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

doi:10.1002/cmdc.201900549

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

^*Corresponding author for this work

Section of Host Defences, Division of Bioscience, Institute of Natural Medicine
Section of Natural Products & Drug Discovery, Division of Medicinal Resources, Institute of Natural Medicine

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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 language	English
Pages (from-to)	125-135
Number of pages	11
Journal	ChemMedChem
Volume	15
Issue number	1
DOIs	https://doi.org/10.1002/cmdc.201900549
State	Published - 2020/01/07

Keywords

antiproliferation
cancer
dearomatization
dimerization
nutrient deprivation

ASJC Scopus subject areas

Drug Discovery
General Pharmacology, Toxicology and Pharmaceutics
Molecular Medicine
Biochemistry
Pharmacology
Organic Chemistry

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

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.",

keywords = "antiproliferation, cancer, dearomatization, dimerization, nutrient deprivation",

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note = "Publisher Copyright: {\textcopyright} 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.",

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month = jan,

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doi = "10.1002/cmdc.201900549",

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AU - Sun, Sijia

AU - Palframan, Matthew J.

AU - Kociok-Köhn, Gabriele

AU - Dibwe, Dya Fita

AU - Watanabe, Shiro

AU - Caggiano, Lorenzo

AU - Awale, Suresh

AU - Lewis, Simon E.

PY - 2020/1/7

Y1 - 2020/1/7

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AB - 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.

KW - antiproliferation

KW - cancer

KW - dearomatization

KW - dimerization

KW - nutrient deprivation

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

Abstract

Keywords

ASJC Scopus subject areas

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