Asymmetric synthesis and evaluation of epoxy-α-acyloxycarboxamides as selective inhibitors of cathepsin L

Abstract

Cathepsin L plays important roles in physiological processes as well as in the development of many pathologies. Recently the attentions were turned to its association with tumor progress what makes essential the development of more potent and selective inhibitors. In this work, epoxipeptidomimetics were investigated as new cathepsin inhibitors. This class of compounds is straightforward obtained by using a green one-pot asymmetric epoxidation/Passerini 3-MCR. A small library of 17 compounds was evaluated against cathepsin L, and among them LSPN423 showed to be the most potent. Investigations of the mechanism suggested a tight binding uncompetitive inhibition.

The 100 facets of the Passerini reaction

“…Among the first reports on the Passerini reaction with chiral aldehydes, 2,3-epoxyaldehydes 130, obtained from 132 by Sharpless epoxidation by Krishna and Lopinti 90 as well as by an organocatalytic procedure by Corrêa and Paixão, 91,92 have been used ( Scheme 38 ).…”

Stereoselective Multicomponent Reactions in the Synthesis or Transformations of Epoxides and Aziridines

“…Then, the other components of Passerini-3CR (carboxylic acid and isocyanide) were added and after 24 h, highly functionalized epoxy α-acyloxycarboxamides 14 were obtained in good yields and stereoselectivity [34]. Those adducts were submitted to inhibition assays against cathepsins K, V, and L, in which the LSPN423 was the most potent and selective against cathepsins L. Further investigations demonstrated that LSPN423 is a tight binding uncompetitive inhibitor with an inhibition constant (K i ) of 1.33 µM [35].…”