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

The natural product FR900359 (FR) has generated significant attention lately, due to its characteristics as potent and selective inhibitor of G_q/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.