Design, synthesis, and structure-activity relationships of pyrimido[4,5-b]indole-4-amines as microtubule depolymerizing agents that are effective against multidrug resistant cells.
Design, synthesis, and structure-activity relationships of pyrimido[4,5-b]indole-4-amines as microtubule depolymerizing agents that are effective against multidrug resistant cells.
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DOI：
10.1016/j.bmcl.2017.05.085
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发表时间：
2017-08-01
影响因子：
2.7
通讯作者：
Gangjee A
中科院分区：
文献类型：
--
作者：
Devambatla RKV;Li W;Zaware N;Choudhary S;Hamel E;Mooberry SL;Gangjee A
为了确定9h -嘧啶[4,5-b]吲哚作为微管解聚剂的结构特征，设计并合成了在2-、4-和5位上具有不同取代基的嘧啶[4,5-b]吲哚2- 8。2,5-取代-4-氯-嘧啶[4,5-b]吲哚与适当的芳胺的亲核置换是合成目标化合物2 - 8的最后一步。化合物2和6在体外对MDA-MB-435、SK-OV-3和HeLa癌细胞具有两位数纳摩尔效价（IC50）。化合物2和6也能解聚微管，与先导化合物1类似。化合物2、3、6和8在表达p -糖蛋白或微管蛋白βIII同型的细胞中有效，这与临床对微管靶向药物的耐药机制有关。采用质子核磁共振和分子模型研究确定了嘧啶[4,5-b]吲哚微管解聚活性的结构基础。
To identify the structural features of 9H-pyrimido[4,5-b]indoles as microtubule depolymerizers, pyrimido[4,5-b]indoles 2–8 with varied substituents at the 2-, 4- and 5-positions were designed and synthesized. Nucleophilic displacement of 2,5-substituted-4-chloro- pyrimido[4,5-b]indoles with appropriate arylamines was the final step employed in the synthesis of target compounds 2–8. Compounds 2 and 6 had two-digit nanomolar potency (IC50) against MDA-MB-435, SK-OV-3 and HeLa cancer cells in vitro. Compounds 2 and 6 also depolymerized microtubules comparable to the lead compound 1. Compounds 2, 3, 6 and 8 were effective in cells expressing P-glycoprotein or the βIII isotype of tubulin, mechanisms that are associated with clinical drug resistance to microtubule targeting drugs. Proton NMR and molecular modeling studies were employed to identify the structural basis for the microtubule depolymerizing activity of pyrimido[4,5-b]indoles.
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影响因子：
7.3
作者：
Gangjee, Aleem;Zaware, Nilesh;Raghavan, Sudhir;Ihnat, Michael;Shenoy, Satyendra;Kisliuk, Roy L.
通讯作者：
Kisliuk, Roy L.
影响因子：
11.5
作者：
Nathan, Paul;Zweifel, Martin;Judson, Ian
通讯作者：
Judson, Ian
影响因子：
3.6
作者：
AbdelMagid, AF;Carson, KG;Shah, RD
通讯作者：
Shah, RD
影响因子：
7.3
作者：
Gangjee, Aleem;Zhao, Ying;Hamel, Ernest
通讯作者：
Hamel, Ernest
影响因子：
3.4
作者：
Harrison, Michael R.;Hahn, Noah M.;Liu, Glenn
通讯作者：
Liu, Glenn