A Landmark in Drug Discovery Based on Complex Natural Product Synthesis

Overview

Journal Sci Rep

Specialty Science

Date 2019 Jun 19

PMID 31209263

Citations 7

Authors

Satoshi Kawano

Ken Ito

Kenzo Yahata

Kazunobu Kira

Takanori Abe

Tsuyoshi Akagi

Makoto Asano

Kentaro Iso

Yuki Sato

Fumiyoshi Matsuura

Isao Ohashi

Yasunobu Matsumoto

Minetaka Isomura

Takeo Sasaki

Takashi Fukuyama

Yusuke Miyashita

Yosuke Kaburagi

Akira Yokoi

Osamu Asano

Takashi Owa

Yoshito Kishi

Affiliations

Soon will be listed here.

Abstract

Despite their outstanding antitumour activity in mice, the limited supply from the natural sources has prevented drug discovery/development based on intact halichondrins. We achieved a total synthesis of C52-halichondrin-B amine (E7130) on a >10 g scale with >99.8% purity under GMP conditions. Interestingly, E7130 not only is a novel microtubule dynamics inhibitor but can also increase intratumoural CD31-positive endothelial cells and reduce α-SMA-positive cancer-associated fibroblasts at pharmacologically relevant compound concentrations. According to these unique effects, E7130 significantly augment the effect of antitumour treatments in mouse models and is currently in a clinical trial. Overall, our work demonstrates that a total synthesis can address the issue of limited material supply in drug discovery/development even for the cases of complex natural products.

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