Abstract
Within this work we telescoped a batch laboratory scale synthesis towards a two-step-one-flow process to synthesize cardiomyogenesis inducing compounds (4,6-diaminopyrimidines) in continuous manner. Special attention was put on a quick and robust screening protocol and subsequent UHPLC analysis. Finally, the robustness of the method was proven by the multi-gram synthesis of VUT-MK142 using a laboratory scale continuous flow reactor, enabling to deliver enough material for extensive biological testing.
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References
Mohammad HP, Baylin SB (2010) Nat Biotechnol 28:1033
Lodish H, Berk A, Kaiser C, Krieger M, Scott M, Bretscher A, Ploegh H, Matsudaira P (2008) Molecular Cell Biology, 6th edn. Freeman, New York
Davis RL, Weintraub H, Lassar AB (1987) Cell 51:987
Kulessa H, Frampton J, Graf T (1995) Genes Dev 9:1250
Gurdon JB, Byrne JA, Simonsson S (2003) Proc Natl Acad Sci USA 100:11819
Gurdon JB, Melton DA (2008) Science 322:1811
Maherali N, Hochedlinger K (2008) Cell Stem Cel 3:595
Lowry WE, Richter L, Yachechko R, Pyle AD, Tchieu J, Sridharan R, Clark AT, Plath K (2008) Proc Natl Acad Sci USA 105:2883
Park I-H, Zhao R, West JA, Yabuuchi A, Huo H, Ince TA, Lerou PH, Lensch MW, Daley GQ (2008) Nature 451:141
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Cell 131:861
Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA (2007) Science 318:1917
Takahashi K, Yamanaka S (2006) Cell 126:663
Firestone AJ, Chen JK (2010) ACS Chem Biol 5:15
Feng B, Ng J-H, Heng J-CD, Ng H-H (2009) Cell Stem Cell 4:301
Urbanek K, Rota M, Cascapera S, Bearzi C, Nascimbene A, De Angelis A, Hosoda T, Chimenti S, Baker M, Limana F, Nurzynska D, Torella D, Rotatori F, Rastaldo R, Musso E, Quaini F, Leri A, Kajstura J, Anversa P (2005) Circ Res 97:663
Wu X, Ding S, Ding Q, Gray NS, Schultz PG (2004) J Am Chem Soc 126:1590
Shen G, Hu Y, Wu J, Jin K, Zhu D, Zhang Y, Yu Y, Lou Y (2012) ChemMedChem 7:733
Sadek H, Hannack B, Choe E, Wang J, Latif S, Garry MG, Garry DJ, Longgood J, Frantz DE, Olson EN, Hsieh J, Schneider JW (2008) Proc Natl Acad Sci USA 105:6063
Wang H, Hao J, Hong CC (2011) ACS Chem Biol 6:192
Gonzalez R, Lee JW, Schultz PG (2011) Angew Chem Int Ed 50:11181
Wu X, Ding S, Schultz PG (2005) 2,4-Diaminopyrimidines as inducers of cardiomyogenesis, their preparation and use in the treatment of cardiomyopathy. PCT Int. Appl. WO 2005068437 A1 20050728, Jul 28, 2005; (2005) Chem Abstr 143:172888
Hartung CG, Backes AC, Felber B, Missio A, Philipp A (2006) Tetrahedron 62:10055
Ingham RJ, Riva E, Nikbin N, Baxendale IR, Ley SV (2012) Org Lett 14:3920
Koley M, Mike AK, Heher P, Koenig X, Schön M, Schnürch M, Hilber K, Weitzer G, Mihovilovic MD (2013) Med Chem Commun 4:1189
Mihovilovic MD, Schnürch M, Koley M, Hilber K, Koenig X (2011) Preparation of phenylaminopyrimidinylamine derivatives and analogs for use as cardiovascular agents. PCT Int. Appl. WO 2011079343 A2 20110707, Jul 7, 2011; (2011) Chem Abstr 155:152546
Mike AK, Koenig X, Koley M, Heher P, Wahl G, Rubi L, Mihovilovic MD, Schnürch M, Weitzer G, Hilber K (2014) Cell Physiol Biochem 33:205
Hoyert DL, Xu J (2012) Natl Vital Stat Rep 61:1
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Schön, M., Dreier, D., Schnürch, M. et al. Library synthesis of cardiomyogenesis inducing compounds using an efficient two-step-one-flow process. Monatsh Chem 147, 523–532 (2016). https://doi.org/10.1007/s00706-015-1605-6
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DOI: https://doi.org/10.1007/s00706-015-1605-6