Sidechain Diversification of Grandifloracin Allows Identification of Analogues with Enhanced Anti-Austerity Activity against Human PANC-1 Pancreatic Cancer Cells

Benjamin E. Alexander, Sijia Sun, Matthew J. Palframan, Gabriele Kociok-Köhn, Dya Fita Dibwe, Shiro Watanabe, Lorenzo Caggiano, Suresh Awale, Simon E. Lewis

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Abstract

The natural product (+)-grandifloracin is a potent “anti-austerity” agent, able to suppress the ability of various pancreatic cancer cell lines to tolerate conditions of nutrient deprivation. Such anti-austerity agents represent a promising approach to cancer chemotherapy. Here we report the synthesis and biological evaluation of racemic analogues of grandifloracin bearing diverse sidechains, of which two show enhanced potency in comparison with the natural product. Additionally, several unexpected by-products containing modifications of the grandifloracin core were isolated, identified and similarly evaluated for biological activity.

Original languageEnglish
Pages (from-to)125-135
Number of pages11
JournalChemMedChem
Volume15
Issue number1
Early online date10 Dec 2019
DOIs
Publication statusPublished - 7 Jan 2020

Keywords

  • antiproliferation
  • cancer
  • dearomatization
  • dimerization
  • nutrient deprivation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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