Condensation Domain Editing of the FR900359 Assembly Line Yields a Novel Analog Amenable to Late‐Stage Functionalization

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.