An Amide Mimic of DesTHPdactylolide: Total Synthesis and Antiproliferative Evaluation

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2021 Mar 23

PMID 33753258

Citations 1

Authors

Guanglin Chen

Maricarmen Gonzalez

Ziran Jiang

Qiang Zhang

Guangdi Wang

Qiao-Hong Chen

Affiliations

Soon will be listed here.

Abstract

(-)-Zampanolide is a unique microtubule stabilizing agent (MSA) with covalent-binding mechanism and low nanomolar anitproliferative potency towards multi-drug resistant cancer cells. MSAs have a special connection with prostate cancer by inhibiting androgen receptor nuclear translocation. Zampanolide and the structurally related dactylolide have thus been sought after by us as lead compounds for development of anti-prostate cancer agents. DesTHPdactylolide is a simplified mimic of dactylolide and has previously been synthesized by us in both configurations, with the (17R) configuration being more potent in suppressing prostate cancer cell proliferation. The current study aims to synthesize an amide mimic of (17R) desTHPdactylolide that was anticipated to be metabolically more stable than (17R) desTHPdactylolide. To this end, the amide mimic has been successfully synthesized through a 26-step transformation from 2-butyn-1-ol. Our WST-1 cell proliferation assay in five human prostate cancer cell models indicated that the lactam moiety can serve as a bioisostere for the lactone in desTHPdactylolide.

Citing Articles

In Vivo Evaluation of (-)-Zampanolide Demonstrates Potent and Persistent Antitumor Efficacy When Targeted to the Tumor Site.

Takahashi-Ruiz L, Morris J, Crews P, Johnson T, Risinger A Molecules. 2022; 27(13).

PMID: 35807495 PMC: 9268097. DOI: 10.3390/molecules27134244.

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