A Cyclic Tripeptide-based Human SIRT3 Inhibitor

Background: Among the seven human sirtuins SIRT1-7, SIRT3 is not lesser functionally understood. However, the identification of its inhibitors has not been quite a success. Objective: In the current study, we intended to see if we were able to develop cyclic tripeptide-based human SIRT3 inhibitors that would harbor the catalytic mechanism-based pan-SIRT1/2/3 inhibitory warhead N^e-thioacetyl-lysine. Methods: In the current study, we prepared the corresponding N-terminus-to-side chain cyclic analog of two of our previously reported linear tripeptidic human SIRT3 inhibitors whose chemical structures both harbor the catalytic mechanism-based pan-SIRT1/2/3 inhibitory warhead N(epsilon)-thioacetyl-lysine at the central position and subjected the analogs to the same sirtuin inhibition assay under the same assay condition as those employed previously in our laboratory for the two parent linear tripeptidic SIRT3 inhibitors. Results: We found that analog 2 exhibited an enhanced SIRT3 inhibitory potency than its linear tripeptidic parent (i.e. compound 2a) and displayed a SIRT3 inhibitory IC50 value of ~340 nM which is smaller than its inhibitory IC50 values against other sirtuins with the following folds: ~2-fold versus SIRT1, ~7.7- fold versus SIRT2, and >68-353-fold versus SIRT5-7. Conclusion: The successful identification of the human SIRT3 inhibitor 2 in the current study would help the further functional dissection and pharmacological exploitation of the SIRT3 deacetylation reaction.