Cyclopropane-derived peptidomimetics. design, synthesis, and evaluation of novel Ras farnesyltransferase inhibitors.
Trisubstituted cyclopropanes have previously been established as rigid replacements of dipeptide arrays in several biological systems. Toward further evaluating the utility of these dipeptide mimics in the design of novel CA(1)A(2)X-based inhibitors of Ras farnesyltransferase (FTase), the conformationally constrained, diastereomeric pseudopeptides CAbuPsi[COcpCO]FM 7-9, the flexible analogue CAbuPsi[CHOHCH(2)]FM (10), and the tetrapeptide CAbuFM (6) were prepared. The orientations of the two peptide backbone substituents and the phenyl group on the cyclopropane rings in 7-9were specifically designed to probe selected topological features of the hydrophobic binding pocket of the A(2) subsite of FTase. The syntheses of the requisite trisubstituted cyclopropane carboxylic acid 22 and the diastereomeric cyclopropyl lactones 32a,b featured diastereoselective intramolecular cyclopropanations of chiral allylic diazoacetates and a new method for introducing side chains onto the C-terminal amino acid of cyclopropane-derived dipeptide replacements via the opening of an N-Boc-aziridine with an organocuprate. These cyclopropane intermediates were then converted into the targeted FTase inhibitors 7-9 by standard peptide coupling techniques. The pseudopeptides 7-9 were found to be competitive inhibitors of Ras FTase with IC(50)s of 1055 nM for 7, 760 nM for 8, and 7200 nM for 9. The flexible analogue 10 of these constrained inhibitors exhibited a IC(50) of 320 nM and hence was slightly more potent than 7 and 8. All of these pseudopeptides were less potent than the tetrapeptide parent CAbuFM (6), which had an IC(50) of 38 nM. Because 7 and 8 are approximately equipotent, it appears that the orientation of the peptide backbone substituents on the cyclopropane rings in 7 and 8 do not have any significant effect on binding affinity and that multiple binding modes are possible without significant changes in affinity. On the other hand, this flexibility does not extend to the orientation of the side chain of the A(2) residue as 7 and 8 were both nearly 1 order of magnitude more potent than 9. Comparison of the relative potencies of 6 and 10 suggests that the amide linkage between the A(1) and the A(2) residues of CA(1)A(2)X-derived FTase inhibitors is important.
Hillier
M C
MC
Department of Chemistry and Biochemistry, Institute of Cellular and Molecular Biology, The University of Texas, Austin, TX 78712, USA.
Davidson
J P
JP
Martin
S F
SF
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D003521:Cyclopropanes / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018716:Molecular Mimicry; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013057:Spectrum Analysis
D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D010455:Peptides; C030797:cyclopropane; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase