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格尔德霉素-阿魏酸缀合物作为一种有效的热休克蛋白90（Hsp90）抑制剂的合成及生物学评价

Synthesis and biological evaluation of geldanamycin-ferulic acid conjugate as a potent Hsp90 inhibitor.

作者信息

Li Zhenyu, Jia Lejiao, Tang Hui, Shen Yuemao, Shen Chengwu

机构信息

Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong University Jinan 250021 Shandong P. R. China

Department of Pharmacy, Shandong University Qilu Hospital No. 107 West Wenhua Road Jinan 250012 Shandong P. R. China.

出版信息

RSC Adv. 2019 Dec 23;9(72):42509-42515. doi: 10.1039/c9ra08665j. eCollection 2019 Dec 18.

DOI:10.1039/c9ra08665j
PMID:35542888
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9076653/
Abstract

A novel geldanamycin-ferulic acid conjugate LZY228 was prepared and evaluated for anti-proliferation activity on human cancer cell line MDA-MB-231. Compound LZY228 exhibited potent cytotoxicity with IC value of 0.27 μM, which was more potent than 17-AAG. Hepatotoxicity test in mice demonstrated that the levels of both AST and ALT of LZY228-treated group were lower than that of GA-treated group, indicating that LZY228 was a promising antitumor candidate. In addition, excellent antitumor potency of LZY228 was observed in MDA-MB-231 xenograft model, which was superior to reference drug 17-AAG. Docking and MD refinement of the Hsp90-LZY228 complex give us an explanation of theoretical binding model of 17-ferulamido-17-demethoxygeldanamycins at molecular level.

摘要

制备了一种新型格尔德霉素-阿魏酸共轭物LZY228，并对其在人癌细胞系MDA-MB-231上的抗增殖活性进行了评估。化合物LZY228表现出强大的细胞毒性，IC值为0.27μM，比17-AAG更具活性。小鼠肝毒性试验表明，LZY228治疗组的AST和ALT水平均低于GA治疗组，表明LZY228是一种有前景的抗肿瘤候选物。此外，在MDA-MB-231异种移植模型中观察到LZY228具有优异的抗肿瘤效力，优于参考药物17-AAG。Hsp90-LZY228复合物的对接和分子动力学精修从分子水平上解释了17-阿魏酰胺-17-去甲氧基格尔德霉素的理论结合模型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563d/9076653/f2ce00149925/c9ra08665j-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563d/9076653/741fe5220023/c9ra08665j-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563d/9076653/0144900d6d80/c9ra08665j-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563d/9076653/12b8c2fc77da/c9ra08665j-s1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563d/9076653/e2a614a5d612/c9ra08665j-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563d/9076653/fa8a1e14cb17/c9ra08665j-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563d/9076653/f2ce00149925/c9ra08665j-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563d/9076653/741fe5220023/c9ra08665j-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563d/9076653/0144900d6d80/c9ra08665j-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563d/9076653/12b8c2fc77da/c9ra08665j-s1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563d/9076653/e2a614a5d612/c9ra08665j-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563d/9076653/fa8a1e14cb17/c9ra08665j-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563d/9076653/f2ce00149925/c9ra08665j-f5.jpg

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