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Stereodivergent Synthesis of Bispyrrolidinoindoline Alkaloidal Scaffolds and Generation of a Lead Candidate with Stereospecific Antiproliferative Activity
Author(s) -
Wada Mitsuhiro,
Suzuki Hiroyuki,
Kato Mitsuyasu,
Oikawa Hideaki,
Tsubouchi Akira,
Oguri Hiroki
Publication year - 2019
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201800815
Subject(s) - stereochemistry , pharmacophore , chemistry , stereocenter , stereospecificity , acetogenin , lead compound , enantioselective synthesis , in vitro , biochemistry , biology , botany , annonaceae , catalysis
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 (IC 50 =3.03 μ m ) 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.