School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
Shandong Peninsula Engineering Research Center of Comprehensive Brine Utilization, Weifang University of Science and Technology, Weifang 262700, Shandong, China.
Bioorg Med Chem. 2020 May 15;28(10):115435. doi: 10.1016/j.bmc.2020.115435. Epub 2020 Mar 13.
Plinabulin, a synthetic analog of the marine natural product "diketopiperazine phenylahistin," displayed depolymerization effects on microtubules and targeted the colchicine site, which has been moved into phase III clinical trials for the treatment of non-small cell lung cancer (NSCLC) and the prevention of chemotherapy-induced neutropenia (CIN). To develop more potent anti-microtubule and cytotoxic derivatives, the co-crystal complexes of plinabulin derivatives were summarized and analyzed. We performed further modifications of the tert-butyl moiety or C-ring of imidazole-type derivatives to build a library of molecules through the introduction of different groups for novel skeletons. Our structure-activity relationship study indicated that compounds 17o (IC = 14.0 nM, NCI-H460) and 17p (IC = 2.9 nM, NCI-H460) with furan groups exhibited potent cytotoxic activities at the nanomolar level against various human cancer cell lines. In particular, the 5-methyl or methoxymethyl substituent of furan group could replace the alkyl group of imidazole at the 5-position to maintain cytotoxic activity, contradicting previous reports that the tert-butyl moiety at the 5-position of imidazole was essential for the activity of such compounds. Immunofluorescence assay indicated that compounds 17o and 17p could efficiently inhibit microtubule polymerization. Overall, the novel furan-diketopiperazine-type derivatives could be considered as a potential scaffold for the development of anti-cancer drugs.
普兰布林是一种海洋天然产物“二酮哌嗪苯并海因”的合成类似物，对微管显示出解聚作用，并靶向秋水仙碱结合位点，该位点已进入非小细胞肺癌 (NSCLC) 治疗和预防化疗引起的中性粒细胞减少症 (CIN) 的 III 期临床试验。为了开发更有效的抗微管和细胞毒性衍生物，总结和分析了普兰布林衍生物的共晶复合物。我们进一步修饰了叔丁基部分或咪唑型衍生物的 C 环，通过引入不同的基团来构建分子库，从而构建新的骨架。我们的构效关系研究表明，具有呋喃基团的化合物 17o（IC=14.0 nM，NCI-H460）和 17p（IC=2.9 nM，NCI-H460）具有很强的细胞毒性活性，在纳摩尔水平上对各种人类癌细胞系表现出很强的细胞毒性活性。特别是，呋喃基团的 5-甲基或甲氧基取代基可以取代咪唑的 5-位上的烷基，以保持细胞毒性活性，这与先前的报告相反，即咪唑的 5-位上的叔丁基部分对这类化合物的活性是必不可少的。免疫荧光分析表明，化合物 17o 和 17p 能有效抑制微管聚合。总的来说，新型呋喃二酮哌嗪类衍生物可作为开发抗癌药物的潜在骨架。
