Structure–Activity Studies on Suramin Analogues as Inhibitors of NAD⁺‐Dependent Histone Deacetylases (Sirtuins)

Abstract

Suramin is a symmetric polyanionic naphthylurea originally used for the treatment of trypanosomiasis and onchocerciasis. Suramin and diverse analogues exhibit a broad range of biological actions in vitro and in vivo, including, among others, antiproliferative and antiviral activity. Suramin derivatives usually target purinergic binding sites. Class III histone deacetylases (sirtuins) are amidohydrolases that require nicotinamide adenine dinucleotide (NAD(+)) as a cofactor for their catalytic mechanism(.) Deacetylation of the target proteins leads to a change in conformation and alters the activity of the proteins in question. Suramin was reported to inhibit human sirtuin 1 (SIRT1). We tested a diverse set of suramin analogues to elucidate the inhibition of the NAD(+)-dependent histone deacetylases SIRT1 and SIRT2 and discovered selective inhibitors of human sirtuins with potency in the two-digit nanomolar range. In addition, the structural requirements for the binding of suramin derivatives to sirtuins were investigated by molecular docking. The recently published X-ray crystal structure of human SIRT5 in complex with suramin and the human SIRT2 structure were used to analyze the interaction mode of the novel suramin derivatives.

Discovery and Characterization of Protein‐Modifying Natural Products by MALDI Mass Spectrometry Reveal Potent SIRT1 and p300 Inhibitors

“…The quality of the assay was confirmed by a Z'-value [18] of 0.5 ( Figure S4). Moreover, we determined an IC 50 value of (0.26 AE 0.02) mm for suramin, a known SIRT1 inhibitor, which is consistent with the literature value of (0.297 AE 0.01) mm, [19] and an IC 50 value of (0.58 AE 0.03) mm for EX-527, another described SIRT1 inhibitor, which is also in the range of recently reported data. [20] The accuracy of these values generated by MALDI was additionally validated by ESI MS (Table S1).…”

Mitochondrial Matrix Ca2+ Accumulation Regulates Cytosolic NAD+/NADH Metabolism, Protein Acetylation, and Sirtuin Expression

“…7A), coincident with the demonstrated increase in SIRT1 expression by mitochondrion-to-cytosol NADH transmission. To mechanistically link SIRT1 to macrophage adherence, HPAECs were pretreated with the SIRT1 enzymatic inhibitors nicotinamide and suramin (51,52) and then incubated with J774 macrophages at the 2-h time point. Both suramin and nicotinamide significantly increased J774 adhesion to histaminetreated HPAECs relative to controls (Fig.…”

SIRT1 Contains N- and C-terminal Regions That Potentiate Deacetylase Activity

“…19) including suramin (20) and EX-527 (21), the most potent SIRT1 inhibitor with an IC 50 value in the mid nanomolar range. Less potent sirtuin inhibitors, such as Ro 31-8220, an adenosine mimic (22), and nicotinamide, a product and noncompetitive inhibitor of sirtuins (23,24), have also been described.…”