Generation of C5-desoxy analogs of tetrahydroisoquinoline alkaloids exhibiting potent DNA alkylating ability

Ryo Tanifuji; Kaori Tsukakoshi; Kazunori Ikebukuro; Hideaki Oikawa; Hiroki Oguri

doi:10.1016/j.bmcl.2019.05.009

Generation of C5-desoxy analogs of tetrahydroisoquinoline alkaloids exhibiting potent DNA alkylating ability

Bioorg Med Chem Lett. 2019 Jul 15;29(14):1807-1811. doi: 10.1016/j.bmcl.2019.05.009. Epub 2019 May 9.

Authors

Ryo Tanifuji¹, Kaori Tsukakoshi², Kazunori Ikebukuro², Hideaki Oikawa³, Hiroki Oguri⁴

Affiliations

¹ Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Nakacho, Koganei, Tokyo 184-8588, Japan.
² Department of Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Nakacho, Koganei, Tokyo 184-8588, Japan.
³ Department of Chemistry, Faculty of Science, Hokkaido University, Kita-ku Kita 10 Jo Nishi 8 Chome, Sapporo 060-0810, Japan.
⁴ Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Nakacho, Koganei, Tokyo 184-8588, Japan. Electronic address: h_oguri@cc.tuat.ac.jp.

PMID: 31109792
DOI: 10.1016/j.bmcl.2019.05.009

Abstract

C5-desoxy analogs of tetrahydroisoquinoline (THIQ) alkaloids were designed and synthesized as hitherto unexplored structural variants for evaluation of their DNA alkylating activities. While chemical synthesis of the C5-desoxy analogs bearing a phenolic hydroxyl group in the A-ring of the saframycins was assumed to be laborious based on semi-synthetic modifications, a chemo-enzymatic approach allowed for concise access to the analogs. The C5-desoxy analog 7 exhibited greater DNA alkylating ability with a wider tolerance for the sequence variations compared to cyanosafracin B. The C5-desoxy A-ring having a C8 phenolic hydroxyl group, and a C1 substituent in the vicinity of the C21 aminonitrile responsible for DNA alkylation, were demonstrated to play pivotal roles in the interaction between the THIQ alkaloids and DNA.

Keywords: Chemo-enzymatic synthesis; DNA alkylation; Saframycins; Tetrahydroisoquinoline alkaloids.

Publication types

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

MeSH terms

Alkaloids / chemistry*
DNA / chemistry*
Humans
Molecular Structure
Stereoisomerism
Tetrahydroisoquinolines / chemistry*

Substances

Alkaloids
Tetrahydroisoquinolines
DNA