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

Bioorg Med Chem. 2011 Jul 15;19(14):4377-85. doi: 10.1016/j.bmc.2011.05.009. Epub 2011 May 27.

Authors

Tatsuro Kawamura¹, Kohei Matsubara, Hitomi Otaka, Etsu Tashiro, Kazutoshi Shindo, Ryo C Yanagita, Kazuhiro Irie, Masaya Imoto

Affiliation

¹ Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan.

PMID: 21696964
DOI: 10.1016/j.bmc.2011.05.009

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.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Biological Products / chemistry*
Biological Products / pharmacology*
Caspase 3 / metabolism
Caspase Inhibitors
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Activation / drug effects
HeLa Cells
Humans
Imides / chemical synthesis
Imides / chemistry
Imides / pharmacology*
Indole Alkaloids / chemical synthesis
Indole Alkaloids / chemistry
Indole Alkaloids / pharmacology*
Lyngbya Toxins / chemistry
Lyngbya Toxins / pharmacology
Magnetic Resonance Spectroscopy
Molecular Structure
Protein Binding / drug effects
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Stereoisomerism
Structure-Activity Relationship
X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors*
X-Linked Inhibitor of Apoptosis Protein / metabolism

Substances

Antineoplastic Agents
Biological Products
C38OX6 compound
Caspase Inhibitors
Imides
Indole Alkaloids
Lyngbya Toxins
Small Molecule Libraries
X-Linked Inhibitor of Apoptosis Protein
teleocidins
Caspase 3