Structure−Activity Studies of Cerulenin Analogues as Protein Palmitoylation Inhibitors

• Published in: Journal of medicinal chemistry 1999-12, Vol.42 (24), p.4932-4941
• Main Authors: Lawrence, David S, Zilfou, Jack T, Smith, Charles D
• Format: Article
• Language: English
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Amides - chemical synthesis; Amides - pharmacology; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Division - drug effects; Cerulenin - analogs & derivatives; Cerulenin - chemistry; Cerulenin - pharmacology; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Epoxy Compounds - chemical synthesis; Epoxy Compounds - pharmacology; Farnesyltranstransferase; Fatty Acid Synthases - antagonists & inhibitors; General aspects; Humans; Medical sciences; Molecular Structure; Oncogene Protein p21(ras) - metabolism; Palmitic Acid - metabolism; Pharmacology. Drug treatments; Structure-Activity Relationship; Tumor Cells, Cultured; Urinary Bladder Neoplasms - pathology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980591s

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.