Structure-activity studies of cerulenin analogues as protein palmitoylation inhibitors

David S. Lawrence, Jack T. Zilfou, Charles D. Smith

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Activation of ras oncogenes occurs in a high percentage of tumors, making the enzymes involved in the posttranslational processing of their encoded proteins (p21s) attractive targets for the development of new drugs. Although most effort has focused on farnesyl transferase, which catalyzes the first processing step, attachment of palmitate to p21 is required for optimal transformation by H-ras and N-ras. We have demonstrated that the natural product cerulenin ([2R,3S]-2,3-epoxy-4-oxo-7,10-trans,trans-dodecadienamide) inhibits the palmitoylation of H-ras-and N-ras-encoded p21s in parallel with inhibition of cell proliferation. More than 30 analogues of cerulenin, both aromatic and aliphatic, with various chain lengths and amide substitutions, have been synthesized for use in SAR studies. Studies on the inhibition of T24 cell proliferation indicate that the α-keto-epoxy moiety is critical for cytotoxicity, while alkyl chain length had only modest effects on potency. Several compounds inhibited the incorporation of [3H]palmitate into p21 in intact T24 cells, with the unsubstituted carboxamides being more active than N,N-dimethyl compounds. In contrast to the effects on palmitoylation, the only compounds which inhibited fatty acid synthase contained alkyl side chains of 12 carbons or fewer. Regression analyses indicated that inhibition of palmitoylation is more closely related to inhibition of proliferation than is inhibition of fatty acid synthase. Further characterization of the molecular pharmacology of these and analogous compounds may define a new class of drugs with antitumor activity.

Original languageEnglish (US)
Pages (from-to)4932-4941
Number of pages10
JournalJournal of Medicinal Chemistry
Volume42
Issue number24
DOIs
StatePublished - Dec 2 1999

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Cerulenin
Lipoylation
Fatty Acid Synthases
Palmitates
Cell Proliferation
Proteins
ras Genes
Transferases
Biological Products
Amides
Antineoplastic Agents
Carbon
Regression Analysis
Pharmacology
Enzymes
Pharmaceutical Preparations
Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Lawrence, David S. ; Zilfou, Jack T. ; Smith, Charles D. / Structure-activity studies of cerulenin analogues as protein palmitoylation inhibitors. In: Journal of Medicinal Chemistry. 1999 ; Vol. 42, No. 24. pp. 4932-4941.
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Structure-activity studies of cerulenin analogues as protein palmitoylation inhibitors. / Lawrence, David S.; Zilfou, Jack T.; Smith, Charles D.

In: Journal of Medicinal Chemistry, Vol. 42, No. 24, 02.12.1999, p. 4932-4941.

Research output: Contribution to journalArticle

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