Sirt1 modulation as a novel approach to the treatment of diseases of aging

Journal of Medicinal Chemistry

Volumn 54, Issue 2, 2011, Pages 417-432

  Blum, Charles A ^a   Ellis, James L ^a   Loh, Christine ^a   Ng, Pui Yee ^a   Perni, Robert B ^a   Stein, Ross L ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE DIPHOSPHATE; HISTONE H1; HISTONE H3; HISTONE H4; NICOTINAMIDE ADENINE DINUCLEOTIDE; NICOTINAMIDE DERIVATIVE; PROTEIN P53; SIRTINOL; SIRTUIN 1;

AGING; DRUG DESIGN; ENZYME ACTIVITY; METABOLIC REGULATION; MODULATION; REVIEW; STRUCTURE ANALYSIS;

AGING; ANIMALS; ANTI-INFLAMMATORY AGENTS; ANTI-OBESITY AGENTS; CATALYSIS; DIABETES MELLITUS, TYPE 2; DRUG EVALUATION, PRECLINICAL; ENZYME ACTIVATORS; HUMANS; HYPOGLYCEMIC AGENTS; KINETICS; SIRTUIN 1; SUBSTRATE SPECIFICITY;

EID: 78751663378     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm100861p     Document Type: Review

References (140)

1. Frye, R. A. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity Biochem. Biophys. Res. Commun. 1999, 260, 273-279
2. Frye, R. A. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins Biochem. Biophys. Res. Commun. 2000, 273, 793-798
3. Finkel, T.; Deng, C. X.; Mostoslavsky, R. Recent progress in the biology and physiology of sirtuins Nature 2009, 460, 587-591
4. Tissenbaum, H. A.; Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans Nature 2001, 410, 227-230
5. Bordone, L.; Cohen, D.; Robinson, A.; Motta, M. C.; van Veen, E.; Czopik, A.; Steele, A. D.; Crowe, H.; Marmor, S.; Luo, J.; Gu, W.; Guarente, L. SIRT1 transgenic mice show phenotypes resembling calorie restriction Aging Cell 2007, 6, 759-767
6. Banks, A. S.; Kon, N.; Knight, C.; Matsumoto, M.; Gutierrez-Juarez, R.; Rossetti, L.; Gu, W.; Accili, D. SirT1 gain of function increases energy efficiency and prevents diabetes in mice Cell Metab. 2008, 8, 333-341
7. Chaudhary, N.; Pfluger, P. T. Metabolic benefits from Sirt1 and Sirt1 activators Curr. Opin. Clin. Nutr. Metab. Care 2009, 12, 431-437
8. Moynihan, K. A.; Grimm, A. A.; Plueger, M. M.; Bernal-Mizrachi, E.; Ford, E.; Cras-Meneur, C.; Permutt, M. A.; Imai, S. Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice Cell Metab. 2005, 2, 105-117
9. Pfluger, P. T.; Herranz, D.; Velasco-Miguel, S.; Serrano, M.; Tschop, M. H. Sirt1 protects against high-fat diet-induced metabolic damage Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 9793-9798
10. Ramsey, K. M.; Mills, K. F.; Satoh, A.; Imai, S. Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cell-specific Sirt1-overexpressing (BESTO) mice Aging Cell 2008, 7, 78-88
11. Rodgers, J. T.; Puigserver, P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1 Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 12861-12866
12. McBurney, M. W.; Yang, X.; Jardine, K.; Hixon, M.; Boekelheide, K.; Webb, J. R.; Lansdorp, P. M.; Lemieux, M. The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis Mol. Cell. Biol. 2003, 23, 38-54
13. Asher, G.; Gatfield, D.; Stratmann, M.; Reinke, H.; Dibner, C.; Kreppel, F.; Mostoslavsky, R.; Alt, F. W.; Schibler, U. SIRT1 regulates circadian clock gene expression through PER2 deacetylation Cell 2008, 134, 317-328
14. +-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control Cell 2008, 134, 329-340
15. + salvage pathway by CLOCK-SIRT1 Science 2009, 324, 654-657
16. + biosynthesis Science 2009, 324, 651-654
17. Oberdoerffer, P.; Michan, S.; McVay, M.; Mostoslavsky, R.; Vann, J.; Park, S. K.; Hartlerode, A.; Stegmuller, J.; Hafner, A.; Loerch, P.; Wright, S. M.; Mills, K. D.; Bonni, A.; Yankner, B. A.; Scully, R.; Prolla, T. A.; Alt, F. W.; Sinclair, D. A. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during Aging Cell 2008, 135, 907-918
18. Wang, R. H.; Sengupta, K.; Li, C.; Kim, H. S.; Cao, L.; Xiao, C.; Kim, S.; Xu, X.; Zheng, Y.; Chilton, B.; Jia, R.; Zheng, Z. M.; Appella, E.; Wang, X. W.; Ried, T.; Deng, C. X. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice Cancer Cell 2008, 14, 312-323
19. Yuan, Z.; Zhang, X.; Sengupta, N.; Lane, W. S.; Seto, E. SIRT1 regulates the function of the Nijmegen breakage syndrome protein Mol. Cell 2007, 27, 149-162
20. Feige, J. N.; Auwerx, J. Transcriptional targets of sirtuins in the coordination of mammalian physiology Curr. Opin. Cell Biol. 2008, 20, 303-309
21. Han, M. K.; Song, E. K.; Guo, Y.; Ou, X.; Mantel, C.; Broxmeyer, H. E. SIRT1 regulates apoptosis and Nanog expression in mouse embryonic stem cells by controlling p53 subcellular localization Cell Stem Cell 2008, 2, 241-251
22. Prozorovski, T.; Schulze-Topphoff, U.; Glumm, R.; Baumgart, J.; Schroter, F.; Ninnemann, O.; Siegert, E.; Bendix, I.; Brustle, O.; Nitsch, R.; Zipp, F.; Aktas, O. Sirt1 contributes critically to the redox-dependent fate of neural progenitors Nat. Cell Biol. 2008, 10, 385-394
23. Potente, M.; Ghaeni, L.; Baldessari, D.; Mostoslavsky, R.; Rossig, L.; Dequiedt, F.; Haendeler, J.; Mione, M.; Dejana, E.; Alt, F. W.; Zeiher, A. M.; Dimmeler, S. SIRT1 controls endothelial angiogenic functions during vascular growth Genes Dev. 2007, 21, 2644-2658
24. Zhang, Q. J.; Wang, Z.; Chen, H. Z.; Zhou, S.; Zheng, W.; Liu, G.; Wei, Y. S.; Cai, H.; Liu, D. P.; Liang, C. C. Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice Cardiovasc. Res. 2008, 80, 191-199
25. Csiszar, A.; Labinskyy, N.; Podlutsky, A.; Kaminski, P. M.; Wolin, M. S.; Zhang, C.; Mukhopadhyay, P.; Pacher, P.; Hu, F.; de Cabo, R.; Ballabh, P.; Ungvari, Z. Vasoprotective effects of resveratrol and SIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations Am. J. Physiol.: Heart Circ. Physiol. 2008, 294, H2721-H2735
26. Lee, J. H.; Song, M. Y.; Song, E. K.; Kim, E. K.; Moon, W. S.; Han, M. K.; Park, J. W.; Kwon, K. B.; Park, B. H. Overexpression of SIRT1 protects pancreatic beta-cells against cytokine toxicity by suppressing the nuclear factor-kappaB signaling pathway Diabetes 2009, 58, 344-351
27. Yoshizaki, T.; Schenk, S.; Imamura, T.; Babendure, J. L.; Sonoda, N.; Bae, E. J.; Oh da, Y.; Lu, M.; Milne, J. C.; Westphal, C.; Bandyopadhyay, G.; Olefsky, J. M. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity Am. J. Physiol.: Endocrinol. Metab. 2010, 298, E419-E428
28. Gan, L.; Mucke, L. Paths of convergence: sirtuins in aging and neurodegeneration Neuron 2008, 58, 10-14
29. Tang, B. L. Sirt1s complex roles in neuroprotection Cell. Mol. Neurobiol. 2009, 29, 1093-1103
30. Firestein, R.; Blander, G.; Michan, S.; Oberdoerffer, P.; Ogino, S.; Campbell, J.; Bhimavarapu, A.; Luikenhuis, S.; de Cabo, R.; Fuchs, C.; Hahn, W. C.; Guarente, L. P.; Sinclair, D. A. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth PLoS One 2008, 3, No. e2020
31. Howitz, K. T.; Bitterman, K. J.; Cohen, H. Y.; Lamming, D. W.; Lavu, S.; Wood, J. G.; Zipkin, R. E.; Chung, P.; Kisielewski, A.; Zhang, L. L.; Scherer, B.; Sinclair, D. A. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan Nature 2003, 425, 191-196
32. Baur, J. A.; Pearson, K. J.; Price, N. L.; Jamieson, H. A.; Lerin, C.; Kalra, A.; Prabhu, V. V.; Allard, J. S.; Lopez-Lluch, G.; Lewis, K.; Pistell, P. J.; Poosala, S.; Becker, K. G.; Boss, O.; Gwinn, D.; Wang, M.; Ramaswamy, S.; Fishbein, K. W.; Spencer, R. G.; Lakatta, E. G.; Le Couteur, D.; Shaw, R. J.; Navas, P.; Puigserver, P.; Ingram, D. K.; de Cabo, R.; Sinclair, D. A. Resveratrol improves health and survival of mice on a high-calorie diet Nature 2006, 444, 337-342
33. Lagouge, M.; Argmann, C.; Gerhart-Hines, Z.; Meziane, H.; Lerin, C.; Daussin, F.; Messadeq, N.; Milne, J.; Lambert, P.; Elliott, P.; Geny, B.; Laakso, M.; Puigserver, P.; Auwerx, J. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha Cell 2006, 127, 1109-1122
34. Csiszar, A.; Labinskyy, N.; Pinto, J. T.; Ballabh, P.; Zhang, H.; Losonczy, G.; Pearson, K.; de Cabo, R.; Pacher, P.; Zhang, C.; Ungvari, Z. Resveratrol induces mitochondrial biogenesis in endothelial cells Am. J. Physiol.: Heart Circ. Physiol. 2009, 297, H13-H20
35. Yang, S. R.; Wright, J.; Bauter, M.; Seweryniak, K.; Kode, A.; Rahman, I. Sirtuin regulates cigarette smoke-induced proinflammatory mediator release via RelA/p65 NF-kappaB in macrophages in vitro and in rat lungs in vivo: implications for chronic inflammation and aging Am. J. Physiol.: Lung Cell. Mol. Physiol. 2007, 292, L567-L576
36. Kundu, J. K.; Surh, Y. J. Cancer chemopreventive and therapeutic potential of resveratrol: mechanistic perspectives Cancer Lett. 2008, 269, 243-261
37. Wang, R. H.; Zheng, Y.; Kim, H. S.; Xu, X.; Cao, L.; Luhasen, T.; Lee, M. H.; Xiao, C.; Vassilopoulos, A.; Chen, W.; Gardner, K.; Man, Y. G.; Hung, M. C.; Finkel, T.; Deng, C. X. Interplay among BRCA1, SIRT1, and survivin during BRCA1-associated tumorigenesis Mol. Cell 2008, 32, 11-20
38. Albani, D.; Polito, L.; Batelli, S.; De Mauro, S.; Fracasso, C.; Martelli, G.; Colombo, L.; Manzoni, C.; Salmona, M.; Caccia, S.; Negro, A.; Forloni, G. The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused by alpha-synuclein or amyloid-beta (1-42) peptide J. Neurochem. 2009, 110, 1445-1456
39. Kim, D.; Nguyen, M. D.; Dobbin, M. M.; Fischer, A.; Sananbenesi, F.; Rodgers, J. T.; Delalle, I.; Baur, J. A.; Sui, G.; Armour, S. M.; Puigserver, P.; Sinclair, D. A.; Tsai, L. H. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimers disease and amyotrophic lateral sclerosis EMBO J. 2007, 26, 3169-3179
40. Lee, M.; Kim, S.; Kwon, O. K.; Oh, S. R.; Lee, H. K.; Ahn, K. Anti-inflammatory and anti-asthmatic effects of resveratrol, a polyphenolic stilbene, in a mouse model of allergic asthma Int. Immunopharmacol. 2009, 9, 418-424
41. Barger, J. L.; Kayo, T.; Vann, J. M.; Arias, E. B.; Wang, J.; Hacker, T. A.; Wang, Y.; Raederstorff, D.; Morrow, J. D.; Leeuwenburgh, C.; Allison, D. B.; Saupe, K. W.; Cartee, G. D.; Weindruch, R.; Prolla, T. A. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice PLoS One 2008, 3 e2264
42. Pearson, K. J.; Baur, J. A.; Lewis, K. N.; Peshkin, L.; Price, N. L.; Labinskyy, N.; Swindell, W. R.; Kamara, D.; Minor, R. K.; Perez, E.; Jamieson, H. A.; Zhang, Y.; Dunn, S. R.; Sharma, K.; Pleshko, N.; Woollett, L. A.; Csiszar, A.; Ikeno, Y.; Le Couteur, D.; Elliott, P. J.; Becker, K. G.; Navas, P.; Ingram, D. K.; Wolf, N. S.; Ungvari, Z.; Sinclair, D. A.; de Cabo, R. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span Cell Metab. 2008, 8, 157-168
43. Smith, J. J.; Kenney, R. D.; Gagne, D. J.; Frushour, B. P.; Ladd, W.; Galonek, H. L.; Israelian, K.; Song, J.; Razvadauskaite, G.; Lynch, A. V.; Carney, D. P.; Johnson, R. J.; Lavu, S.; Iffland, A.; Elliott, P. J.; Lambert, P. D.; Elliston, K. O.; Jirousek, M. R.; Milne, J. C.; Boss, O. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo BMC Syst. Biol. 2009, 3, 31
44. Armour, S. M.; Baur, J. A.; Hsieh, S. N.; Land-Bracha, A.; Thomas, S. M.; Sinclair, D. A. Inhibition of mammalian S6 kinase by resveratrol suppresses autophagy Aging (Albany, N.Y.) 2009, 1, 515-528
45. Dasgupta, B.; Milbrandt, J. Resveratrol stimulates AMP kinase activity in neurons Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 7217-7222
46. Um, J. H.; Park, S. J.; Kang, H.; Yang, S.; Foretz, M.; McBurney, M. W.; Kim, M. K.; Viollet, B.; Chung, J. H. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol Diabetes 2010, 59, 554-563
47. Baur, J. A. Resveratrol, sirtuins, and the promise of a DR mimetic Mech. Ageing Dev. 2010, 131, 261-269
48. Chen, D.; Bruno, J.; Easlon, E.; Lin, S. J.; Cheng, H. L.; Alt, F. W.; Guarente, L. Tissue-specific regulation of SIRT1 by calorie restriction Genes Dev. 2008, 22, 1753-1757
49. Purushotham, A.; Schug, T. T.; Xu, Q.; Surapureddi, S.; Guo, X.; Li, X. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation Cell Metab. 2009, 9, 327-338
50. Alcendor, R. R.; Gao, S.; Zhai, P.; Zablocki, D.; Holle, E.; Yu, X.; Tian, B.; Wagner, T.; Vatner, S. F.; Sadoshima, J. Sirt1 regulates aging and resistance to oxidative stress in the heart Circ. Res. 2007, 100, 1512-1521
51. Kabra, N.; Li, Z.; Chen, L.; Li, B.; Zhang, X.; Wang, C.; Yeatman, T.; Coppola, D.; Chen, J. SirT1 is an inhibitor of proliferation and tumor formation in colon cancer J. Biol. Chem. 2009, 284, 18210-18217
52. Hida, Y.; Kubo, Y.; Murao, K.; Arase, S. Strong expression of a longevity-related protein, SIRT1, in Bowens disease Arch. Dermatol. Res. 2007, 299, 103-106
53. Huffman, D. M.; Grizzle, W. E.; Bamman, M. M.; Kim, J. S.; Eltoum, I. A.; Elgavish, A.; Nagy, T. R. SIRT1 is significantly elevated in mouse and human prostate cancer Cancer Res. 2007, 67, 6612-6618
54. Stunkel, W.; Peh, B. K.; Tan, Y. C.; Nayagam, V. M.; Wang, X.; Salto-Tellez, M.; Ni, B.; Entzeroth, M.; Wood, J. Function of the SIRT1 protein deacetylase in cancer Biotechnol. J. 2007, 2, 1360-1368
55. Zorn, J. A.; Wells, J. A. Turning enzymes ON with small molecules Nat. Chem. Biol. 2010, 6, 179-188
56. Lavu, S.; Boss, O.; Elliott, P. J.; Lambert, P. D. Sirtuins - novel therapeutic targets to treat age-associated diseases Nat. Rev. Drug Discovery 2008, 7, 841-853
57. Sauve, A. A.; Celic, I.; Acalos, J.; Deng, H.; Boeke, J. D.; Schramm, V. L. Chemistry of gene silencing: the mechanism of NAD-dependent deacetylation reactions Biochemistry 2001, 40, 15456-15463
58. Sauve, A. A.; Schramm, V. L. Sir2 regulation by nicotinamide results from switching between base exchange and deacetylation chemistry Biochemistry 2003, 42, 9249-9256
59. Sauve, A. A.; Wolberger, C.; Schramm, V. L.; Boeke, J. D. The biochemistry of sirtuins Annu. Rev. Biochem. 2006, 75, 435-465
60. Sauve, A. A. Pharmaceutical strategies for activating sirtuins Curr. Pharm. Des. 2009, 15, 45-56
61. Avalos, J. L.; Bever, K. M.; Wolberger, C. Mechanism of sirtuin inhibition by nicotinamide: altering the NAD(+) cosubstrate specificity of a Sir2 enzyme Mol. Cell 2005, 17, 855-868
62. Avalos, J. L.; Boeke, J. D.; Wolberger, C. Structural basis for the mechanism and regulation of Sir2 enzymes Mol. Cell 2004, 13, 639-648
63. + and acetylated peptide Structure 2006, 14, 1231-1240
64. Min, J.; Landry, J.; Sternglanz, R.; Xu, R. M. Crystal structure of a SIR2 homolog-NAD complex Cell 2001, 105, 269-279
65. +- dependent histone/protein deacetylases Biochemistry 2004, 43, 9877-9887
66. Jin, L.; Wei, W.; Jiang, Y.; Peng, H.; Cai, J.; Mao, C.; Dai, H.; Choy, W.; Bemis, J. E.; Jirousek, M. R.; Milne, J. C.; Westphal, C. H.; Perni, R. B. Crystal structures of human SIRT3 displaying substrate-induced conformational changes J. Biol. Chem. 2009, 284, 24394-24405
67. Blander, G.; Olejnik, J.; Krzymanska-Olejnik, E.; McDonagh, T.; Haigis, M.; Yaffe, M. B.; Guarente, L. SIRT1 shows no substrate specificity in vitro J. Biol. Chem. 2005, 280, 9780-9785
68. Garske, A. L.; Denu, J. M. SIRT1 top 40 hits: use of one-bead, one-compound acetyl-peptide libraries and quantum dots to probe deacetylase specificity Biochemistry 2006, 45, 94-101
69. Smith, B. C.; Hallows, W. C.; Denu, J. M. A continuous microplate assay for sirtuins and nicotinamide-producing enzymes Anal. Biochem. 2009, 394, 101-109
70. Szczepankiewicz, B. G.; Ng, P. Y. Sirtuin modulators: targets for metabolic diseases and beyond Curr. Top. Med. Chem. 2008, 8, 1533-1544
71. Cen, Y. Sirtuin inhibitors: the approach to affinity and selectivity Biochim. Biophys. Acta 2009, 1635-1644
72. Alcain, F. J.; Villalba, J. M. Sirtuin activators Expert Opin. Ther. Pat. 2009, 19, 403-414
73. Alcain, F. J.; Villalba, J. M. Sirtuin inhibitors Expert Opin. Ther. Pat. 2009, 19, 283-294
74. Napper, A. D.; Hixon, J.; McDonagh, T.; Keavey, K.; Pons, J. F.; Barker, J.; Yau, W. T.; Amouzegh, P.; Flegg, A.; Hamelin, E.; Thomas, R. J.; Kates, M.; Jones, S.; Navia, M. A.; Saunders, J. O.; DiStefano, P. S.; Curtis, R. Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1 J. Med. Chem. 2005, 48, 8045-8054
75. +-dependent histone deacetylases (sirtuins) ChemMedChem 2007, 2, 1419-1431
76. +-dependent deacetylase SIRT5 by suramin Structure 2007, 15, 377-389
77. Fatkins, D. G.; Monnot, A. D.; Zheng, W. N-epsilon-thioacetyl-lysine: a multi-facet functional probe for enzymatic protein lysine N-epsilon- deacetylation Bioorg. Med. Chem. Lett. 2006, 16, 3651-3656
78. Smith, B. C.; Denu, J. M. Mechanism-based inhibition of Sir2 deacetylases by thioacetyl-lysine peptide Biochemistry 2007, 46, 14478-14486
79. Fatkins, D. G.; Zheng, W. Substituting N -thioacetyl-lysine for N -acetyl-lysine in peptide substrates as a general approach to inhibiting human NAD-dependent protein deacetylases Int. J. Mol. Sci. 2008, 9, 1-11
80. +-dependent histone deacetylases Anal. Biochem. 2003, 319, 42-48
81. Suzuki, T.; Asaba, T.; Imai, E.; Tsumoto, H.; Nakagawa, H.; Miyata, N. Identification of a cell-active non-peptide sirtuin inhibitor containing N -thioacetyl lysine Bioorg. Med. Chem. Lett. 2009, 19, 5670-5672
82. Asaba, T.; Suzuki, T.; Ueda, R.; Tsumoto, H.; Nakagawa, H.; Miyata, N. Inhibition of human sirtuins by in situ generation of an acetylated lysine-ADP-ribose conjugate J. Am. Chem. Soc. 2009, 131, 6989-6996
83. Chakrabarty, S. P.; Ramapanicker, R.; Mishra, R.; Chandrasekaran, S.; Balaram, H. Development and characterization of lysine based tripeptide analogues as inhibitors of Sir2 activity Bioorg. Med. Chem. 2009, 17, 8060-8072
84. Suzuki, T.; Imai, K.; Nakagawa, H.; Miyata, N. 2-Anilinobenzamides as SIRT inhibitors ChemMedChem 2006, 1, 1059-1062
85. Suzuki, T.; Imai, K.; Imai, E.; Iida, S.; Ueda, R.; Tsumoto, H.; Nakagawa, H.; Miyata, N. Design, synthesis, enzyme inhibition, and tumor cell growth inhibition of 2-anilinobenzamide derivatives as SIRT1 inhibitors Bioorg. Med. Chem. 2009, 17, 5900-5905
86. Lara, E.; Mai, A.; Calvanese, V.; Altucci, L.; Lopez-Nieva, P.; Martinez-Chantar, M. L.; Varela-Rey, M.; Rotili, D.; Nebbioso, A.; Ropero, S.; Montoya, G.; Oyarzabal, J.; Velasco, S.; Serrano, M.; Witt, M.; Villar-Garea, A.; Imhof, A.; Mato, J. M.; Esteller, M.; Fraga, M. F. Salermide, a sirtuin inhibitor with a strong cancer-specific proapoptotic effect Oncogene 2009, 28, 781-791
87. Pasco, M. Y.; Rotili, D.; Altucci, L.; Farina, F.; Rouleau, G. A.; Mai, A.; Neri, C. Characterization of sirtuin inhibitors in nematodes expressing a muscular dystrophy protein reveals muscle cell and behavioral protection by specific sirtinol analogues J. Med. Chem. 2010, 1407-1411
88. Heltweg, B.; Gatbonton, T.; Schuler, A. D.; Posakony, J.; Li, H.; Goehle, S.; Kollipara, R.; Depinho, R. A.; Gu, Y.; Simon, J. A.; Bedalov, A. Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes Cancer Res. 2006, 66, 4368-4377
89. Lain, S.; Hollick, J. J.; Campbell, J.; Staples, O. D.; Higgins, M.; Aoubala, M.; McCarthy, A.; Appleyard, V.; Murray, K. E.; Baker, L.; Thompson, A.; Mathers, J.; Holland, S. J.; Stark, M. J.; Pass, G.; Woods, J.; Lane, D. P.; Westwood, N. J. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator Cancer Cell 2008, 13, 454-463
90. Medda, F.; Russell, R. J.; Higgins, M.; McCarthy, A. R.; Campbell, J.; Slawin, A. M.; Lane, D. P.; Lain, S.; Westwood, N. J. Novel cambinol analogs as sirtuin inhibitors: synthesis, biological evaluation, and rationalization of activity J. Med. Chem. 2009, 52, 2673-2682
91. Huhtiniemi, T.; Wittekindt, C.; Laitinen, T.; Leppanen, J.; Salminen, A.; Poso, A.; Lahtela-Kakkonen, M. Comparative and pharmacophore model for deacetylase SIRT1 J. Comput.-Aided Mol. Des. 2006, 20, 589-599
92. Huhtiniemi, T.; Suuronen, T.; Rinne, V. M.; Wittekindt, C.; Lahtela-Kakkonen, M.; Jarho, E.; Wallen, E. A.; Salminen, A.; Poso, A.; Leppanen, J. Oxadiazole-carbonylaminothioureas as SIRT1 and SIRT2 inhibitors J. Med. Chem. 2008, 51, 4377-4380
93. Uciechowska, U.; Schemies, J.; Neugebauer, R. C.; Huda, E. M.; Schmitt, M. L.; Meier, R.; Verdin, E.; Jung, M.; Sippl, W. Thiobarbiturates as sirtuin inhibitors: virtual screening, free-energy calculations, and biological testing ChemMedChem 2008, 3, 1965-1976
94. Sanders, B. D.; Jackson, B.; Brent, M.; Taylor, A. M.; Dang, W.; Berger, S. L.; Schreiber, S. L.; Howitz, K.; Marmorstein, R. Identification and characterization of novel sirtuin inhibitor scaffolds Bioorg. Med. Chem. 2009, 17, 7031-7041
95. +-dependent histone deacetylases, from kinase to sirtuin inhibition J. Med. Chem. 2006, 49, 7307-7316
96. Huber, K.; Schemies, J.; Uciechowska, U.; Wagner, J. M.; Rumpf, T.; Lewrick, F.; Suss, R.; Sippl, W.; Jung, M.; Bracher, F. Novel 3-arylideneindolin-2-ones as inhibitors of NAD(+)-dependent histone deacetylases (sirtuins) J. Med. Chem. 2010, 53, 1383-1386
97. Tavares, J.; Ouaissi, A.; Kong Thoo Lin, P.; Loureiro, I.; Kaur, S.; Roy, N.; Cordeiro-da-Silva, A. Bisnaphthalimidopropyl derivatives as inhibitors of Leishmania SIR2 related protein 1 ChemMedChem 2010, 5, 140-147
98. Pervaiz, S.; Holme, A. L. Resveratrol: its biologic targets and functional activity Antioxid. Redox Signaling 2009, 11, 2851-2897
99. Baur, J. A.; Pearson, K. J.; Price, N. L.; Jamieson, H. A.; Lerin, C.; Kalra, A.; Prabhu, V. V.; Allard, J. S.; Lopez-Lluch, G.; Lewis, K.; Pistell, P. J.; Poosala, S.; Becker, K. G.; Boss, O.; Gwinn, D.; Wang, M.; Ramaswamy, S.; Fishbein, K. W.; Spencer, R. G.; Lakatta, E. G.; Le Couteur, D.; Shaw, R. J.; Navas, P.; Puigserver, P.; Ingram, D. K.; de Cabo, R.; Sinclair, D. A. Resveratrol improves health and survival of mice on a high-calorie diet Nature 2006, 444, 337-342
100. Rasbach, K. A.; Schnellmann, R. G. Isoflavones promote mitochondrial biogenesis J. Pharmacol. Exp. Ther. 2008, 325, 536-543
101. Davis, J. M.; Murphy, E. A.; Carmichael, M. D.; Davis, B. Quercetin increases brain and muscle mitochondrial biogenesis and exercise tolerance Am. J. Physiol.: Regul., Integr. Comp. Physiol. 2009, 296, R1071-R1077
102. Bitterman, K. J.; Anderson, R. M.; Cohen, H. Y.; Latorre-Esteves, M.; Sinclair, D. A. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1 J. Biol. Chem. 2002, 277, 45099-45107
103. Sauve, A. A.; Moir, R. D.; Schramm, V. L.; Willis, I. M. Chemical activation of Sir2-dependent silencing by relief of nicotinamide inhibition Mol. Cell 2005, 17, 595-601
104. Mai, A.; Valente, S.; Meade, S.; Carafa, V.; Tardugno, M.; Nebbioso, A.; Galmozzi, A.; Mitro, N.; De Fabiani, E.; Altucci, L.; Kazantsev, A. Study of 1,4-dihydropyridine structural scaffold: discovery of novel sirtuin activators and inhibitors J. Med. Chem. 2009, 52, 5496-5504
105. Milne, J. C.; Lambert, P. D.; Schenk, S.; Carney, D. P.; Smith, J. J.; Gagne, D. J.; Jin, L.; Boss, O.; Perni, R. B.; Vu, C. B.; Bemis, J. E.; Xie, R.; Disch, J. S.; Ng, P. Y.; Nunes, J. J.; Lynch, A. V.; Yang, H.; Galonek, H.; Israelian, K.; Choy, W.; Iffland, A.; Lavu, S.; Medvedik, O.; Sinclair, D. A.; Olefsky, J. M.; Jirousek, M. R.; Elliott, P. J.; Westphal, C. H. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes Nature 2007, 450, 712-716
106. Bemis, J. E.; Vu, C. B.; Xie, R.; Nunes, J. J.; Ng, P. Y.; Disch, J. S.; Milne, J. C.; Carney, D. P.; Lynch, A. V.; Jin, L.; Smith, J. J.; Lavu, S.; Iffland, A.; Jirousek, M. R.; Perni, R. B. Discovery of oxazolo[4,5- b ]pyridines and related heterocyclic analogs as novel SIRT1 activators Bioorg. Med. Chem. Lett. 2009, 19, 2350-2353
107. Vu, C. B.; Bemis, J. E.; Disch, J. S.; Ng, P. Y.; Nunes, J. J.; Milne, J. C.; Carney, D. P.; Lynch, A. V.; Smith, J. J.; Lavu, S.; Lambert, P. D.; Gagne, D. J.; Jirousek, M. R.; Schenk, S.; Olefsky, J. M.; Perni, R. B. Discovery of imidazo[1,2- b ]thiazole derivatives as novel SIRT1 activators J. Med. Chem. 2009, 1275-1283
108. Vu, C. B.; Oalmann, C. J.; Perni, R. B.; Disch, J. S.; Szczepankiewicz, B.; Gualtieri, G.; Casaubon, R. L. Solubilized Thiazolopyridines. WO 2009/061453 A1, 2009.
109. Koppetsch, K. J.; Oalmann, C. J.; Szczepankiewicz, B.; Vu, C. B.; Gualtieri, G.; Casaubon, R. L.; Disch, J. S.; Lynch, A. V.; Song, J.; Gagne, D. J.; Cote, A.; Davis, M.; Lainez, E.; Perni, R. B. Abstracts of Papers, 240th National Meeting of the American Chemical Society, Boston, MA, Aug 22-26, 2010; American Chemical Society: Washington, DC, 2010; MEDI-74.
110. Vu, C. B.; Disch, J. S.; Ng, P. Y.; Blum, C. A.; Perni, R. B. Benzimidazoles and Related Analogs as Sirtuin Modulators. WO 2010/003048 A1, 2010.
111. Disch, J. S.; Vu, C. B.; McPherson, L.; Ng, P. Y.; Bemis, J. E.; Carney, D. P.; Lynch, A. V.; Loh, C.; Ribich, S.; Romero, P.; Smith, J. J.; Song, J.; Gagne, D. J.; Cote, A.; Davis, M.; Lainez, E.; Perni, R. B. Abstracts of Papers, 240th National Meeting of the American Chemical Society, Boston, MA, Aug 22-26, 2010; American Chemical Society: Washington, DC, 2010; MEDI-70.
112. Tomomi, A.; Suziki, T.; Ueda, R.; Tsumoto, H.; Nakagawa, H.; Miyata, N. Inhibition of human sirtuins by in situ generation of an acetylated Lys-ADP-ribose conjugate J. Am. Chem. Soc. 2009, 131, 6989-6996
113. Borra, M. T.; Smith, B. C.; Denu, J. M. Mechanism of human SIRT1 activation by resveratrol J. Biol. Chem. 2005, 280, 17187-17195
114. Kaeberlein, M.; McDonagh, T.; Heltweg, B.; Hixon, J.; Westman, E. A.; Caldwell, S. D.; Napper, A.; Curtis, R.; DiStefano, P. S.; Fields, S.; Beldalov, A.; Kennedy, B. K. Substrate-specific activation of sirtuins by resveratrol J. Biol. Chem. 2005, 280, 17038-17045
115. Beher, D.; Wu, J.; Cumine, S.; Kim, K. W.; Lu, S. C.; Atangan, L.; Wang, M. Resveratrol is not a direct activator of SIRT1 enzyme activity Chem. Biol. Drug Des. 2009, 619-624
116. Pacholec, M.; Bleasdale, J. E.; Chrunyk, B.; Cunningham, D.; Flynn, D.; Garofalo, R. S.; Griffith, D.; Griffor, M.; Loulakis, P.; Pabst, B.; Qiu, X.; Stockman, B.; Thanabal, V.; Varghese, A.; Ward, J.; Withka, J.; Ahn, K. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1 J. Biol. Chem. 2010, 285, 8340-8351
117. Segel, I. H. Enzyme Kinetics; John Wiley & Sons: New York, 1975.
118. Erlanger, B. F.; Wasserman, N. H.; Cooper, A. G.; Monk, R. J. Allosterice activation of the hydrolysis of specific substrates by chymotrypsin Eur. J. Biochem. 1976, 61, 287-295
119. Aharony, D.; Stein, R. L. Kinetic mechanism of guinea pig neutrophil 5-lipoxygenase J. Biol. Chem. 1986, 261, 11512-11519
120. Cabrol, C.; Huzarska, M. A.; Dinolfo, C.; Rodriguez, M. C.; Reinstatler, L.; Ni, J.; Yeh, L. A.; Cuny, G. D.; Stein, R. L.; Selkoe, D. J.; Leissring, M. A. Small molecule activators of insulin degrading enzyme PLoS One 2009, 4 e5274
121. Song, E. S.; Juliano, M. A.; Juliano, L.; Fried, M. G.; Wagner, S. L.; Hersh, L. B. ATP effects on insulin-degrading enzyme are mediated primarily through its triphosphate moiety J. Biol. Chem. 2004, 279, 54216-54220
122. Eliasson, R.; Pontis, E.; Sun, X.; Reichard, P. Allosteric control of the substrate specificity of the anaerobic ribonucleotide reductase from Escherichia coli J. Biol. Chem. 1994, 269, 26052-26057
123. While this manuscript was in the process of review, a paper appeared (ref 140) that addresses the mechanism of action of STACs in general and, more specifically, the claim made by Pacholec et al. (ref 116) that activation is indirect, involving the formation of activator-substrate complexes. The paper reports, in agreement with Pacholec et al., that certain STACs can form complexes with the TAMRA-peptide, but it concludes that these complexes are not involved in the activation of SIRT1. Rather, Dai et al. present evidence suggesting that STACs interact directly with this enzyme and activate deacetylation by an allosteric mechanism. Such a mechanism can account for the substrate structural-dependence of SIRT1 activation, as well as the observation of Dai et al. that STACs can accelerate the deacetylation of unlabeled peptides composed only of natural amino acids.
124. Feige, J. N.; Lagouge, M.; Canto, C.; Strehle, A.; Houten, S. M.; Milne, J. C.; Lambert, P. D.; Mataki, C.; Elliott, P. J.; Auwerx, J. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation Cell Metab. 2008, 8, 347-358
125. Yoshizaki, T.; Milne, J. C.; Imamura, T.; Schenk, S.; Sonoda, N.; Babendure, J. L.; Lu, J. C.; Smith, J. J.; Jirousek, M. R.; Olefsky, J. M. SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes Mol. Cell. Biol. 2009, 29, 1363-1374
126. Yamazaki, Y.; Usui, I.; Kanatani, Y.; Matsuya, Y.; Tsuneyama, K.; Fujisaka, S.; Bukhari, A.; Suzuki, H.; Senda, S.; Imanishi, S.; Hirata, K.; Ishiki, M.; Hayashi, R.; Urakaze, M.; Nemoto, H.; Kobayashi, M.; Tobe, K. Treatment with SRT1720, a SIRT1 activator, ameliorates fatty liver with reduced expression of lipogenic enzymes in MSG mice Am. J. Physiol.: Endocrinol. Metab. 2009, 1179-1186
127. Liu, Y.; Dentin, R.; Chen, D.; Hedrick, S.; Ravnskjaer, K.; Schenk, S.; Milne, J.; Meyers, D. J.; Cole, P.; Yates, J., 3rd; Olefsky, J.; Guarente, L.; Montminy, M. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange Nature 2008, 456, 269-273
128. Funk, J. A.; Odejinmi, S.; Schnellmann, R. G. SRT1720 induces mitochondrial biogenesis and rescues mitochondrial function after oxidant injury in renal proximal tubule cells J. Pharmacol. Exp. Ther. 2010, 593-601
129. He, W.; Wang, Y.; Zhang, M. Z.; You, L.; Davis, L. S.; Fan, H.; Yang, H. C.; Fogo, A. B.; Zent, R.; Harris, R. C.; Breyer, M. D.; Hao, C. M. Sirt1 activation protects the mouse renal medulla from oxidative injury J. Clin. Invest. 2010, 1056-1068
130. de Cabo, R. National Institute on Aging, Baltimore, MD. Personal Communication, 2010.
131. Jarolim, S.; Millen, J.; Heeren, G.; Laun, P.; Goldfarb, D. S.; Breitenbach, M. A novel assay for replicative lifespan in Saccharomyces cerevisiae FEMS Yeast Res. 2004, 5, 169-177
132. Yang, H.; Baur, J. A.; Chen, A.; Miller, C.; Adams, J. K.; Kisielewski, A.; Howitz, K. T.; Zipkin, R. E.; Sinclair, D. A. Design and synthesis of compounds that extend yeast replicative lifespan Aging Cell 2007, 6, 35-43
133. Viswanathan, M.; Kim, S. K.; Berdichevsky, A.; Guarente, L. A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span Dev. Cell 2005, 9, 605-615
134. Bass, T. M.; Weinkove, D.; Houthoofd, K.; Gems, D.; Partridge, L. Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans Mech. Ageing Dev. 2007, 128, 546-552
135. Wood, J. G.; Rogina, B.; Lavu, S.; Howitz, K.; Helfand, S. L.; Tatar, M.; Sinclair, D. Sirtuin activators mimic caloric restriction and delay ageing in metazoans Nature 2004, 430, 686-689
136. Picard, F.; Kurtev, M.; Chung, N.; Topark-Ngarm, A.; Senawong, T.; Machado De Oliveira, R.; Leid, M.; McBurney, M. W.; Guarente, L. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma Nature 2004, 429, 771-776
137. Fischer-Posovszky, P.; Kukulus, V.; Tews, D.; Unterkircher, T.; Debatin, K. M.; Fulda, S.; Wabitsch, M. Resveratrol regulates human adipocyte number and function in a Sirt1-dependent manner Am. J. Clin. Nutr. 2010, 5-15
138. Boily, G.; He, X. H.; Pearce, B.; Jardine, K.; McBurney, M. W. SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol Oncogene 2009, 28, 2882-2893
139. Haigis, M. C.; Sinclair, D. A. Mammalian sirtuins: biological insights and disease relevance Annu. Rev. Pathol. 2010, 5, 253-295
140. Dai, H.; Kustigian, L.; Carney, D.; Case, A.; Considine, T.; Hubbard, B. P.; Perni, R. B.; Riera, T. V.; Szczepankiewicz, B.; Vlasuk, G. P.; Stein, R. L. SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and activator J. Biol. Chem. 2010, 285, 32695-32703