212262-55-0Relevant articles and documents
Synthesis and evaluation of antiproliferative microtubule-destabilising combretastatin A-4 piperazine conjugates
O'Boyle, Niamh M.,Ana, Gloria,Kelly, Patrick M.,Nathwani, Seema M.,Noorani, Sara,Fayne, Darren,Bright, Sandra A.,Twamley, Brendan,Zisterer, Daniela M.,Meegan, Mary J.
supporting information, p. 6184 - 6200 (2019/07/04)
Microtubules are a validated clinical target for the treatment of many cancers. We describe the design, synthesis, biochemical evaluation, and molecular modelling studies of a series of analogues of the microtubule-destabilising agent, combretastatin A-4 (CA-4). Our series of 33 novel compounds contain the CA-4 core structure with modifications to the stilbene linking group, and are predominantly piperazine derivatives. Synthesis was achieved in a two-step process by firstly obtaining the acrylic acid via a Perkin reaction using microwave enhanced synthesis, followed by coupling using either DCC or Mukaiyama's reagent. All target compounds were screened for antiproliferative activity in MCF-7 breast cancer cells. Hydroxyl derivative (E)-3-(4-hydroxy-3-methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-2-(3,4,5-trimethoxyphenyl) propenone (4m) displayed potent antiproliferative activity (IC50 = 190 nM). Two amino-containing derivatives, (E)-3-(3-amino-4-methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-2-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (4q) and (E)-3-(3-amino-4-methoxyphenyl)-1-(4-(p-tolyl)piperazin-1-yl)-2-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (4x), were the most potent with IC50 values of 130 nM and 83 nM respectively. Representative compounds were shown to depolymerise tubulin, induce G2/M arrest and apoptosis in MCF-7 cells but not peripheral blood mononuclear cells, and induce cleavage of the DNA repair enzyme poly ADP ribose polymerase (PARP) in MCF-7 cells. Modelling studies predict that the compounds bind to tubulin within the colchicine-binding site. These compounds are a valuable addition to the library of CA-4 analogues and 4m, 4q and 4x will be developed further as novel, water-soluble molecules targeting microtubules.
Synthesis and mechanistic studies of novel spin-labeled combretastatin derivatives as potential antineoplastic agents
Liu, Ying-Qian,Li, Xiao-Jing,Zhao, Chun-Yan,Nan, Xiang,Tian, Jing,Morris-Natschke, Susan L.,Zhang, Zhi-Jun,Yang, Xiao-Ming,Yang, Liu,Li, Lin-Hai,Zhou, Xing-Wen,Lee, Kuo-Hsiung
, p. 1248 - 1256 (2013/03/14)
Two series (14a-d and 21a-h) of novel spin-labeled combretastatin derivatives were synthesized and evaluated for cytotoxicity against four tumor cell lines (K562, SGC-7901, Hela and HepG-2). Simultaneously, a representative compound 21a was selected to investigate the antitumor mechanisms of these synthetic compounds. The results indicated that some of the compounds showed significant cytotoxicity against four tumor cell lines in vitro and were more active than etoposide, a clinically available anticancer drug. Among the newly synthesized compounds, 21a, 21b and 21c displayed the greatest cytotoxicity against three tested tumor cell lines (HEPG-2, BGC-832 and Hela), with IC 50 values ranging from 0.15 to 1.05 μM, compared with values of 0.014-0.403 μM for 3-amino-deoxycombretastatin A-4 (3). In addition, the mechanistic analysis revealed that compound 21a effectively interfered with tubulin dynamics to prevent mitosis in cancer cells, leading to cell cycle arrest and, eventually, dose dependent apoptosis.
Synthesis and biological evaluation of 4β-acrylamidopodophyllotoxin congeners as DNA damaging agents
Kamal, Ahmed,Suresh, Paidakula,Janaki Ramaiah,Mallareddy, Adla,Kumar, Banala Ashwini,Raju, Paidakula,Vinay Gopal,Pushpavalli,Lavanya,Sarma, Pranjal,Pal-Bhadra, Manika
experimental part, p. 4589 - 4600 (2011/09/19)
A series of new 4β-acrylamidopodophyllotoxin derivatives (13a-o) were synthesized by coupling of substituted acrylic acids (10a-l and 11m-o) to the 4β-aminopodophyllotoxin. The synthesized derivatives 13a-o were evaluated for their cytotoxicity against fi
