Sirtuins inhibitors

Figure 3.7 Molecular structures of sirtuin inhibitors mentioned in the text.

Figure 3.10 Molecular structure of the sirtuin inhibitors suramin and NF675.

Neugebauer, R.C., Uchiechowska, U., Meier, R., Hruby, H., Valkov, V, Verdin, E. et al. (2008) Stucture activity studies on sphtomicin derivatives as sirtuin inhibitors and computational prediction of binding mode. Journal of Medicinal Chemistry, 51, 1203-1213. 

Figure 10.1 Inhibitors and activators of sirtuins. Inhibitors. 1, sirtinol 2, splitomicin 3, cambinol 4, H R-73 5, EX-527 6, AGK-2 7, tenovin-6 8, nicotinamide. Activators 9, resveratrol 10, SRT-1720 11, isonicotinamide.

As discussed previously, nicotinamide is an endogenous sirtuin inhibitor that promotes the chemical reversal of the covalent reaction intermediates and generation of NAD and acetyl lysine, resulting in nicotinamide exchange. Isonicotinmide is competitive with nicotinamide in the exchange reaction thus promoting deacetylation both in vitro and in vivo. 

Mai, A., Cheng, D., Bedford, M.T, Valente, S., Nebbioso, A., Perrone, A., Brosch, G., Sbardella, G., De Beilis, F., Miceli, M. and Altucci, L. (2008) Epigenetic multiple ligands Mixed histone/protein methyltransferase, acetyltransferase, and class 111 deacetylase (sirtuin) inhibitors. Journal of Medicinal Chemistry, 51, 2279-2290. 

Several structurally diverse sirtuin inhibitors have been reported, some of which are illustrated in Fig. 10. Nicotinamide is a product of NAD+ degradation that occurs during sirtuin-mediated catalytic process. Its inhibitory function at high concentrations is a result of a reaction with the ribosyl oxycarbenium intermediate formed as part of the mechanism, thus reversing the catalytic process and preventing deacetylation. Sirtinol 26 and salermide 27 [116], cambinol 28 [117], the tenovins 29 [118], and splitomycin 30 all show moderate inhibitory activity in the micromolar range. 

Sanders BD et al (2009) Identification and characterization of novel sirtuin inhibitor scaffolds. Bioorg Med Chem 17(19) 7031-7041... 

M.L., Meier, R., Verdin, E., Jung, M., and Sippl, W. (2008) Thiobarbiturates as sirtuin inhibitors virtual screening, free-energy calculations, and biological testing. ChemMedChem, 3 1965—1976. 

Neugebauer RC, Uchiechowska U, Meier R, Hmby H, Valkov V, Verdin E, Sippl W, Jung M (2008) Structure-activity studies on splitomicin derivatives as sirtuin inhibitors and computational prediction of binding mode. J Med Chem 51 1203-1213 Costantini S, Sharma A, Raucci R, Costantini M, Autiero I, Colonna G (2013) Genealogy of an ancient protein family the Sirtuins, a family of disordered members. BMC Evol Biol 13 60... 

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