Sterically induced conformational restriction: Discovery and preclinical evaluation of novel pyrrolo[3,2-d]pyrimidines as microtubule targeting agents.
Sterically induced conformational restriction: Discovery and preclinical evaluation of novel pyrrolo[3,2-d]pyrimidines as microtubule targeting agents.
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DOI：
10.1016/j.bmc.2018.09.025
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发表时间：
2018-11-01
影响因子：
3.5
通讯作者：
Gangjee A
中科院分区：
文献类型：
--
作者：
Pavana RK;Shah K;Gentile T;Dybdal-Hargreaves NF;Risinger AL;Mooberry SL;Hamel E;Gangjee A
报道了9个N-5取代吡咯并[3，2-d]嘧啶-4-胺的发现、合成及生物活性评价。鉴定了具有微管解聚活性的新化合物。这些化合物中的一些还规避了临床相关的肿瘤耐药机制（P-糖蛋白和βIII微管蛋白的表达）。化合物4、5和8-13是培养物中癌细胞的一至两位数纳摩尔（IC 50）抑制剂。与最近的报道（Banerjee et al. J. Med. Chem. 2018，61，1704-1718）相反，通过1H NMR和分子建模确定的最具活性化合物的构象与先前报道的相似，并与最近报道的X射线晶体结构一致。与对照相比，化合物11（作为HCl盐易溶于水）在三种异种移植模型[MDA-MB-435、MDA-MB-231和NCI/ADR-RES]中提供了统计学上显著的肿瘤生长抑制。化合物11没有表现出明显的动物毒性，目前正在进行进一步的临床前开发。
The discovery, synthesis and biological evaluations of a series of nine N5-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds with microtubule depolymerizing activity were identified. Some of these compounds also circumvent clinically relevant tumor resistance mechanisms (expression of P-glycoprotein and βIII tubulin). Compounds 4, 5, and 8–13 were one to two-digit nanomolar (IC50) inhibitors of cancer cells in culture. Contrary to recent reports (Banerjee et al. J. Med. Chem. 2018, 61, 1704–1718), the conformation of the most active compounds determined by 1H NMR and molecular modeling are similar to that reported previously and in keeping with recently reported x-ray crystal structures. Compound 11, freely water soluble as the HCl salt, afforded statistically significant inhibition of tumor growth in three xenograft models [MDA-MB-435, MDA-MB-231 and NCI/ADR-RES] compared with controls. Compound 11 did not display overt animal toxicity and is currently slated for further preclinical development.
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影响因子：
11.2
作者：
Risinger AL;Jackson EM;Polin LA;Helms GL;LeBoeuf DA;Joe PA;Hopper-Borge E;Ludueña RF;Kruh GD;Mooberry SL
通讯作者：
Mooberry SL
2,5-Diaryl-2,3-二氢-1,3,4-氧化二唑类类似物的设计，合成和生物学评估。
影响因子：
7.3
作者：
Lee L;Robb LM;Lee M;Davis R;Mackay H;Chavda S;Babu B;O'Brien EL;Risinger AL;Mooberry SL;Lee M
通讯作者：
Lee M
影响因子：
3.5
作者：
Pavana RK;Choudhary S;Bastian A;Ihnat MA;Bai R;Hamel E;Gangjee A
通讯作者：
Gangjee A
影响因子：
11.5
作者：
Komlodi-Pasztor, Edina;Sackett, Dan L.;Fojo, Antonio Tito
通讯作者：
Fojo, Antonio Tito
杂环稠合嘧啶作为针对秋水仙碱结合位点的新型微管蛋白聚合抑制剂：结构基础和抗肿瘤功效
影响因子：
7.3
作者：
Banerjee S;Arnst KE;Wang Y;Kumar G;Deng S;Yang L;Li GB;Yang J;White SW;Li W;Miller DD
通讯作者：
Miller DD