Sidechain Diversification of Grandifloracin Allows Identification of Analogues with Enhanced Anti‐Austerity Activity against Human PANC‐1 Pancreatic Cancer Cells. (10th December 2019)

• Record Type: Journal Article
• Authors: Alexander, Benjamin E.; Sun, Sijia; Palframan, Matthew J.; Kociok‐Köhn, Gabriele; Dibwe, Dya Fita; Watanabe, Shiro; Caggiano, Lorenzo; Awale, Suresh; Lewis, Simon E.
• Is Part Of: ChemMedChem. Volume 15:Number 1(2020)
• Page Start: 125
• Page End: 135
• Publication Date: 2019-12-10
• Subjects: cancer -- nutrient deprivation -- antiproliferation -- dearomatization -- dimerization; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201900549
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Abstract : Austerity measures : Grandifloracin is a natural product that is known to exhibit anti‐austerity activity, i. e . it is able to abolish the ability of pancreatic cancer cells to survive under "austere" conditions of nutrient deprivation. Herein we report the synthesis and biological evaluation of analogues of grandifloracin, as well as our findings on rearrangement and fragmentation reactions of the dimeric grandifloracin core. Live imaging, fluorescence microscopy and colony formation experiments with the most active analogue are described.