Cyclopropenes as Potential Warheads for Inhibitors of Cysteine Proteases

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.