Synthetic analogues of TNP-470 and ovalicin reveal a common molecular basis for inhibition of angiogenesis and immunosuppression

Benjamin E. Turk, Zhuang Su, Jun Liu

Research output: Contribution to journalArticle

Abstract

TNP-470 (1), a synthetic derivative of the natural product fumagillin (2), potently inhibits angiogenesis in vivo and the growth of endothelial cell cultures in vitro. The structurally related natural product ovalicin (3) also inhibits angiogenesis but possesses potent immunosuppressive activity. The recent finding that all three drugs bind and inhibit the same target, methionine aminopeptidase 2 (MetAP2), raised the question of whether TNP-470 is also immunosuppressive and whether inhibition of MetAP2 underlies both activities of ovalicin. To address these questions, we synthesized a series of analogues of TNP-470 and ovalicin and tested them for their abilities to inhibit the proliferation of either endothelial cell or mixed lymphocyte cultures. TNP-470 and its analogues were found to possess both immunosuppressive and anti-angiogenic activities. A strong correlation was observed between the ability of compounds to inhibit bovine and human endothelial cell growth and their ability to inhibit the mouse mixed lymphocyte reaction (MLR), implying that the two activities share a common molecular basis, i.e., inhibition of MetAP2. Interestingly, ovalicin and several other compounds behaved differently in the human MLR than in either the mouse MLR or human endothelial cell proliferation assays, pointing to possible species-specific and cell type-specific differences in the metabolism or uptake of these compounds. Copyright (C) 1998 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)1163-1169
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume6
Issue number8
DOIs
StatePublished - Aug 1998
Externally publishedYes

Fingerprint

Lymphocytes
Endothelial cells
Immunosuppression
Mixed Lymphocyte Culture Test
Immunosuppressive Agents
Endothelial Cells
Biological Products
Cell culture
Cell proliferation
Cell growth
Growth
Metabolism
Assays
Cell Culture Techniques
Cell Proliferation
Derivatives
ovalicin
O-(chloroacetylcarbamoyl)fumagillol
Pharmaceutical Preparations
methionine aminopeptidase 2

Keywords

  • Angiogenesis
  • Immunosuppression
  • MetAP2
  • Ovalicin
  • TNP-470

ASJC Scopus subject areas

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

Cite this

Synthetic analogues of TNP-470 and ovalicin reveal a common molecular basis for inhibition of angiogenesis and immunosuppression. / Turk, Benjamin E.; Su, Zhuang; Liu, Jun.

In: Bioorganic and Medicinal Chemistry, Vol. 6, No. 8, 08.1998, p. 1163-1169.

Research output: Contribution to journalArticle

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