Aminothiazoles as Potent and Selective Sirt2 Inhibitors: A Structure-Activity Relationship Study

Journal of Medicinal Chemistry

Volumn 59, Issue 4, 2016, Pages 1599-1612

  Schiedel, Matthias ^a   Rumpf, Tobias ^a   Karaman, Berin ^b   Lehotzky, Attila ^c   Oláh, Judit ^c   Gerhardt, Stefan ^a   Ovádi, Judit ^c   Sippl, Wolfgang ^b   Einsle, Oliver ^a   Jung, Manfred ^a  

^a UNIVERSITY OF FREIBURG   (Germany)

^b MARTIN LUTHER UNIVERSITY HALLE WITTENBERG   (Germany)

^c INSTITUTE OF EXPERIMENTAL MEDICINE   (Hungary)

Author keywords

[No Author keywords available]

Indexed keywords

2 CHLORO N [5 [(7 CHLORO 1 NAPHTHYL)METHYL]THIAZOL 2 YL]ACETAMIDE; 2 MERCAPTO 4,6 DIMETHYLPYRIMIDINE DERIVATIVE; 5 (1 NAPHTHYLMETHYL) 1,3,4 THIADIAZOL 2 AMINE; 5 (M TOLYLMETHYL)THIAZOL 2 AMINE; 5 [(7 CHLORO 1 NAPHTHYL)METHYL]THIAZOL 2 AMINE; 7 CHLORO 1 NITRO NAPHTHALENE; 7 CHLORONAPHTHALEN 1 AMINE; 8 NITRONAPHTHALEN 2 AMINE; AMINOTHIAZOLE DERIVATIVE; METHYL GROUP; N [5 [(7 CHLORO 1 NAPHTHYL)METHYL]THIAZOL 2 YL] 2 (4,6 DIMETHYLPYRIMIDIN 2 YL)SULFANYLACETAMIDE; PYRIMIDINE; SIRTUIN 2; SIRTUIN 2 INHIBITOR; THIAZOLE DERIVATIVE; TUBULIN; UNCLASSIFIED DRUG; ENZYME INHIBITOR; LIGAND; PROTEIN BINDING; SIRT2 PROTEIN, HUMAN;

ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; ENZYME INHIBITION; HELA CELL LINE; IN VITRO STUDY; MOLECULAR DOCKING; PROTEIN ACETYLATION; PROTEIN STRUCTURE; STRUCTURE ACTIVITY RELATION; AMINATION; ANTAGONISTS AND INHIBITORS; CHEMISTRY; HUMAN; METABOLISM; X RAY CRYSTALLOGRAPHY;

AMINATION; CRYSTALLOGRAPHY, X-RAY; ENZYME INHIBITORS; HELA CELLS; HUMANS; LIGANDS; MOLECULAR DOCKING SIMULATION; PROTEIN BINDING; SIRTUIN 2; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES; TUBULIN;

EID: 84959372234     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b01517     Document Type: Article

References (62)

1. de Ruijter, A. J.; van Gennip, A. H.; Caron, H. N.; Kemp, S.; van Kuilenburg, A. B. Histone deacetylases (HDACs): characterization of the classical HDAC family Biochem. J. 2003, 370, 737-749 10.1042/bj20021321
2. Sauve, A. A. Sirtuin chemical mechanisms Biochim. Biophys. Acta, Proteins Proteomics 2010, 1804, 1591-1603 10.1016/j.bbapap.2010.01.021
3. Feldman, J. L.; Baeza, J.; Denu, J. M. Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins J. Biol. Chem. 2013, 288, 31350-31356 10.1074/jbc.C113.511261
4. Jiang, H.; Khan, S.; Wang, Y.; Charron, G.; He, B.; Sebastian, C.; Du, J.; Kim, R.; Ge, E.; Mostoslavsky, R.; Hang, H. C.; Hao, Q.; Lin, H. SIRT6 regulates TNF-alpha secretion through hydrolysis of long-chain fatty acyl lysine Nature 2013, 496, 110-113 10.1038/nature12038
5. Du, J.; Zhou, Y.; Su, X.; Yu, J. J.; Khan, S.; Jiang, H.; Kim, J.; Woo, J.; Kim, J. H.; Choi, B. H.; He, B.; Chen, W.; Zhang, S.; Cerione, R. A.; Auwerx, J.; Hao, Q.; Lin, H. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase Science 2011, 334, 806-809 10.1126/science.1207861
6. +-dependent tubulin deacetylase Mol. Cell 2003, 11, 437-444 10.1016/S1097-2765(03)00038-8
7. Yeung, F.; Hoberg, J. E.; Ramsey, C. S.; Keller, M. D.; Jones, D. R.; Frye, R. A.; Mayo, M. W. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase EMBO J. 2004, 23, 2369-2380 10.1038/sj.emboj.7600244
8. Vaziri, H.; Dessain, S. K.; Ng Eaton, E.; Imai, S. I.; Frye, R. A.; Pandita, T. K.; Guarente, L.; Weinberg, R. A. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase Cell 2001, 107, 149-159 10.1016/S0092-8674(01)00527-X
9. North, B. J.; Rosenberg, M. A.; Jeganathan, K. B.; Hafner, A. V.; Michan, S.; Dai, J.; Baker, D. J.; Cen, Y.; Wu, L. E.; Sauve, A. A.; van Deursen, J. M.; Rosenzweig, A.; Sinclair, D. A. SIRT2 induces the checkpoint kinase BubR1 to increase lifespan EMBO J. 2014, 33, 1438-1453 10.15252/embj.201386907
10. 32P-NAD Biochemistry 2009, 48, 2878-2890 10.1021/bi802093g
11. Haigis, M. C.; Guarente, L. P. Mammalian sirtuins-emerging roles in physiology, aging, and calorie restriction Genes Dev. 2006, 20, 2913-2921 10.1101/gad.1467506
12. Verdin, E.; Hirschey, M. D.; Finley, L. W.; Haigis, M. C. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling Trends Biochem. Sci. 2010, 35, 669-675 10.1016/j.tibs.2010.07.003
13. +-dependent sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response J. Biol. Chem. 2012, 287, 25758-25769 10.1074/jbc.M112.362343
14. Feige, J. N.; Auwerx, J. Transcriptional targets of sirtuins in the coordination of mammalian physiology Curr. Opin. Cell Biol. 2008, 20, 303-309 10.1016/j.ceb.2008.03.012
15. Schemies, J.; Uciechowska, U.; Sippl, W.; Jung, M. NAD(+) -dependent histone deacetylases (sirtuins) as novel therapeutic targets Med. Res. Rev. 2010, 30, 861-889 10.1002/med.20178
16. Beirowski, B.; Gustin, J.; Armour, S. M.; Yamamoto, H.; Viader, A.; North, B. J.; Michan, S.; Baloh, R. H.; Golden, J. P.; Schmidt, R. E.; Sinclair, D. A.; Auwerx, J.; Milbrandt, J. Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling Proc. Natl. Acad. Sci. U. S. A. 2011, 108, E952-961 10.1073/pnas.1104969108
17. de Oliveira, R. M.; Sarkander, J.; Kazantsev, A. G.; Outeiro, T. F. SIRT2 as a therapeutic target for age-related disorders Front. Pharmacol. 2012, 3, 82 10.3389/fphar.2012.00082
18. Pais, T. F.; Szego, E. M.; Marques, O.; Miller-Fleming, L.; Antas, P.; Guerreiro, P.; de Oliveira, R. M.; Kasapoglu, B.; Outeiro, T. F. The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation EMBO J. 2013, 32, 2603-2616 10.1038/emboj.2013.200
19. Zhao, T.; Alam, H. B.; Liu, B.; Bronson, R. T.; Nikolian, V. C.; Wu, E.; Chong, W.; Li, Y. Selective inhibition of SIRT2 improves outcomes in a lethal septic model Curr. Mol. Med. 2015, 15, 634-641 10.2174/156652401507150903185852
20. Eskandarian, H. A.; Impens, F.; Nahori, M. A.; Soubigou, G.; Coppee, J. Y.; Cossart, P.; Hamon, M. A. A role for SIRT2-dependent histone H3K18 deacetylation in bacterial infection Science 2013, 341, 1238858 10.1126/science.1238858
21. Kim, H. S.; Vassilopoulos, A.; Wang, R. H.; Lahusen, T.; Xiao, Z.; Xu, X.; Li, C.; Veenstra, T. D.; Li, B.; Yu, H.; Ji, J.; Wang, X. W.; Park, S. H.; Cha, Y. I.; Gius, D.; Deng, C. X. SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity Cancer Cell 2011, 20, 487-499 10.1016/j.ccr.2011.09.004
22. Yang, M. H.; Laurent, G.; Bause, A. S.; Spang, R.; German, N.; Haigis, M. C.; Haigis, K. M. HDAC6 and SIRT2 regulate the acetylation state and oncogenic activity of mutant K-RAS Mol. Cancer Res. 2013, 11, 1072-1077 10.1158/1541-7786.MCR-13-0040-T
23. Donmez, G.; Outeiro, T. F. SIRT1 and SIRT2: emerging targets in neurodegeneration EMBO Mol. Med. 2013, 5, 344-352 10.1002/emmm.201302451
24. Park, S. H.; Zhu, Y.; Ozden, O.; Kim, H. S.; Jiang, H.; Deng, C. X.; Gius, D.; Vassilopoulos, A. SIRT2 is a tumor suppressor that connects aging, acetylome, cell cycle signaling, and carcinogenesis Transl. Cancer Res. 2012, 1, 15-21
25. Lawson, M.; Uciechowska, U.; Schemies, J.; Rumpf, T.; Jung, M.; Sippl, W. Inhibitors to understand molecular mechanisms of NAD(+)-dependent deacetylases (sirtuins) Biochim. Biophys. Acta, Gene Regul. Mech. 2010, 1799, 726-739 10.1016/j.bbagrm.2010.06.003
26. Cui, H.; Kamal, Z.; Ai, T.; Xu, Y.; More, S. S.; Wilson, D. J.; Chen, L. Discovery of potent and selective sirtuin 2 (SIRT2) inhibitors using a fragment-based approach J. Med. Chem. 2014, 57, 8340-8357 10.1021/jm500777s
27. Suzuki, T.; Khan, M. N. A.; Sawada, H.; Imai, E.; Itoh, Y.; Yamatsuta, K.; Tokuda, N.; Takeuchi, J.; Seko, T.; Nakagawa, H.; Miyata, N. Design, synthesis, and biological activity of a novel series of human sirtuin-2-selective inhibitors J. Med. Chem. 2012, 55, 5760-5773 10.1021/jm3002108
28. Disch, J. S.; Evindar, G.; Chiu, C. H.; Blum, C. A.; Dai, H.; Jin, L.; Schuman, E.; Lind, K. E.; Belyanskaya, S. L.; Deng, J.; Coppo, F.; Aquilani, L.; Graybill, T. L.; Cuozzo, J. W.; Lavu, S.; Mao, C.; Vlasuk, G. P.; Perni, R. B. Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3 J. Med. Chem. 2013, 56, 3666-3679 10.1021/jm400204k
29. Di Fruscia, P.; Zacharioudakis, E.; Liu, C.; Moniot, S.; Laohasinnarong, S.; Khongkow, M.; Harrison, I. F.; Koltsida, K.; Reynolds, C. R.; Schmidtkunz, K.; Jung, M.; Chapman, K. L.; Steegborn, C.; Dexter, D. T.; Sternberg, M. J. E.; Lam, E. W. F.; Fuchter, M. J. The Discovery of a highly selective 5,6,7,8-tetrahydrobenzo[4,5]thieno[ 2,3-d] pyrimidin-4(3H)-one SIRT2 inhibitor that is neuroprotective in an in vitro Parkinson's disease model ChemMedChem 2015, 10, 69-82 10.1002/cmdc.201402431
30. Outeiro, T. F.; Kontopoulos, E.; Altmann, S. M.; Kufareva, I.; Strathearn, K. E.; Amore, A. M.; Volk, C. B.; Maxwell, M. M.; Rochet, J. C.; McLean, P. J.; Young, A. B.; Abagyan, R.; Feany, M. B.; Hyman, B. T.; Kazantsev, A. G. Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease Science 2007, 317, 516-519 10.1126/science.1143780
31. 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.; Inhof, 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 10.1038/onc.2008.436
32. Peck, B.; Chen, C. Y.; Ho, K. K.; Di Fruscia, P.; Myatt, S. S.; Coombes, R. C.; Fuchter, M. J.; Hsiao, C. D.; Lam, E. W. SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2 Mol. Cancer Ther. 2010, 9, 844-55 10.1158/1535-7163.MCT-09-0971
33. Yamagata, K.; Goto, Y.; Nishimasu, H.; Morimoto, J.; Ishitani, R.; Dohmae, N.; Takeda, N.; Nagai, R.; Komuro, I.; Suga, H.; Nureki, O. Structural basis for potent inhibition of SIRT2 deacetylase by a macrocyclic peptide inducing dynamic structural change Structure 2014, 22, 345-352 10.1016/j.str.2013.12.001
34. Rumpf, T.; Schiedel, M.; Karaman, B.; Roessler, C.; North, B. J.; Lehotzky, A.; Olah, J.; Ladwein, K. I.; Schmidtkunz, K.; Gajer, M.; Pannek, M.; Steegborn, C.; Sinclair, D. A.; Gerhardt, S.; Ovadi, J.; Schutkowski, M.; Sippl, W.; Einsle, O.; Jung, M. Selective Sirt2 inhibition by ligand-induced rearrangement of the active site Nat. Commun. 2015, 6, 6263 10.1038/ncomms7263
35. Chubb, F. L.; Nissenbaum, J. Some hypoglycemic thiadiazoles Can. J. Chem. 1959, 37, 1121-1123 10.1139/v59-165
36. Zav'yalov, S. I.; Kravchenko, N. E.; Ezhova, G. I.; Kulikova, L. B.; Zavozin, A. G.; Dorofeeva, O. V. Synthesis of 2-aminothiazole derivatives Pharm. Chem. J. 2007, 41, 105-108 10.1007/s11094-007-0023-4
37. Meerwein, H.; Büchner, E.; van Emster, K. Über die Einwirkung aromatischer Diazoverbindungen auf α, β-ungesättigte Carbonylverbindungen J. Prakt. Chem. 1939, 152, 237-266 10.1002/prac.19391520705
38. Bülow, C.; Sproesser, T. Über primäre Disazokombinationen des Benzyläthyl-m-amidophenols Ber. Dtsch. Chem. Ges. 1908, 41, 1684-1692 10.1002/cber.19080410226
39. Obushak, N. D.; Matiichuk, V. S.; Vasylyshin, R. Y.; Ostapyuk, Y. V. Heterocyclic syntheses on the basis of arylation products of unsaturated compounds: X. 3-aryl.-2-chloropropanals as reagents for the synthesis of 2-amino-1,3-thiazole derivatives Russ. J. Org. Chem. 2004, 40, 383-389 10.1023/B:RUJO.0000034976.75646.85
40. Obushak, N. D.; Lyakhovich, M. B.; Bilaya, E. E. Arenediazonium tetrachlorocuprates(II). Modified versions of the Meerwein and Sandmeyer reactions Russ. J. Org. Chem. 2002, 38, 38-46 10.1023/A:1015394423091
41. Morrison, D. C.; Lee, H. P. C. A new preparation of 8-Nitro-2-Naphthylamine J. Org. Chem. 1962, 27, 3336-3337 10.1021/jo01056a522
42. Beech, W. F.; Legg, N. Aminohydroxynaphthoic acids 0.1. Synthesis of 6-amino-4-hydroxy-2-naphthoic acid (carboxy gamma-acid) J. Chem. Soc. 1949, 1887-1889 10.1039/jr9490001887
43. Heltweg, B.; Trapp, J.; Jung, M. In vitro assays for the determination of histone deacetylase activity Methods 2005, 36, 332-337 10.1016/j.ymeth.2005.03.003
44. Kazantsev, A. G. Compositions and methods for modulating sirtuin activity, and therapeutic use. U.S. Patent No. 20090259044, 2009.
45. Neugebauer, R. C.; Uchiechowska, U.; Meier, R.; Hruby, H.; Valkov, V.; Verdin, E.; Sippl, W.; Jung, M. Structure-activity studies on splitomicin derivatives as sirtuin inhibitors and computational prediction of binding mode J. Med. Chem. 2008, 51, 1203-1213 10.1021/jm700972e
46. North, B. J.; Schwer, B.; Ahuja, N.; Marshall, B.; Verdin, E. Preparation of enzymatically active recombinant class III protein deacetylases Methods 2005, 36, 338-345 10.1016/j.ymeth.2005.03.004
47. Kabsch, W. XDS Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 125-132 10.1107/S0907444909047337
48. Karplus, P. A.; Diederichs, K. Linking crystallographic model and data quality Science 2012, 336, 1030-1033 10.1126/science.1218231
49. Winn, M. D.; Ballard, C. C.; Cowtan, K. D.; Dodson, E. J.; Emsley, P.; Evans, P. R.; Keegan, R. M.; Krissinel, E. B.; Leslie, A. G. W.; McCoy, A.; McNicholas, S. J.; Murshudov, G. N.; Pannu, N. S.; Potterton, E. A.; Powell, H. R.; Read, R. J.; Vagin, A.; Wilson, K. S. Overview of the CCP4 suite and current developments Acta Crystallogr., Sect. D: Biol. Crystallogr. 2011, 67, 235-242 10.1107/S0907444910045749
50. Vagin, A.; Teplyakov, A. Molecular replacement with MOLREP Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 22-25 10.1107/S0907444909042589
51. Emsley, P.; Lohkamp, B.; Scott, W. G.; Cowtan, K. Features and development of Coot Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 486-501 10.1107/S0907444910007493
52. Murshudov, G. N.; Skubak, P.; Lebedev, A. A.; Pannu, N. S.; Steiner, R. A.; Nicholls, R. A.; Winn, M. D.; Long, F.; Vagin, A. A. REFMAC5 for the refinement of macromolecular crystal structures Acta Crystallogr., Sect. D: Biol. Crystallogr. 2011, 67, 355-367 10.1107/S0907444911001314
53. Chen, V. B.; Arendall, W. B.; Headd, J. J.; Keedy, D. A.; Immormino, R. M.; Kapral, G. J.; Murray, L. W.; Richardson, J. S.; Richardson, D. C. MolProbity: all-atom structure validation for macromolecular crystallography Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 12-21 10.1107/S0907444909042073
54. Laskowski, R. A.; Macarthur, M. W.; Moss, D. S.; Thornton, J. M. Procheck-a program to check the stereochemical quality of protein structures J. Appl. Crystallogr. 1993, 26, 283-291 10.1107/S0021889892009944
55. Adams, P. D.; Afonine, P. V.; Bunkoczi, G.; Chen, V. B.; Davis, I. W.; Echols, N.; Headd, J. J.; Hung, L. W.; Kapral, G. J.; Grosse-Kunstleve, R. W.; McCoy, A. J.; Moriarty, N. W.; Oeffner, R.; Read, R. J.; Richardson, D. C.; Richardson, J. S.; Terwilliger, T. C.; Zwart, P. H. PHENIX: a comprehensive Python-based system for macromolecular structure solution Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 213-221 10.1107/S0907444909052925
56. Krissinel, E. Fold recognition using efficient short fragment clustering J. Mol. Biochem. 2012, 1, 76-85
57. Brunger, A. T. Free R-value-a novel statistical quantity for assessing the accuracy of crystal-structures Nature 1992, 355, 472-475 10.1038/355472a0
58. Wang, J. M.; Wolf, R. M.; Caldwell, J. W.; Kollman, P. A.; Case, D. A. Development and testing of a general amber force field J. Comput. Chem. 2004, 25, 1157-1174 10.1002/jcc.20035
59. Jakalian, A.; Jack, D. B.; Bayly, C. I. Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation J. Comput. Chem. 2002, 23, 1623-1641 10.1002/jcc.10128
60. Slynko, I.; Scharfe, M.; Rumpf, T.; Eib, J.; Metzger, E.; Schüle, R.; Jung, M.; Sippl, W. Virtual screening of PRK1 inhibitors: Ensemble docking, rescoring using binding free energy calculation and QSAR model development J. Chem. Inf. Model. 2014, 54, 138-150 10.1021/ci400628q
61. Hale, W. J.; Williams, A. G. The constitution of acetylacetone-thiourea J. Am. Chem. Soc. 1915, 37, 594-600 10.1021/ja02168a020
62. Tan, T. F.; Li, Y. X.; Bai, L. G.; Wu, B. P.; Guo, H. Y.; Suo, Z. C. A facile synthesis and optical properties of novel 2-substituted-5-naphthylmethylene thiadiazole derivatives Adv. Mater. Res. 2014, 1052, 188-192 10.4028/www.scientific.net/AMR.1052.188