Synthesis and biological evaluation of a post-synthetically modified Trp-based diketopiperazine

Abstract

A series of C2-arylated analogues of the diketopiperazine brevianamide F has been synthesized using a mild Pd-catalyzed CH-activation procedure. Biological evaluation of the new derivatives in different cell lines shows that this modification is responsible for the remarkable change in activity, turning a mild antibiotic and antifungal natural product (brevianamide F) into novel antitumoral compounds.Furthermore, the approach stated represents a new straightforward and versatile methodology with promising applications in peptidomimetics and medicinal chemistry.

New peptide architectures through C–H activation stapling between tryptophan–phenylalanine/tyrosine residues

“…The initial experiments were carried out using the conditions previously applied in the arylation of the Trp diketopiperazine: 41 Overall, 5 mol% Pd(OAc) 2 , AgBF 4 (1.0 eq.) and o -nitrobenzoic acid (2-NO 2 BzOH) (1.5 eq.)…”

“…The main restriction is that lower conversions are obtained for sequences that comprise methionine, cysteine or histidine residues, presumably because of selective hydrolysis of the peptide bond catalysed by bidentate palladium coordination; on-going experiments along this line show that working in nonaqueous solvents allows reasonable arylations (unpublished results). Later we reported on the arylation of Trp-diketopiperazines 41 and related transformations of Trp derivatives, leading to the generation of Fmoc-protected arylated Trps that are amenable to direct incorporation in solid-phase peptide synthesis (SPPS) 42 . These processes work well with N -protected peptides in dimethylformamide (DMF) or in aqueous environments.…”

Late‐Stage Diversification of Tryptophan‐Derived Biomolecules

“…To expand the substrate scope, tryptophan‐based diketopiperazine brevianamide F was modified resulting in analogues with exceptional cytotoxicities in HeLa cells . Additionally, optimisation of the reaction conditions such as replacing 2‐nitrobenzoic acid by trifluoroacetic acid even allowed for conversion of unprotected tryptophan .…”

A Trp-BODIPY cyclic peptide for fluorescence labelling of apoptotic bodies

“…[14][15] However, most labelling methods alter the molecular properties of small peptides. Our group has optimized C-H activation methodologies [16][17][18][19] and pioneered the Trp-BODIPY fluorogenic amino acid for non-perturbative labelling of peptide sequences. 20 The Trp-BODIPY amino acid emits fluorescence once labelled peptides bind to their corresponding targets, which leads to the rigidification and fluorescence enhancement of the Trp-BODIPY fluorophore ( Figure S1 in Electronic Supplementary Information).…”