Silibinin enhances anti-renal fibrosis effect of MK-521 via downregulation of TGF-β signaling pathway.

Renal fibrosis is a common characteristic of chronic kidney disease (CKD), and it can lead to end-stage renal disease. It has been reported that silibinin or lisinopril (MK-521) can inhibit the progression of renal fibrosis. However, the effect of combination of silibinin with MK-521 on renal fibrosis remains unclear.

Bivalent SIRT1 inhibitors.

In the current study, bivalent compounds 1-17 constructed by covalently linking the ɛ-amino group of lysine in a tripeptidic scaffold to a functionality via a linker were prepared and examined for their inhibitory potencies against SIRT1, a prototypical member of the β-nicotinamide adenine dinucleotide (β-NAD)-dependent sirtuin family of protein N-acyl-lysine deacylases. A few of them were found to be stronger SIRT1 inhibitors than the N-acetyl-lysine-containing monovalent counterparts 18 and 19. As exemplified with compounds 6 and 18, a bivalent SIRT1 inhibitor could exhibit a greater degree of inhibitory selectivity among SIRT1/2/3 than the corresponding monovalent counterpart.

Novel sirtuin inhibitory warheads derived from the N(ε)-acetyl-lysine analog L-2-amino-7-carboxamidoheptanoic acid.

Built upon the catalytic mechanism-based pan-SIRT1/2/3 inhibitory warhead L-2-amino-7-carboxamidoheptanoic acid (L-ACAH, a close structural analog of N(ε)-acetyl-lysine) that our laboratory discovered recently, in the current study, its carboxamide NH2-ethylated analog was found to be a ∼2.4-6.6-fold stronger SIRT1/2/3 inhibitory warhead than L-ACAH.

Novel thiourea-based sirtuin inhibitory warheads.

N(ε)-Thiocarbamoyl-lysine was recently demonstrated by our laboratory to be a potent catalytic mechanism-based SIRT1/2/3 inhibitory warhead, in the current study, among the prepared analogs of N(ε)-thiocarbamoyl-lysine with its terminal NH2 mono-substituted with alkyl and aryl groups, we found that N(ε)-methyl-thiocarbamoyl-lysine and N(ε)-carboxyethyl-thiocarbamoyl-lysine, respectively, also behaved as strong inhibitory warheads against SIRT1/2/3 and SIRT5, typical deacetylases and deacylase in the human sirtuin family, respectively. Moreover, N(ε)-methyl-thiocarbamoyl-lysine was found in the study to be a ∼ 2.5-18.

The chemical biology of sirtuins.

The sirtuin family of enzymes are able to catalyze the N(ε)-acyl-lysine deacylation reaction on histone and non-histone protein substrates. Over the past years since the discovery of its founding member (i.e.