Synthesis and antiproliferative evaluation of new zampanolide mimics
Synthesis and antiproliferative evaluation of new zampanolide mimics
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DOI：
10.1039/c9ob00556k
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发表时间：
2019-04-21
影响因子：
3.2
通讯作者：
Chen, Qiao-Hong
中科院分区：
文献类型：
--
作者：
Chen, Guanglin;Patanapongpibul, Manee;Chen, Qiao-Hong
（-）-赞潘生丁是一种海洋微管稳定性大环内酯，体外实验表明其是一种有前途的抗癌先导化合物。通过其独特的与β-微管蛋白的共价结合，赞潘生丁对多药耐药癌细胞表现出比紫杉醇更上级的细胞毒性。然而，有限的可利用性的赞潘鲁肽阻碍了其作为一个可行的候选药物的进一步体内评价。如果可以稳定其化学上脆弱的侧链，则Zampanlavine被设想为变得更像药物;因此，该项目旨在使用直接的合成方法开发具有稳定侧链的Zampanlavine的模拟物。为此，已经从可商购的2-丁炔-1-醇作为起始材料，通过24步序列合成了12种具有共轭和平面侧链的新型赞潘生丁模拟物（51-62）。Horner-Wadsworth-Emmons反应结合了α，β-不饱和酮侧链，并且还闭合了核心大环。在三种紫杉醇敏感性和两种紫杉醇耐药性人前列腺癌细胞模型中的WST-1细胞增殖测定证实，适当设计的侧链可以作为赞潘鲁肽中N-酰基半缩醛胺侧链的生物电子等排体。具有17 R手性中心的模拟物52被鉴定为最佳候选物，其对紫杉醇敏感的前列腺癌细胞系（PC-3和DU 145）和紫杉醇耐药的前列腺癌细胞系（PC-3/DTX和DU 145/DTX）的IC 50值为0.29-0.46 μ M。赞潘生丁模拟物52对紫杉醇敏感细胞系和紫杉醇抗性细胞系表现出相当的抗增殖效力，相对抗性在0.9-1.6的范围内。
(-)-Zampanolide is a marine microtubule-stabilizing macrolide that has been shown by in vitro experiments to be a promising anticancer lead compound. Through its unique covalent-binding with beta-tubulin, zampanolide exhibits cytotoxic potency towards multi-drug resistant cancer cells that is superior to paclitaxel. However, the limited availability of zampanolide impedes its further in vivo evaluation as a viable drug candidate. Zampanolide is envisioned to become more drug-like if its chemically fragile side chain can be stabilized; hence, this project aims to develop mimics of zampanolide with a stable side chain using straightforward synthetic methods. To this end, twelve novel zampanolide mimics (51-62) with conjugated and planar side chains have been synthesized via a 24-step sequence for each mimic from commercially available 2-butyn-1-ol as starting material. A Horner-Wadsworth-Emmons reaction incorporates the a, beta-unsaturated ketone side chain and also closes the core macrocycle. WST-1 cell proliferation assays in three docetaxel-sensitive and two docetaxel-resistant human prostate cancer cell models confirm that a suitably designed side chain can serve as a bioisostere for the N-acyl hemiaminal side chain in zampanolide. Mimic 52 with a 17R chiral center was identified as the optimal candidate with IC50 values of 0.29-0.46 mu M against both docetaxel-sensitive (PC-3 and DU145) and docetaxel-resistant prostate cancer cell lines (PC-3/DTX and DU145/DTX). Zampanolide mimic 52 exhibited equivalent antiproliferative potency towards both docetaxel-sensitive and docetaxel-resistant cell lines, with relative resistance in the range of 0.9-1.6.