Stereodivergent Synthesis of Bispyrrolidinoindoline Alkaloidal Scaffolds and Generation of a Lead Candidate with Stereospecific Antiproliferative Activity

Abstract

Systematic stereochemical diversification of the “privileged structures” of natural products allowed the generation of a lead compound exhibiting potent cytotoxic activities at high cellular densities against a human colon cancer cell line. Structure–activity relationship studies revealed that all six stereogenic centers were essential for the pharmacophore.

Abstract

The fungal secondary metabolites (+)‐WIN 64821 and (−)‐ditryptophenaline are biosynthesized through condensation of l‐tryptophan and l‐phenylalanine, followed by reductive dimerization with generation of stereochemical variations. Inspired by the stereodivergent biogenetic process, we designed and synthesized a collection of bispyrrolidinoindoline diketopiperazine alkaloids and their analogues with systematic diversification of the stereochemistry of the privileged structural motif of the fungal alkaloids. Not only the stereochemical modifications of (+)‐WIN 64821 at the 3‐/3′‐, 11‐/11′‐, and 15‐/15′‐positions, but also ring cleavage of the diketopiperazine moieties, allowed the generation of a lead compound exhibiting potent growth inhibitory activity (IC₅₀=3.03 μm) toward human colon cancer cells. Structure–activity relationship studies revealed that all six stereogenic centers were essential for the pharmacophore. High cell densities dramatically intensified the cytotoxic activities of the lead compound.