Novel pyrazolo[4,3-d]pyrimidine microtubule targeting agents (MTAs): Synthesis, structure-activity relationship, in vitro and in vivo evaluation as antitumor agents.
Novel pyrazolo[4,3-d]pyrimidine microtubule targeting agents (MTAs): Synthesis, structure-activity relationship, in vitro and in vivo evaluation as antitumor agents.
复制标题
新型吡唑并[4，3-d]嘧啶微管靶向剂(MTA)的合成、构效关系、体外和体内抗肿瘤活性评价。
DOI：
10.1016/j.bmcl.2021.127923
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发表时间：
2021-06-01
影响因子：
2.7
通讯作者：
Gangjee A
中科院分区：
文献类型：
--
作者：
Islam F;Quadery TM;Bai R;Luckett-Chastain LR;Hamel E;Ihnat MA;Gangjee A
本文介绍了一系列新型N1-甲基吡唑并[4，3-d]嘧啶类微管蛋白聚合和秋水仙碱结合抑制剂的设计、合成和生物活性评价。目标化合物的合成涉及吡唑并骨架的烷基化，得到两个区域异构体。用1H NMR和NOESY光谱对它们进行了分离、表征和鉴定。所有化合物，除了10，抑制[3 H]秋水仙碱结合微管蛋白，和有效的抑制与CA-4获得的类似。化合物9和11-13强烈抑制微管蛋白的聚合，其IC 50值分别为0.45、0.42、0.49和0.42 μM。化合物14-16抑制微管蛋白聚合，IC 50接近1 μM。化合物9、12、13和16抑制MCF-7乳腺癌细胞系并规避β III-微管蛋白介导的癌细胞对紫杉烷类和其它MTA的抗性，并且化合物9-17规避Pgp介导的药物抗性。在标准NCI测试方案中，化合物9对大多数肿瘤细胞系（包括几种多药耐药表型）表现出优异的效力，具有低至亚纳摩尔的GI 50值（≤10 nM）。在小鼠异种移植模型中，化合物9在减少MCF-7 TUBB 3（β III-微管蛋白过表达）肿瘤方面显著（P <0.0001）优于紫杉醇。总的来说，这些研究支持吡唑并[4，3-d]嘧啶支架作为新一代微管蛋白抑制剂和9作为优于紫杉醇的抗癌剂的进一步临床前开发。
The design, synthesis, and biological evaluation of a series novel N1‑methyl pyrazolo[4,3-d]pyrimidines as inhibitors of tubulin polymerization and colchicine binding were described here. Synthesis of target compounds involved alkylation of the pyrazolo scaffold, which afforded two regioisomers. These were separated, characterized and identified with 1H NMR and NOESY spectroscopy. All compounds, except 10, inhibited [3H] colchicine binding to tubulin, and the potent inhibition was similar to that obtained with CA-4. Compounds 9 and 11–13 strongly inhibited the polymerization of tubulin, with IC50 values of 0.45, 0.42, 0.49 and 0.42 μM, respectively. Compounds 14–16 inhibited the polymerization of tubulin with IC50s near ~1 μM. Compounds 9 12, 13 and 16 inhibited MCF-7 breast cancer cell lines and circumvented βIII-tubulin mediated cancer cell resistance to taxanes and other MTAs, and compounds 9–17 circumvented Pgp-mediated drug resistance. In the standard NCI testing protocol, compound 9 exhibited excellent potency with low to sub nanomolar GI50 values (≤10 nM) against most tumor cell lines, including several multidrug resistant phenotypes. Compound 9 was significantly (P <0.0001) better than paclitaxel at reducing MCF-7 TUBB3 (βIII-tubulin overexpressing) tumors in a mouse xenograft model. Collectively, these studies support the further preclinical development of the pyrazolo[4,3-d]pyrimidine scaffold as a new generation of tubulin inhibitors and 9 as an anticancer agent with advantages over paclitaxel.
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影响因子：
2.7
作者：
Devambatla RKV;Li W;Zaware N;Choudhary S;Hamel E;Mooberry SL;Gangjee A
通讯作者：
Gangjee A
影响因子：
3.5
作者：
Golani, Lalit K.;Islam, Farhana;Gangjee, Aleem
通讯作者：
Gangjee, Aleem
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：
5.5
作者：
Hao, MH
通讯作者：
Hao, MH
影响因子：
3.5
作者：
Pavana RK;Shah K;Gentile T;Dybdal-Hargreaves NF;Risinger AL;Mooberry SL;Hamel E;Gangjee A
通讯作者：
Gangjee A