Design, synthesis, and biological evaluation of (E)-N-aryl-2-arylethenesulfonamide analogues as potent and orally bioavailable microtubule-targeted anticancer agents.
Design, synthesis, and biological evaluation of (E)-N-aryl-2-arylethenesulfonamide analogues as potent and orally bioavailable microtubule-targeted anticancer agents.
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（E）-N-芳基-2-芳基甲磺酰胺类似物的设计，合成和生物学评估是有效和口服可生物可用的微管靶向抗癌剂。
DOI：
10.1021/jm400575x
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发表时间：
2013-07-11
影响因子：
7.3
通讯作者：
Reddy EP
中科院分区：
文献类型：
--
作者：
Reddy MV;Mallireddigari MR;Pallela VR;Cosenza SC;Billa VK;Akula B;Subbaiah DR;Bharathi EV;Padgaonkar A;Lv H;Gallo JM;Reddy EP
合成了一系列新的（E）-N-芳基-2-芳基乙烯磺酰胺类化合物（6），并对其抗癌活性进行了评价。该系列中的一些化合物对广泛的癌细胞系（IC 50值范围为5至10 nM）显示出强效的细胞毒性，包括所有耐药细胞系。用化合物（E）-N-（3-氨基-4-甲氧基苯基）-2-（2′，4 ′，6 ′-三甲氧基苯基）乙烯磺酰胺（6 t）进行的裸鼠异种移植物测定显示肿瘤大小显著减小，表明它们作为抗癌剂的体内潜力。化合物6 t的初步药物开发研究预测相对于许多临床使用的抗有丝分裂剂具有增加的血脑屏障渗透性。机制研究表明，6 t和其他一些类似物破坏微管的形成，有丝分裂纺锤体的形成和有丝分裂期的细胞停滞。化合物6 t在体外和体内抑制纯化的微管蛋白聚合，并规避P-糖蛋白介导的耐药性。化合物6 t特异性地与秋水仙碱竞争结合微管蛋白，并且具有与鬼臼毒素相似的亲合力，表明其在微管蛋白上的结合位点。
A series of novel (E)-N-aryl-2-arylethenesulfonamides (6) were synthesized and evaluated for their anticancer activity. Some of the compounds in this series showed potent cytotoxicity against a wide spectrum of cancer cell-lines (IC50 values ranging from 5 to 10 nM) including all drug resistant cell-lines. Nude mice xenograft assays with compound (E)-N-(3-Amino-4-methoxyphenyl)-2-(2′,4′,6′-trimethoxyphenyl)ethenesulfonamide (6t) showed dramatic reduction in tumor size indicating their in vivo potential as anticancer agents. A preliminary drug development study with compound 6t is predicted to have increased blood-brain barrier permeability relative to many clinically used anti-mitotic agents. Mechanistic studies indicate that 6t and some other analogs disrupted microtubule formation, formation of mitotic spindles and arrest of cells in mitotic phase. Compound 6t inhibited purified tubulin polymerization in vitro and in vivo and circumvented drug resistance mediated by P-glycoprotein. Compound 6t specifically competed with colchicine binding to tubulin and with similar avidity as podophylltoxin indicating its binding site on tubulin.
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影响因子：
2.7
作者：
Kemnitzer, William;Sirisoma, Nilantha;Cai, Sui Xiong
通讯作者：
Cai, Sui Xiong
影响因子：
8.8
作者：
通讯作者：
--
DOI：
10.2174/1568011023354290
发表时间：
2002-01-01
期刊：
Current Medicinal Chemistry - Anti-Cancer Agents
影响因子：
--
作者：
Jordan, M. A.
通讯作者：
Jordan, M. A.
卤代苄基秋水仙碱 B 环类似物的合成和生物学评价
影响因子：
7.3
作者：
Cosentino, Laura;Redondo-Horcajo, Mariano;Pors, Klaus
通讯作者：
Pors, Klaus
影响因子：
7.3
作者：
Ballatore, Carlo;Brunden, Kurt R.;Huryn, Donna M.;Trojanowski, John Q.;Lee, Virginia M. -Y.;Smith, Amos B., III
通讯作者：
Smith, Amos B., III