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Chembiochem. 2019 May 15;20(10):1273-1281. doi: 10.1002/cbic.201800815. Epub 2019 Mar 28.

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

Author information

1
Department of Chemistry, Faculty of Science, Hokkaido University, Kita-ku Kita 10 Jo Nishi 8 Chome, Sapporo, 060-0810, Japan.
2
Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan.
3
Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Nakacho, Koganei, Tokyo, 184-8588, Japan.

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.

KEYWORDS:

alkaloids; antitumor agents; cytotoxicity; indoles; structure-activity relationships

PMID:
30638296
DOI:
10.1002/cbic.201800815

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