Pistorius, Dominik, Richard, Etienne, Buntin, Kathrin, Dresen, Kathrin, Wollbrett, Severine, Weber, Eric, Haberkorn, Anne and Petersen, Frank (2024) Condensation domain editing of the FR900359 assembly line yield a novel analog amenable to late-stage functionalization. ChemBioChem. ISSN 1439-42271439-7633

Abstract

The natural product FR900359 (FR) has generated significant attention lately, due to its characteristics as potent and selective inhibitor of Gq/11 mediated signal transduction of associated G protein-coupled receptors (GPCRs). This makes FR both a widely used pharmacological tool compound and a lead molecule for targeted cancer therapy. The exploration of structure-activity-relationship (SAR) of the scaffold by total synthesis has been complicated by its structural complexity and its incompatibility with standard approaches of solid-phase peptide synthesis. Options for late-stage functionalization of FR are limited due to a lack of tractable functional groups. Here we present a mixed approach combining i) genetic engineering of the FR-assembly line in Chromobacterium vaccinii, to obtain a novel FR analog featuring a primary amine, with ii) its subsequent synthetic modification and biological profiling for further SAR exploration of the FR scaffold.

Item Type:	Article
Keywords:	FR900359 natural products genetic engineering late-stage functionalization uveal melanoma
Date Deposited:	28 Sep 2024 00:45
Last Modified:	28 Sep 2024 00:45
URI:	https://oak.novartis.com/id/eprint/54144