Cyclopropenes as Potential Warheads for Inhibitors of Cysteine Proteases

Purujit N Gurjar,Anish K Vadukoot,Thi N Nguyen,Vladislav A Litosh,Aron P Bercz

doi:10.13189/ujc.2015.030103

Abstract

Over expression of cysteine proteases in human body causes neurodegenerative diseases, destruction of cartilage tissue, and bone atrophy, and some of them are implicated in destructive role of malignant tumors and cancer metastasis. Several non-human cysteine proteases play a key role in life cycles of certain foreign invasive organisms. Therefore, inhibition of cysteine proteases represents an important venue for finding potential therapeutic agents against Alzheimer's disease, multiple sclerosis, ischemic stroke, myocardial infarcts, carcinoma progression, as well as some parasital and viral infections. Affinity labeling agents used as inhibitors of cysteine proteases normally bear an electrophilic warhead, a reactive group that covalently binds the active site cysteine residue thereby inactivating the enzyme, but achieving both high activity and selectivity remains challenging. We are developing cyclopropene derivatives that show selective binding of thiol residues of cysteine. Several derivatives of cyclopropenes have been synthesized and evaluated as potential cysteine-binding warheads. Their stability in aqueous media and reactivity toward cysteine and other amino acid chemical probes was examined. We have found that 1,2-cyclopropene moiety irreversibly binds the thiol group of cysteine, leaving other amino acid residues unaffected, which has the advantage for targeting enzymes expressed in foreign organisms or promoting carcinoma progression.

Highlights

Cysteine proteases are protein processing and protein degrading enzymes whose overexpression in human body may result in serious pathological changes
Dependent, and the inhibition is not always restricted to cysteine proteases, often affecting aspartate and serine proteases as well.10a Surprisingly, among carbocyclic unsaturated three-membered ring compounds, only cyclopropenone derivatives have been used as cysteine protease inhibitors,[11] and their binding appears to be reversible (Figure 1).11b This suggests the addition of the cysteine thiol group to the 3-carbonyl, rather than to the cyclopropene double bond
We report the synthesis of model cyclopropenes and their evaluation as potential warheads that could be incorporated into the existing cysteine protease inhibitors in order to increase their selectivity and potency

Summary

Introduction

Cysteine proteases are protein processing and protein degrading enzymes whose overexpression in human body may result in serious pathological changes. Other cyclopropene derivatives turned out to be sufficiently stable toward hydrolysis, so we proceeded with studies of their reactivity toward N-acetyl cysteine methyl ester. 1H NMR studies to determine reaction rate for addition of cyclopropene derivatives to methyl N-acetylcysteinate

Results

Conclusion