Stereocomplementary Chemoenzymatic Pictet-Spengler Reactions for Formation of Rare Azepino-indole Frameworks: Discovery of Antimalarial Compounds

Yunrui Cai, Nana Shao, Hujun Xie, Yushi Futamura, Santosh Panjikar, Haicheng Liu, Huajian Zhu, Hiroyuki Osada, Hongbin Zou*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Strictosidine synthase (STR1) catalyzes a Pictet-Spengler reaction (PSR) forming strictosidine, a likely biosynthetic key to all higher plant monoterpenoid indole alkaloids. Increasing the biocatalytic capacity of the enzyme may make it a powerful tool for generation of compound libraries with enhanced structural diversity and pharmaceutical activity. Herein two production routes of a rare class of azepino[3,4,5-cd]-indoles are developed: A complementary STR1-dependent chemoenzymatic and stereoselectively chemical route to an epimeric 1H-azepino[3,4,5-cd]indolyl strictosidine or vincoside, respectively. Mechanisms of the asymmetric catalysis are proposed based on computational calculations and X-ray analysis of STR1-ligand complexes. Further chemoenzymatic manipulation of the complementary PSR products resulted in several diverse and complex azepino-indole alkaloids, in which two alkaloids with the epimeric center directs the discovered antimalaria activity: 4α(S) with IC50 ≈ 3.4 μM, 4β(R) with IC50 ≈ 6.1 μM. The chemoenzymatic synthesis may significantly extend the applications of the enantiospecific STR1-based PSR in the future.

Original languageEnglish
Pages (from-to)7443-7448
Number of pages6
JournalACS Catalysis
Volume9
Issue number8
DOIs
Publication statusPublished - 2019 Aug 2
Externally publishedYes

Keywords

  • Pictet-Spengler reactions
  • antimalarial activity
  • azepino-indole alkaloids
  • complementary stereoselectivity
  • phosphate
  • strictosidine synthase

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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