A landmark in drug discovery based on complex natural product synthesis

被引：30

作者：

Kawano, Satoshi ^{[1
]}

Ito, Ken ^{[1
]}

Yahata, Kenzo ^{[2
]}

Kira, Kazunobu ^{[1
]}

Abe, Takanori ^{[1
]}

Akagi, Tsuyoshi ^{[1
]}

Asano, Makoto ^{[1
]}

Iso, Kentaro ^{[1
]}

Sato, Yuki ^{[1
]}

Matsuura, Fumiyoshi ^{[3
]}

Ohashi, Isao ^{[1
]}

Matsumoto, Yasunobu ^{[1
]}

Isomura, Minetaka ^{[1
]}

Sasaki, Takeo ^{[1
]}

Fukuyama, Takashi ^{[1
]}

Miyashita, Yusuke ^{[4
]}

Kaburagi, Yosuke ^{[1
]}

Yokoi, Akira ^{[1
]}

Asano, Osamu ^{[1
]}

Owa, Takashi ^{[5
]}

Kishi, Yoshito ^{[2
]}

机构：

[1] Eisai & Co Ltd, Tsukuba, Ibaraki, Japan

[2] Harvard Univ, Cambridge, MA 02138 USA

[3] Eisai & Co Ltd, Bunkyo Ku, Tokyo, Japan

[4] Eisai & Co Ltd, Kamisu, Ibaraki, Japan

[5] Eisai Inc, Woodcliff Lake, NJ USA

来源：

SCIENTIFIC REPORTS | 2019年 / 9卷 / 1期

关键词：

ANTITUMOR POLYETHER MACROLIDES; ANTINEOPLASTIC AGENTS; HALICHONDRIN-B; BREAST-CANCER; TUBULIN; ANTIBODY; MICROTUBULES; CETUXIMAB; DISEASE; BINDING;

D O I：

10.1038/s41598-019-45001-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 alpha-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.

引用

页数：9

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