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Synthesis and antiproliferative evaluation of new zampanolide mimics
- Source :
- Organic & Biomolecular Chemistry. 17:3830-3844
- Publication Year :
- 2019
- Publisher :
- Royal Society of Chemistry (RSC), 2019.
-
Abstract
- (–)–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 IC(50) 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.
- Subjects :
- Antineoplastic Agents
010402 general chemistry
01 natural sciences
Biochemistry
Article
Structure-Activity Relationship
chemistry.chemical_compound
DU145
In vivo
Tumor Cells, Cultured
Side chain
Humans
Structure–activity relationship
Physical and Theoretical Chemistry
Cell Proliferation
Dose-Response Relationship, Drug
Molecular Structure
010405 organic chemistry
Cell growth
Organic Chemistry
Combinatorial chemistry
0104 chemical sciences
chemistry
Cancer cell
Macrolides
Bioisostere
Drug Screening Assays, Antitumor
Lead compound
Subjects
Details
- ISSN :
- 14770539 and 14770520
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- Organic & Biomolecular Chemistry
- Accession number :
- edsair.doi.dedup.....c997cfab809698057ae383f4d0950c72