Development of Pyrazolone and Isoxazol-5-one Cambinol Analogues as Sirtuin Inhibitors

Abstract

Sirtuins are a family of NAD+-dependent protein deacetylases that play critical roles in epigenetic regulation, stress responses, and cellular aging in eukaryotic cells. In an effort to identify small molecule inhibitors of sirtuins for potential use as chemotherapeutics as well as tools to modulate sirtuin activity, we previously identified a nonselective sirtuin inhibitor called cambinol (IC50 ≈ 50 μM for SIRT1 and SIRT2) with in vitro and in vivo antilymphoma activity. In the current study, we used saturation transfer difference (STD) NMR experiments with recombinant SIRT1 and 20 to map parts of the inhibitor that interacted with the protein. Our ongoing efforts to optimize cambinol analogues for potency and selectivity have resulted in the identification of isoform selective analogues: 17 with >7.8-fold selectivity for SIRT1, 24 with >15.4-fold selectivity for SIRT2, and 8 with 6.8- and 5.3-fold selectivity for SIRT3 versus SIRT1 and SIRT2, respectively. In vitro cytotoxicity studies with these compounds as well as EX527, a potent and selective SIRT1 inhibitor, suggest that antilymphoma activity of this compound class may be predominantly due to SIRT2 inhibition.

1,2,3-Triazole-Dithiocarbamate Hybrids, a Group of Novel Cell Active SIRT1 Inhibitors

“…In contrast, there is no agonist has been reported for SIRT2 toward any pathological processes [41]. In terms of cancer therapy, there are articles about predominant effect of non-selective inhibitors on both SIRT1 and SIRT2 [36,42]. Compound 3a had promising anti-proliferative activity as well as SIRT1 inhibitory effect.…”

“…Several compounds targeting both SIRT1 and SIRT2 were described to have much stronger antitumor activity both in vitro and in vivo, and SIRT2 has been recognized as a tumor therapy target [19,36]. Hence, additional experiments to confirm the acetylation status of alpha-tubulin, a substrate of SIRT2, were also performed.…”

Fluorous Supported Synthesis of Pyrazolone Derivatives From Allylic Alcohols Using a Palladium-Catalyzed Strategy

“…[1][2][3][4] They were first extensively developed for their anti-inflammatory, 5 analgesic 6 and antipyretic 7 properties. More recently, great attention has been paid to their versatile role as antimicrobial, 8 antiparasitic, 9 antiviral 10 and antineoplastic 11 agents. For instance, edaravone (1) is a potent drug used in the treatment of brain ischemia 12 and was shown to alleviate Alzheimer's disease-type pathologies, 13 metamidole (2) is known to have antipyretic and analgesic activities, 7 the pyrazole (3) is known to possess HIV-1 integrase inhibitory properties 14 and (4) has idiopathic pulmonary fibrosis activity 15 ( Figure 1).…”

Morita–Baylis–Hillman adducts as building blocks of heterocycles: a simple approach to 4-substituted pyrazolones, and mechanism investigation via ESI–MS(/MS)

“…1). Recently, Simon et al [23] have reported a new class of pyrazolones and isoxazol-5-ones that inhibit Sirtuin, which can potentially be used in the treatment of lymphomas (Fig. 2).…”