Conformationally Defined Analogs of Prolylamides. trans-Prolyl Peptidomimetics

Article abstract of DOI:10.1021/jo00076a018

The cis and trans conformations of prolylamides are both energetically accessible, in contrast to the peptide bonds of the remaining mammalian amino acids.The synthesis of a rigid, conformationally defined peptidomimetic of the trans-prolylamide bond has been developed in this study, and illustrative leucinylproline derivatives (4, 10a, 10b, and 11) were assayed for their abilities to inhibit the peptidyl prolyl isomerase activity of recombinant human FK-binding protein 12 (FKBP 12).These trans-prolyl peptidomimetics possess a trans-substituted alkene in place of the proline peptide bond and were synthesized via a six step sequence culminating in the selective addition of isobutylmagnesium bromide to 2(E)-(2-oxoethylidene)-1-methylcyclopentanecarboxylate (9).Synthesis of the dipeptide analogs was accomplished in six steps with a 20percent overall yield.Elaboeation of the dipeptide analog gave the Leu-Pro-tyrosyl tripeptide analog in three additional steps.The tripeptide mimic 4 proved to be a potent inhibitor of the prolyl isomerase activity of recombinant hFKBP 12, exhibiting an inhibition constant (K_i) of 8.6 μM; the dipeptidomimetics possessed a modest capacity for isomerase inhibition with inhibition constants ranging from 127 μM for the α-enone analog 11 to 730 and 1390 μM for the allylic alcohol mimetics 10a and 10b, respectively.