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

Research output: Contribution to journalArticle

21 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 languageEnglish
Pages (from-to)4377-4385
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number14
DOIs
Publication statusPublished - 2011 Jul 15

Fingerprint

Biological Products
Libraries
Metabolites
Molecules
Small Molecule Libraries
Drug Discovery
Complex Mixtures
Reaction products
Caspase 3
Pharmaceutical Preparations
Purification
Seed
Seeds
Diodes
Cells
Neoplasms

Keywords

  • C38OX6
  • Cancer
  • Chemical library
  • Natural product
  • Unnatural Natural Product
  • XIAP

ASJC Scopus subject areas

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

Cite this

Generation of 'Unnatural Natural Product' library and identification of a small molecule inhibitor of XIAP. / Kawamura, Tatsuro; Matsubara, Kohei; Otaka, Hitomi; Tashiro, Etsu; Shindo, Kazutoshi; Yanagita, Ryo C.; Irie, Kazuhiro; Imoto, Masaya.

In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 14, 15.07.2011, p. 4377-4385.

Research output: Contribution to journalArticle

Kawamura, Tatsuro ; Matsubara, Kohei ; Otaka, Hitomi ; Tashiro, Etsu ; Shindo, Kazutoshi ; Yanagita, Ryo C. ; Irie, Kazuhiro ; Imoto, Masaya. / Generation of 'Unnatural Natural Product' library and identification of a small molecule inhibitor of XIAP. In: Bioorganic and Medicinal Chemistry. 2011 ; Vol. 19, No. 14. pp. 4377-4385.
@article{418bbc3322f44305a757a1701576b87c,
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",
year = "2011",
month = "7",
day = "15",
doi = "10.1016/j.bmc.2011.05.009",
language = "English",
volume = "19",
pages = "4377--4385",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "14",

}

TY - JOUR

T1 - Generation of 'Unnatural Natural Product' library and identification of a small molecule inhibitor of XIAP

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

PY - 2011/7/15

Y1 - 2011/7/15

N2 - 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.

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

UR - http://www.scopus.com/inward/record.url?scp=79959929573&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79959929573&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2011.05.009

DO - 10.1016/j.bmc.2011.05.009

M3 - Article

VL - 19

SP - 4377

EP - 4385

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 14

ER -