1. An amide mimic of desTHPdactylolide: Total synthesis and antiproliferative evaluation
- Author
-
Guanglin Chen, Maricarmen Gonzalez, Guangdi Wang, Qiang Zhang, Ziran Jiang, and Qiao-Hong Chen
- Subjects
Lactams ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,01 natural sciences ,Biochemistry ,Article ,Lactones ,chemistry.chemical_compound ,Prostate cancer ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Molecular Biology ,Cell Proliferation ,Natural product ,010405 organic chemistry ,Chemistry ,Cell growth ,Organic Chemistry ,Cancer ,Bridged Bicyclo Compounds, Heterocyclic ,medicine.disease ,0104 chemical sciences ,Androgen receptor ,010404 medicinal & biomolecular chemistry ,Cancer cell ,Lactam ,Molecular Medicine ,Bioisostere ,Drug Screening Assays, Antitumor - 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.
- Published
- 2021