxazole derivatives were designed and synthesized with excellent stability in liver microsomes as potent BRD4 inhibitors, and were evaluated for their BRD4 inhibitory activities in vitro. Gratifyingly, compound 11 h [3‐((1‐(2,4‐difluorophenyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl)‐6‐(3,5‐dimethylisoxazol‐4‐yl)‐4‐phenyl‐3,4‐dihydroquinazolin‐2(1H)‐one] exhibited robust potency for BRD4(1) and BRD4(2) inhibition with IC50 values of 27.0 and 180 nm , respectively. Docking studies were performed to illustrate the strategy of modification and analyze the conformation in detail. Furthermore, compound 11 h was found to potently inhibit cell proliferation in the BRD4‐sensitive cell lines HL‐60 and MV4‐11, with IC50 values of 0.120 and 0.09 μm , respectively. Compound 11 h was further demonstrated to downregulate c‐Myc levels in HL‐60 cells. In summary, these results suggest that compound 11 h is most likely a potential BRD4 inhibitor and is a lead compound for further investigations. 相似文献
2.
Dr. Julien Defaux Dr. Maud Antoine Prof. Marc Le Borgne Dr. Tilmann Schuster Dr. Irene Seipelt Dr. Babette Aicher Dr. Michael Teifel Dr. Eckhard Günther Dr. Matthias Gerlach Prof. Pascal Marchand 《ChemMedChem》2014,9(1):217-232
As part of our research projects to identify new chemical entities of biological interest, we developed a synthetic approach and the biological evaluation of (7‐aryl‐1,5‐naphthyridin‐4‐yl)ureas as a novel class of Aurora kinase inhibitors for the treatment of malignant diseases based on pathological cell proliferation. 1,5‐Naphthyridine derivatives showed excellent inhibitory activities toward Aurora kinases A and B, and the most active compound, 1‐cyclopropyl‐3‐[7‐(1‐methyl‐1H‐pyrazol‐4‐yl)‐1,5‐naphthyridin‐4‐yl]urea ( 49 ), displayed IC50 values of 13 and 107 nM against Aurora kinases A and B, respectively. In addition, the selectivity toward a panel of seven cancer‐related protein kinases was highlighted. In vitro ADME properties were also determined in order to rationalize the difficulties in correlating antiproliferative activity with Aurora kinase inhibition. Finally, the good safety profile of these compounds imparts promising potential for their further development as anticancer agents. 相似文献
3.
Identification of Aminoimidazole and Aminothiazole Derivatives as Src Family Kinase Inhibitors 下载免费PDF全文
Dr. Cinzia Maria Francini Dr. Anna Lucia Fallacara Dr. Roberto Artusi Dr. Laura Mennuni Dr. Alessia Calgani Dr. Adriano Angelucci Prof. Silvia Schenone Prof. Maurizio Botta 《ChemMedChem》2015,10(12):2027-2041
Src family kinases (SFKs) are a family of non‐receptor tyrosine kinases (TKs) implicated in the regulation of many cellular processes. The aberrant activity of these TKs has been associated with the growth and progression of cancer. In particular, c‐Src is overexpressed or hyperactivated in a variety of solid tumors and is most likely a strong promoting factor for the development of metastasis. Herein, the synthesis of new 4‐aminoimidazole and 2‐aminothiazole derivatives and their in vitro biological evaluation are described for their potential use as SFK inhibitors. Initially, 2‐aminothiazole analogues of dasatinib and 4‐aminoimidazole derivatives were synthesized and tested against the SFKs Src, Fyn, Lyn, and Yes. Five hits were identified as the most promising compounds, with Ki values in the range of 90–480 nm . A combination of molecular docking, homology modeling, and molecular dynamics were then used to investigate the possible binding mode of such compounds within the ATP binding site of the SFKs. Finally, the antiproliferative activities of the best candidates were evaluated against SH‐SY5Y and K562 cell lines. Compound 3 b [2‐(4‐{2‐methyl‐6‐[(5‐phenylthiazol‐2‐yl)amino]pyrimidin‐4‐yl}piperazin‐1‐yl)ethanol] was found to be the most active inhibitor. 相似文献
4.
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
5.
The Discovery of Potent Nonstructural Protein 5A (NS5A) Inhibitors with a Unique Resistance Profile—Part 1 下载免费PDF全文
Thien Duc Tran Florian Wakenhut Dr. Chris Pickford Stephen Shaw Dr. Mike Westby Caroline Smith‐Burchnell Lesa Watson Michael Paradowski Dr. Jared Milbank Dr. Rebecca A. Brimage Rebecca Halstead Dr. Rebecca Glen Dr. Craig P. Wilson Fiona Adam Duncan Hay Jean‐Yves Chiva Carly Nichols Dr. David C. Blakemore Iain Gardner Satish Dayal Dr. Andrew Pike Rob Webster Dr. David C. Pryde 《ChemMedChem》2014,9(7):1378-1386
Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol–Myers–Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl‐imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)‐1‐((S)‐2‐(4‐(4‐(6‐(2‐((S)‐1‐((methoxycarbonyl)‐L ‐valyl)pyrrolidin‐2‐yl)‐1H‐imidazol‐5‐yl)quinoxalin‐2‐yl)phenyl)‐1H‐imidazol‐2‐yl)pyrrolidin‐1‐yl)‐3‐methyl‐1‐oxobutan‐2‐yl)carbamate ( 17 ), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half‐life. This compound represents a promising lead that warrants further evaluation. 相似文献
6.
Synthesis and Biological Evaluation of Imidazo[2,1‐b][1,3,4]thiadiazole‐Linked Oxindoles as Potent Tubulin Polymerization Inhibitors 下载免费PDF全文
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
7.
Synthesis and Biological Evaluation of 1‐Methyl‐1H‐indole–Pyrazoline Hybrids as Potential Tubulin Polymerization Inhibitors 下载免费PDF全文
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
8.
Carbazole Aminoalcohols Induce Antiproliferation and Apoptosis of Human Tumor Cells by Inhibiting Topoisomerase I 下载免费PDF全文
Dr. Weisi Wang Xiao Sun Deheng Sun Dr. Shizhu Li Yang Yu Tingyuan Yang Junmin Yao Dr. Zhuo Chen Dr. Liping Duan 《ChemMedChem》2016,11(24):2675-2681
Novel carbazole aminoalcohols were designed and synthesized as anticancer agents. Among them, alkylamine‐chain‐substituted compounds showed the most promising antiproliferative activity, with IC50 values in the single‐digit micromolar range against two human tumor cell lines. Topoisomerase I (topo I) is likely to be one of the targets of these compounds. Results of comet assays and molecular docking indicate that the representative compounds may act as topo I poisons, causing single‐strand DNA damage by stabilizing the topo I–DNA cleavage complex. In particular, the most potent compound, 1‐(butylamino)‐3‐(3,6‐dichloro‐9H‐carbazol‐9‐yl)propan‐2‐ol ( 6 ), was shown to be able to induce G2‐phase cell‐cycle arrest and apoptosis in HeLa cells. 相似文献
9.
Design of gem‐Difluoro‐bis‐Tetrahydrofuran as P2 Ligand for HIV‐1 Protease Inhibitors to Improve Brain Penetration: Synthesis,X‐ray Studies,and Biological Evaluation 下载免费PDF全文
Prof. Dr. Arun K. Ghosh Sofiya Yashchuk Akira Mizuno Nilanjana Chakraborty Johnson Agniswamy Yuan‐Fang Wang Manabu Aoki Pedro Miguel Salcedo Gomez Masayuki Amano Prof. Irene T. Weber Dr. Hiroaki Mitsuya 《ChemMedChem》2015,10(1):107-115
The structure‐based design, synthesis, biological evaluation, and X‐ray structural studies of fluorine‐containing HIV‐1 protease inhibitors are described. The synthesis of both enantiomers of the gem‐difluoro‐bis‐THF ligands was carried out in a stereoselective manner using a Reformatskii–Claisen reaction as the key step. Optically active ligands were converted into protease inhibitors. Two of these inhibitors, (3R,3aS,6aS)‐4,4‐difluorohexahydrofuro[2,3‐b]furan‐3‐yl(2S,3R)‐3‐hydroxy‐4‐((N‐isobutyl‐4‐methoxyphenyl)sulfonamido)‐1‐phenylbutan‐2‐yl) carbamate ( 3 ) and (3R,3aS,6aS)‐4,4‐difluorohexahydrofuro[2,3‐b]furan‐3‐yl(2S,3R)‐3‐hydroxy‐4‐((N‐isobutyl‐4‐aminophenyl)sulfonamido)phenylbutan‐2‐yl) carbamate ( 4 ), exhibited HIV‐1 protease inhibitory Ki values in the picomolar range. Both 3 and 4 showed very potent antiviral activity, with respective EC50 values of 0.8 and 3.1 nM against the laboratory strain HIV‐1LAI. The two inhibitors exhibited better lipophilicity profiles than darunavir, and also showed much improved blood–brain barrier permeability in an in vitro model. A high‐resolution X‐ray structure of inhibitor 4 in complex with HIV‐1 protease was determined, revealing that the fluorinated ligand makes extensive interactions with the S2 subsite of HIV‐1 protease, including hydrogen bonding interactions with the protease backbone atoms. Moreover, both fluorine atoms on the bis‐THF ligand formed strong interactions with the flap Gly 48 carbonyl oxygen atom. 相似文献
10.
Synthesis,Biological Activity,and Mechanism of Action of 2‐Pyrazyl and Pyridylhydrazone Derivatives,New Classes of Antileishmanial Agents 下载免费PDF全文
Dr. Elaine S. Coimbra Dr. Luciana M. R. Antinarelli Mariana de A. Crispi Dr. Thais C. M. Nogueira Dr. Alessandra C. Pinheiro Dr. Marcus V. N. de Souza 《ChemMedChem》2018,13(14):1387-1394
In this work, we report the antileishmanial activity of 23 compounds based on 2‐pyrazyl and 2‐pyridylhydrazone derivatives. The compounds were tested against the promastigotes of Leishmania amazonensis and L. braziliensis, murine macrophages, and intracellular L. amazonensis amastigotes. The most potent antileishmanial compound was selected for investigation into its mechanism of action. Among the evaluated compounds, five derivatives [(E)‐3‐((2‐(pyridin‐2‐yl)hydrazono)methyl)benzene‐1,2‐diol ( 2 b ), (E)‐4‐((2‐(pyridin‐2‐yl)hydrazono)methyl)benzene‐1,3‐diol ( 2 c ), (E)‐4‐nitro‐2‐((2‐(pyrazin‐2‐yl)hydrazono)methyl)phenol ( 2 s ), (E)‐2‐(2‐(pyridin‐2‐ylmethylene)hydrazinyl)pyrazine ( 2 u ), and (E)‐2‐(2‐((5‐nitrofuran‐2‐yl)methylene)hydrazinyl)pyrazine ( 2 v )] exhibited significant activity against L. amazonensis amastigote forms, with IC50 values below 20 μm . The majority of the compounds did not show any toxic effect on murine macrophages. Preliminary studies on the mode of action of members of this hydrazine‐derived series indicate that the accumulation of reactive oxygen species (ROS) and disruption of parasite mitochondrial function are important for the pharmacological effect on L. amazonensis promastigotes. 相似文献
11.
Prof. Guofan Jin Fuyan Xiao Zhenwang Li Dr. Xueyong Qi Dr. Lei Zhao Prof. Xianyu Sun 《ChemMedChem》2020,15(7):600-609
A series of novel quinoline and quinolinium iodide derivatives were designed and synthesized to discover potential anticancer and antibacterial agents. With regard to anticancer properties, in vitro cytotoxicities against three human cancer cell lines (A-549, HeLa and SGC-7901) were evaluated. The antibacterial properties against two strains, Escherichia coli (ATCC 29213) and Staphylococcus aureus (ATCC 8739), along with minimum inhibitory concentration (MIC) values were evaluated. The target alkyliodine substituted compounds exhibited significant antitumor and antibacterial activity, of which compound 8-((4-(benzyloxy)phenyl)amino)-7-(ethoxycarbonyl)-5-propyl-[1,3]dioxolo[4,5-g]quinolin-5-ium ( 12 ) was found to be the most potent derivative with IC50 values of 4.45±0.88, 4.74±0.42, 14.54±1.96, and 32.12±3.66 against A-549, HeLa, SGC-7901, and L-02 cells, respectively, stronger than the positive controls 5-FU and MTX. Furthermore, compound 12 had the most potent bacterial inhibitory activity. The MIC of this compound against both E. coli and S. aureus was 3.125 nmol ⋅ mL−1, which was smaller than that against the reference agents amoxicillin and ciprofloxacin. 相似文献
12.
Synthesis and Biological Evaluation of Benzo[b]furans as Inhibitors of Tubulin Polymerization and Inducers of Apoptosis 下载免费PDF全文
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
13.
Dr. Variam U. Jeankumar Dr. Shalini Saxena Dr. Rahul Vats Rudraraju Srilakshmi Reshma Renuka Janupally Dr. Pushkar Kulkarni Prof. Perumal Yogeeswari Prof. Dharmarajan Sriram 《ChemMedChem》2016,11(5):539-548
In this study we explored the pharmaceutically underexploited ATPase domain of DNA gyrase (GyrB) as a potential platform for developing novel agents that target Mycobacterium tuberculosis. In this effort a combination of ligand‐ and structure‐based pharmacophore modeling was used to identify structurally diverse small‐molecule inhibitors of the mycobacterial GyrB domain based on the crystal structure of the enzyme with a pyrrolamide inhibitor (PDB ID: 4BAE ). Pharmacophore modeling and subsequent in vitro screening resulted in an initial hit compound 5 [(E)‐5‐(5‐(2‐(1H‐benzo[d]imidazol‐2‐yl)‐2‐cyanovinyl)furan‐2‐yl)isophthalic acid; IC50=4.6±0.1 μm ], which was subsequently tailored through a combination of molecular modeling and synthetic chemistry to yield the optimized lead compound 24 [(E)‐3‐(5‐(2‐cyano‐2‐(5‐methyl‐1H‐benzo[d]imidazol‐2‐yl)vinyl)thiophen‐2‐yl)benzoic acid; IC50=0.3±0.2 μm ], which was found to display considerable in vitro efficacy against the purified GyrB enzyme and potency against the H37Rv strain of M. tuberculosis. Structural handles were also identified that will provide a suitable foundation for further optimization of these potent analogues. 相似文献
14.
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
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.
Tihomir Tomašić Nace Zidar Andreja Kovač Dr. Samo Turk Mihael Simčič Didier Blanot Dr. Manica Müller‐Premru Prof. Dr. Metka Filipič Prof. Dr. Simona Golič Grdadolnik Prof. Dr. Anamarija Zega Prof. Dr. Marko Anderluh Prof. Dr. Stanislav Gobec Prof. Dr. Danijel Kikelj Prof. Dr. Lucija Peterlin Mašič Prof. Dr. 《ChemMedChem》2010,5(2):286-295
Mur ligases participate in the intracellular path of bacterial peptidoglycan biosynthesis and constitute attractive, although so far underexploited, targets for antibacterial drug discovery. A series of hydroxy‐substituted 5‐benzylidenethiazolidin‐4‐ones were synthesized and tested as inhibitors of Mur ligases. The most potent compound 5 a was active against MurD–F with IC50 values between 2 and 6 μm, making it a promising multitarget inhibitor of Mur ligases. Antibacterial activity against different strains, inhibitory activity against protein kinases, mutagenicity and genotoxicity of 5 a were also investigated, and kinetic and NMR studies were conducted. 相似文献
17.
Design and Synthesis of Imidazo[2,1‐b]thiazole–Chalcone Conjugates: Microtubule‐Destabilizing Agents 下载免费PDF全文
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
18.
Effects of the Tumor‐Vasculature‐Disrupting Agent Verubulin and Two Heteroaryl Analogues on Cancer Cells,Endothelial Cells,and Blood Vessels 下载免费PDF全文
Katharina Mahal Dr. Marcus Resch Prof. Dr. Ralf Ficner Prof. Dr. Rainer Schobert Dr. Bernhard Biersack Dr. Thomas Mueller 《ChemMedChem》2014,9(4):847-854
Two analogues of the discontinued tumor vascular‐disrupting agent verubulin (Azixa®, MPC‐6827, 1 ) featuring benzo‐1,4‐dioxan‐6‐yl (compound 5 a ) and N‐methylindol‐5‐yl (compound 10 ) residues instead of the para‐anisyl group on the 4‐(methylamino)‐2‐methylquinazoline pharmacophore, were prepared and found to exceed the antitumor efficacy of the lead compound. They were antiproliferative with single‐digit nanomolar IC50 values against a panel of nine tumor cell lines, while not affecting nonmalignant fibroblasts. Indole 10 surpassed verubulin in seven tumor cell lines including colon, breast, ovarian, and germ cell cancer cell lines. In line with docking studies indicating that compound 10 may bind the colchicine binding site of tubulin more tightly (Ebind=?9.8 kcal mol?1) than verubulin (Ebind=?8.3 kcal mol?1), 10 suppressed the formation of vessel‐like tubes in endothelial cells and destroyed the blood vessels in the chorioallantoic membrane of fertilized chicken eggs at nanomolar concentrations. When applied to nude mice bearing a highly vascularized 1411HP germ cell xenograft tumor, compound 10 displayed pronounced vascular‐disrupting effects that led to hemorrhages and extensive central necrosis in the tumor. 相似文献
19.
Discovery of Quinoline‐Derived Trifluoromethyl Alcohols,Determination of Their in vivo Toxicity and Anticancer Activity in a Zebrafish Embryo Model 下载免费PDF全文
Prof. Dr. Vinoth Sittaramane Jihan Padgett Philip Salter Ashley Williams Shauntelle Luke Rebecca McCall Prof. Dr. Jonathan F. Arambula Vincent B. Graves Mark Blocker David Van Leuven Keturah Bowe Julia Heimberger Hannah C. Cade Supriya Immaneni Prof. Dr. Abid Shaikh 《ChemMedChem》2015,10(11):1802-1807
In this study the rational design, synthesis, and anticancer activity of quinoline‐derived trifluoromethyl alcohols were evaluated. Members of this novel class of trifluoromethyl alcohols were identified as potent growth inhibitors in a zebrafish embryo model. Synthesis of these compounds was carried out with an sp3‐C?H functionalization strategy of methyl quinolines with trifluoromethyl ketones. A zebrafish embryo model was also used to explore the toxicity of ethyl 4,4,4‐trifluoro‐3‐hydroxy‐3‐(quinolin‐2‐ylmethyl)butanoate ( 1 ), 2‐benzyl‐1,1,1‐trifluoro‐3‐(quinolin‐2‐yl)propan‐2‐ol ( 2 ), and trifluoro‐3‐(isoquinolin‐1‐yl)‐2‐(thiophen‐2‐yl)propan‐2‐ol ( 3 ). Compounds 2 and 3 were found to be more toxic than compound 1 ; apoptotic staining assays indicated that compound 3 causes increased cell death. In vitro cell proliferation assays showed that compound 2 , with an LC50 value of 14.14 μm , has more potent anticancer activity than cisplatin. This novel class of inhibitors provides a new direction in the discovery of effective anticancer agents. 相似文献
20.
Indene Compounds Synthetically Derived from Vitamin D Have Selective Antibacterial Action on Helicobacter pylori 下载免费PDF全文
Kiyofumi Wanibuchi Kouichi Hosoda Masato Ihara Kentaro Tajiri Yuki Sakai Hisashi Masui Takashi Takahashi Yoshikazu Hirai Hirofumi Shimomura 《Lipids》2018,53(4):393-401
Helicobacter pylori infects the human stomach and is closely linked with the development of gastric cancer. When detected, this pathogen can be eradicated from the human stomach using wide‐spectrum antibiotics. However, year by year, H. pylori strains resistant to the antibacterial action of antibiotics have been increasing. The development of new antibacterial substances effective against drug‐resistant H. pylori is urgently required. Our group has recently identified extremely selective bactericidal effects against H. pylori in (1R,3aR,7aR)‐1‐[(1R)‐1,5‐dimethylhexyl]octahydro‐7a‐methyl‐4H‐inden‐4‐one (VDP1) (otherwise known as Grundmann's ketone), an indene compound derived from the decomposition of vitamin D3 and proposed the antibacterial mechanism whereby VDP1 induces the bacteriolysis by interacting at least with PtdEtn (dimyristoyl‐phosphatidylethanolamine [di‐14:0 PtdEtn]) retaining two 14:0 fatty acids of the membrane lipid constituents. In this study, we synthesized new indene compounds ((1R,3aR,7aR)‐1‐((2R,E)‐5,6‐dimethylhept‐3‐en‐2‐yl)‐7a‐methyloctahydro‐4H‐inden‐4‐one [VD2‐1], (1R,3aR,7aR)‐1‐((S)‐1‐hydroxypropan‐2‐yl)‐7a‐methyloctahydro‐1H‐inden‐4‐ol [VD2‐2], and (1R,3aR,7aR)‐7a‐methyl‐1‐((R)‐6‐methylheptan‐2‐yl)octahydro‐1H‐inden‐4‐ol [VD3‐1]) using either vitamin D2 or vitamin D3 as materials. VD2‐1 and VD3‐1 selectively disrupted the di‐14:0 PtdEtn vesicles without destructing the vesicles of PtdEtn (dipalmitoyl‐phosphatidylethanolamine) retaining two 16:0 fatty acids. In contrast, VD2‐2, an indene compound lacking an alkyl group, had no influence on the structural stability of both PtdEtn vesicles. In addition, VD2‐1 and VD3‐1 exerted extremely selective bactericidal action against H. pylori without affecting the viability of commonplace bacteria. Meanwhile, VD2‐2 almost forfeited the bactericidal effects on H. pylori. These results suggest that the alkyl group of the indene compounds has a crucial conformation to interact with di‐14:0 PtdEtn of H. pylori membrane lipid constituents whereby the bacteriolysis is ultimately induced. 相似文献