Synthesis of Trifluoromethyl Ketone Containing Amino Acid Building Blocks for the Preparation of Peptide-Based Histone Deacetylase (HDAC) Inhibitors

Abstract

Trifluoromethyl ketones (TFMKs) are electrophilic moieties which hydrate readily in aqueous media to give geminal diols. This ability has been exploited for the development of histone deacetylase (HDAC) inhibitors, because HDAC enzymes contain a Zn²⁺ ion which may be chelated by this functionality. Interestingly, TFMKs are exceptional Zn²⁺-binding groups for targeting the intriguing class IIa HDAC isozymes, involved in transcription factor recruitment and gene regulation. Here, we have developed a scalable and inexpensive synthetic procedure for preparation of the enantiomerically pure TFMK-containing amino acid building block (S)-2-amino-9,9,9-trifluoro-8-oxononanoic acid (Atona). In addition, we propose a protecting group strategy applicable to automated solid-phase peptide synthesis and demonstrate the ability of Atona-containing peptides to inhibit the enzymatic activity of class IIa HDACs with nanomolar potency. We envision that this synthesis will motivate the further development of peptide-based probes for the study of class IIa HDACs.

Key words

trifluoromethyl ketones - histone deacetylase - histone deacetylase inhibitors - epigenetic - amino acids - peptides - protecting groups

• References

• 1 Yang X.-J. Seto E. Nat. Rev. Mol. Cell Biol. 2008; 9: 206
• 2 Hai Y. Shinsky SA. Porter NJ. Christianson DW. Nat. Commun. 2017; 8: 15368
• 3 Jakovcevski M. Akbarian S. Nat. Med. 2012; 18: 1194
• 4 Tough DF. Tak PP. Tarakhovsky A. Prinjha RK. Nat. Rev. Drug Discovery 2016; 15: 835
• 5 Falkenberg KJ. Johnstone RW. Nat. Rev. Drug Discovery 2014; 13: 673
• 6 Ahuja N. Sharma AR. Baylin SB. Annu. Rev. Med. 2016; 67: 73
• 7 Lahm A, Paolini C, Pallaoro M, Nardi M, Jones P, Neddermann P, Sambucini S, Bottomley MJ, Lo SurdoP, Carfí A, Koch U, De Francesco R, Steinkühler C, Gallinari P. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 17335
• 8 Bradner JE. West N. Grachan ML. Greenberg EF. Haggarty SJ. Warnow T. Mazitschek R. Nat. Chem. Biol. 2010; 6: 238
• 9 Verdin E. Dequiedt F. Kasler HG. Trends Genet. 2003; 19: 286
• 10 Jose B. Oniki Y. Kato T. Nishino N. Sumida Y. Yoshida M. Bioorg. Med. Chem. Lett. 2004; 14: 5343
• 11 Bottomley MJ, Lo Surdo P, Di Giovine P, Cirillo A, Scarpelli R, Ferrigno F, Jones P, Neddermann P, De Francesco R, Steinkühler C, Gallinari P, Carfí A. J. Biol. Chem. 2008; 283: 26694
• 12 Micelli C. Rastelli G. Drug Discovery Today 2015; 20: 718
• 13 Imperiali B. Abeles RH. Biochemistry 1986; 25: 3760
• 14 Liang TC. Abeles RH. Biochemistry 1987; 26: 7603
• 15 Mehdi S. Bioorg. Chem. 1993; 21: 249
• 16 LaPlante SR. Bonneau PR. Aubry N. Cameron DR. Déziel R. Grand-Maître C. Plouffe C. Tong L. Kawai SH. J. Am. Chem. Soc. 1999; 121: 2974
• 17 Wolfenden R. Annu. Rev. Biophys. Bioeng. 1976; 5: 271
• 18 Gelb MH. Svaren JP. Abeles RH. Biochemistry 1985; 24: 1813
• 19 Christianson DW. Lipscomb WN. J. Am. Chem. Soc. 1986; 108: 4998
• 20 Trimble LA. Street IP. Perrier H. Tremblay NM. Weech PK. Bernstein MA. Biochemistry 1993; 32: 12560
• 21 Dzhekieva L. Adediran SA. Herman R. Kerff F. Duez C. Charlier P. Sauvage E. Pratt RF. Biochemistry 2013; 52: 2128
• 22 Decroos C. Bowman CM. Christianson DW. Bioorg. Med. Chem. 2013; 21: 4530
• 23 Krämer A. Wagner T. Yildiz Ö. Meyer-Almes F.-J. Biochemistry 2016; 55: 6858
• 24 Frey RR, Wada CK, Garland RB, Curtin ML, Michaelides MR, Li J, Pease LJ, Glaser KB, Marcotte PA, Bouska JJ, Murphy SS, Davidsen SK. Bioorg. Med. Chem. Lett. 2002; 12: 3443
• 25 Jones P. Altamura S. De Francesco R. Gallinari P. Lahm A. Neddermann P. Rowley M. Serafini S. Steinkühler C. Bioorg. Med. Chem. Lett. 2008; 18: 1814
• 26 Jones P, Bottomley MJ, Carfí A, Cecchetti O, Ferrigno F, Lo Surdo P, Ontoria JM, Rowley M, Scarpelli R, Schultz-Fademrecht C, Steinkühler C. Bioorg. Med. Chem. Lett. 2008; 18: 3456
• 27 Muraglia E. Altamura S. Branca D. Cecchetti O. Ferrigno F. Orsale MV. Palumbi MC. Rowley M. Scarpelli R. Steinkühler C. Jones P. Bioorg. Med. Chem. Lett. 2008; 18: 6083
• 28 Scarpelli R. Di Marco A. Ferrigno F. Laufer R. Marcucci I. Muraglia E. Ontoria JM. Rowley M. Serafini S. Steinkühler C. Jones P. Bioorg. Med. Chem. Lett. 2008; 18: 6078
• 29 Wegener D. Deubzer HE. Oehme I. Milde T. Hildmann C. Schwienhorst A. Witt O. Anti-Cancer Drugs 2008; 19: 849
• 30 Ontoria JM. Altamura S. Di Marco A. Ferrigno F. Laufer R. Muraglia E. Palumbi MC. Rowley M. Scarpelli R. Schultz-Fademrecht C. Serafini S. Steinkühler C. Jones P. J. Med. Chem. 2009; 52: 6782
• 31 Hutt DM. Olsen CA. Vickers CJ. Herman D. Chalfant MA. Montero A. Leman LJ. Burkle R. Maryanoff BE. Balch WE. Ghadri MR. ACS Med. Chem. Lett. 2011; 2: 703
• 32 Madsen AS. Kristensen HM. Lanz G. Olsen CA. ChemMedChem 2014; 9: 614
• 33 Cai J. Wei H. Hong KH. Wu X. Zong X. Cao M. Wang P. Li L. Sun C. Chen B. Zhou G. Chen J. Ji M. Bioorg. Med. Chem. 2015; 23: 3457
• 34 Albrow VE. Grimley RL. Clulow J. Rose CR. Sun J. Warmus JS. Tate EW. Jones LH. Storer RI. Mol. BioSyst. 2016; 12: 1781
• 35 Gong C.-J. Gao A.-H. Zhang Y.-M. Su M.-B. Chen F. Sheng L. Zhou Y.-B. Li J.-Y. Li J. Nan F.-J. Eur. J. Med. Chem. 2016; 112: 81
• 36 Madsen AS. Olsen CA. MedChemComm 2016; 7: 464
• 37 Meyners C. Mertens M. Wessig P. Meyer-Almes F.-J. Chem. Eur. J. 2017; 23: 3107
• 38 Depetter Y. Geurs S. Bussche FV. De Vreese R. Franceus J. Desmet T. De Wever O. D’hooghe M. MedChemComm 2018; 9: 1011
• 39 Maolanon A. Kristensen H. Leman L. Ghadiri R. Olsen CA. ChemBioChem 2017; 18: 5
• 40 Marsilje TH. Hedrick MP. Desharnais J. Tavassoli A. Zhang Y. Wilson IA. Benkovic SJ. Boger DL. Bioorg. Med. Chem. 2003; 11: 4487
• 41 Krishnamurti R. Bellew DR. Prakash GS. J. Org. Chem. 1991; 56: 984
• 42 Ilies M. Dowling DP. Lombardi PM. Christianson DW. Bioorg. Med. Chem. Lett. 2011; 21: 5854
• 43 Rudzinski DM. Kelly CB. Leadbeater NE. Chem. Commun. 2012; 48: 9610
• 44 Yang D. Zhou Y. Xue N. Qu J. J. Org. Chem. 2013; 78: 4171
• 45 Yang D. Zhou Y. Song Y. Qu J. J. Fluorine Chem. 2015; 173: 6
• 46 Anthore L. Zard SZ. Org. Lett. 2015; 17: 3058
• 47 Kahnberg P. Lucke AJ. Glenn MP. Boyle GM. Tyndall JD. Parsons PG. Fairlie DP. J. Med. Chem. 2006; 49: 7611
• 48 Boivin J. El Kaim L. Zard SZ. Tetrahedron 1995; 51: 2573
• 49 Sigma-Aldrich, cat. number 01818, >0.5 U/mg. Several lots from this reagent were employed with similar results.
• 50 Montero A. Beierle JM. Olsen CA. Ghadiri MR. J. Am. Chem. Soc. 2009; 131: 3033
• 51 Marfey P. Carlsberg Res. Commun. 1984; 49: 591
• 52 Bhushan R. Brückner H. Amino Acids 2004; 27: 231
• 53 Rink H. Tetrahedron Lett. 1987; 28: 3787
• 54 Wang Z. Zang C. Cui K. Schones DE. Barski A. Peng W. Zhao K. Cell 2009; 138: 1019
• 55 Peptide crude purity calculated by HPLC analysis with UV detection at 210 nm.
• 56 Middleton W. Krespan C. J. Org. Chem. 1965; 30: 1398
• 57 Wegener D. Wirsching F. Riester D. Schwienhorst A. Chem. Biol. 2003; 10: 61
• 58 Moreno-Yruela C. Galleano I. Madsen AS. Olsen CA. Cell Chem. Biol. 2018; 25: 849
• 59 Dose A. Sindlinger J. Bierlmeier J. Bakirbas A. Schulze-Osthoff K. Einsele-Scholz S. Hartl M. Essmann F. Finkemeier I. Schwarzer D. Angew. Chem. Int. Ed. 2016; 55: 1192
• 60 Hartl M. Füßl M. Boersema PJ. Jost JO. Kramer K. Bakirbas A. Sindlinger J. Plöchinger M. Leister D. Uhrig G. Moorhead GB. G. Cox J. Salvucci ME. Schwarzer D. Mann M. Finkemeier I. Mol. Syst. Biol. 2017; 13: 949
• 61 Wu M. Hayward D. Kalin JH. Song Y. Schwabe JW. Cole PA. eLife 2018; 7: e37231
• 62 Compound 8 and the deacetylated (S)-2-amino-9,9,9-trifluoro-8-oxononanoate nonanoic acid intermediate could be separated by partitioning between the aqueous reaction mixture and an appropriate organic phase, but it was not necessary for the scale of our synthesis.
• 63 Madsen AS. Olsen CA. J. Med. Chem. 2012; 55: 5582
• 64 Galleano I. Schiedel M. Jung M. Madsen AS. Olsen CA. J. Med. Chem. 2016; 59: 1021