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Issue 15, 2019
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Synthesis and antiproliferative evaluation of new zampanolide mimics

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(−)-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 β-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 α,β-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 μM 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.

Graphical abstract: Synthesis and antiproliferative evaluation of new zampanolide mimics

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Supplementary files

Article information

08 Mar 2019
25 Mar 2019
First published
25 Mar 2019

Org. Biomol. Chem., 2019,17, 3830-3844
Article type

Synthesis and antiproliferative evaluation of new zampanolide mimics

G. Chen, M. Patanapongpibul, Z. Jiang, Q. Zhang, S. Zheng, G. Wang, J. D. White and Q. Chen, Org. Biomol. Chem., 2019, 17, 3830
DOI: 10.1039/C9OB00556K

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