Generation of 'Unnatural Natural Product' library and identification of a small molecule inhibitor of XIAP

Tatsuro Kawamura; Kohei Matsubara; Hitomi Otaka; Etsu Tashiro; Kazutoshi Shindo; Ryo C. Yanagita; Kazuhiro Irie; Masaya Imoto

doi:10.1016/j.bmc.2011.05.009

Generation of 'Unnatural Natural Product' library and identification of a small molecule inhibitor of XIAP

Tatsuro Kawamura, Kohei Matsubara, Hitomi Otaka, Etsu Tashiro, Kazutoshi Shindo, Ryo C. Yanagita, Kazuhiro Irie, Masaya Imoto

Department of Biosciences and Informatics

Research output: Contribution to journal › Article › peer-review

27 Citations (Scopus)

Abstract

Natural products have been utilized for drug discovery. To increase the source diversity, we generated a new chemical library consisting of chemically modified microbial metabolites termed 'Unnatural Natural Products' by chemical conversion of microbial metabolites in crude broth extracts followed by purification of reaction products with the LC-photo diode array-MS system. Using this library, we discovered an XIAP inhibitor, C38OX6, which restored XIAP-suppressed enzymatic activity of caspase-3 in vitro. Furthermore, C38OX6 sensitized cancer cells to anticancer drugs, whereas the unconverted natural product did not. These findings suggest that our library could be a useful source for drug seeds.

Original language	English
Pages (from-to)	4377-4385
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry
Volume	19
Issue number	14
DOIs	https://doi.org/10.1016/j.bmc.2011.05.009
Publication status	Published - 2011 Jul 15

Keywords

C38OX6
Cancer
Chemical library
Natural product
Unnatural Natural Product
XIAP

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmc.2011.05.009

Cite this

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title = "Generation of 'Unnatural Natural Product' library and identification of a small molecule inhibitor of XIAP",

abstract = "Natural products have been utilized for drug discovery. To increase the source diversity, we generated a new chemical library consisting of chemically modified microbial metabolites termed 'Unnatural Natural Products' by chemical conversion of microbial metabolites in crude broth extracts followed by purification of reaction products with the LC-photo diode array-MS system. Using this library, we discovered an XIAP inhibitor, C38OX6, which restored XIAP-suppressed enzymatic activity of caspase-3 in vitro. Furthermore, C38OX6 sensitized cancer cells to anticancer drugs, whereas the unconverted natural product did not. These findings suggest that our library could be a useful source for drug seeds.",

keywords = "C38OX6, Cancer, Chemical library, Natural product, Unnatural Natural Product, XIAP",

author = "Tatsuro Kawamura and Kohei Matsubara and Hitomi Otaka and Etsu Tashiro and Kazutoshi Shindo and Yanagita, {Ryo C.} and Kazuhiro Irie and Masaya Imoto",

note = "Funding Information: We are grateful to T. Watabe, Y. Fujimoto, and Y. Matsui (Keio University) for help with construction of the UNP library. This study was supported in part by a 2009 Innovative Research Program Award from the Japanese Society of Bioscience, Biotechnology, and Agrochemistry (JSBBA). T.K. was a research assistant for the Global COE Program for Human Metabolomic Systems Biology. ",

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doi = "10.1016/j.bmc.2011.05.009",

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AU - Kawamura, Tatsuro

AU - Matsubara, Kohei

AU - Otaka, Hitomi

AU - Tashiro, Etsu

AU - Shindo, Kazutoshi

AU - Yanagita, Ryo C.

AU - Irie, Kazuhiro

AU - Imoto, Masaya

N1 - Funding Information: We are grateful to T. Watabe, Y. Fujimoto, and Y. Matsui (Keio University) for help with construction of the UNP library. This study was supported in part by a 2009 Innovative Research Program Award from the Japanese Society of Bioscience, Biotechnology, and Agrochemistry (JSBBA). T.K. was a research assistant for the Global COE Program for Human Metabolomic Systems Biology.

PY - 2011/7/15

Y1 - 2011/7/15

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AB - Natural products have been utilized for drug discovery. To increase the source diversity, we generated a new chemical library consisting of chemically modified microbial metabolites termed 'Unnatural Natural Products' by chemical conversion of microbial metabolites in crude broth extracts followed by purification of reaction products with the LC-photo diode array-MS system. Using this library, we discovered an XIAP inhibitor, C38OX6, which restored XIAP-suppressed enzymatic activity of caspase-3 in vitro. Furthermore, C38OX6 sensitized cancer cells to anticancer drugs, whereas the unconverted natural product did not. These findings suggest that our library could be a useful source for drug seeds.

KW - C38OX6

KW - Cancer

KW - Chemical library

KW - Natural product

KW - Unnatural Natural Product

KW - XIAP

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ER -

Generation of 'Unnatural Natural Product' library and identification of a small molecule inhibitor of XIAP

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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