Collective Synthesis and Biological Evaluation of Tryptophan-Based Dimeric Diketopiperazine Alkaloids

Shinji Tadano; Yukihiro Sugimachi; Michinori Sumimoto; Sachiko Tsukamoto; Hayato Ishikawa

doi:10.1002/chem.201503417

Collective Synthesis and Biological Evaluation of Tryptophan-Based Dimeric Diketopiperazine Alkaloids

Chemistry. 2016 Jan 22;22(4):1277-91. doi: 10.1002/chem.201503417. Epub 2015 Nov 24.

Authors

Shinji Tadano¹, Yukihiro Sugimachi¹, Michinori Sumimoto², Sachiko Tsukamoto³, Hayato Ishikawa⁴

Affiliations

¹ Department of Chemistry, Graduate School of Science and Technology, Kumamoto University, 2-39-1, Kurokami, Chuo-ku, Kumamoto, 860-8555, Japan.
² Division of Material Science and Engineering, Graduate School of Science and Engineering, Yamaguchi University, 2-16-1 Tokiwadai, Ube, 755-8611, Japan.
³ Department of Natural Medicines, Graduate School of Pharmaceutical Sciences, Kumamoto University, Oe-honmachi 5-1, Chuo-ku, Kumamoto, 862-0973, Japan.
⁴ Department of Chemistry, Graduate School of Science and Technology, Kumamoto University, 2-39-1, Kurokami, Chuo-ku, Kumamoto, 860-8555, Japan. ishikawa@sci.kumamoto-u.ac.jp.

PMID: 26598794
DOI: 10.1002/chem.201503417

Abstract

A concise two one-pot synthesis of WIN 64821, eurocristatine, 15,15'-bis-epi-eurocristatine, ditryptophenaline, ditryptoleucine A, WIN 64745, cristatumin C, asperdimin, naseseazine A, and naseseazine B is detailed, based on a unique bioinspired dimerization reaction of tryptophan derivatives in aqueous acidic solution and a one-pot procedure for the construction of diketopiperazine rings. Total yields of these alkaloid syntheses were from 10 up to 27 %. In addition, 1'-(2-phenylethylene)-ditryptophenaline was synthesized by using three one-pot operations. The studies detailed herein provided synthesized natural products for inhibitory activities of ubiquitin-specific protease 7 (USP7) and foam cell formation in macrophages. The newly listed biological evaluation for tryptophan-based dimeric diketopiperazine alkaloids discovered 15,15'-bis-epi-eurocristatine, 1'-(2-phenylethylene)-ditryptophenaline, and WIN 64745 as new drug candidates.

Keywords: alkaloids; amino acids; bioinspired reaction; dimerization; one-pot reactions.

Publication types

Research Support, Non-U.S. Gov't