Novel synthesis of nucleoside 5'-triphosphates and their derivatives

Abstract

Disclosed are compounds of nucleoside 5 '-triphosphates of formula (I), or derivatives thereof, or pharmaceutically acceptable salts of said nucleoside 5 '-triphosphates or said derivatives, wherein the Base of formula (I) is Adenine (A), Cytosine (C), Guanine (G), Thymine (T), Uracil (U), modified nucleobase or unnatural nucleobase; R1 is H or OH, R2 is H or OH, X is independently selected from the group consisting of O, S and Se; and Y is independently selected from the group consisting of O, B (borano, or BH3), S, and Se. Also disclosed are processes of preparing the compounds of formula (I), said process comprising steps according to Scheme A.

Description

[0001] related application [0002] This application claims priority to US Provisional Application 61 / 375,560, filed August 20, 2010, and US Provisional Application 61 / 375,992, filed August 23, 2010. Background technique [0003] Natural nucleoside 5'-triphosphates (NTP and dNTP) are basic building blocks for the synthesis of nucleic acids (RNA and / or DNA) and are used in DNA replication, transcription and translation [G.Storz, Science2002, 296, 1260-3; M.T. McManus, P.A. Sharp, Nat Rev Genet 2002, 3, 737-47; M. Mandal, R.R. Breaker, Nat Rev Mol Cell Biol 2004, 5, 451-63]. Nucleic acids are involved in many important biological systems, including genetic information storage, gene expression, catalysis and numerous other biochemical processes / annurev.bi.54.070185.002055]. Nucleoside 5'-triphosphates have many important therapeutic and diagnostic uses [N.A. Golubeva, Ivanov, A.V., vanov, M.A., Batyunina, O.A., Shipitsyn, A.V.Tunitskaya, V.L. and Alexandrova, L.A., Mosco Unive...

AI Technical Summary

Problems solved by technology

This strategy often requires protection of the sugar moiety, such as the use of acid-labile groups; however, this one-pot strategy is not applicable to all derivatives [K. Burgess, D. Cook, Chem Rev 2000, 100, 2047-60]

There are many other synthetic strategies [Y.Ahmadibeni, R.K.Tiwari, G.Sun, K.Parang, Org Lett2009, 11, 2157-6010.1021 / ol900320r; W.Wu, C.L. Freel Meyers, R.F.Borch, Org Lett2004, 6, 2257 -6010.1021 / ol049267j; Q.Sun, J.P.Edathil, R.Wu, E.D.Smidansky, C.E.Cameron, B.R.Peterson, Org Lett2008,10, 1703-610.1021 / ol8003029; S.Warnecke, C.Meier, Nucleic Acids Symp Ser (Oxf )2008, 583-4nrn295[pii]10.1093 / nass / nrn295; A.T.Horhota, J.W.Szostak, L.W.McLaughlin, Org Lett2006,8, 5345-710.1021 / ol062232u; M.Yoshikawa, T.Kato, T.Takenishi, Lett1h 50, 5065-8; S. Aketani, K. Tanaka, K. Yamamoto, A. Ishihama, H. Cao, A. Tengeiji, S. Hiraoka, M. Shiro, M. Shionoya, J Med Chem2002, 45, 5594- 603jm020193w[pii]; R.S.J.H.R.J.H.S.J.H.Beijnen, Nucleosides, Nucleotides and Nucleic Acids2009, 29, 14-26], the strategy was developed for the preparation of nucleoside triphosphates, but in some protocols, manipulations often require protection of the sugar moiety, longer Synthetic pathways, difficult to purify and isolate the desired product, and low yields [K.Burgess, D.Cook, Chem Rev2000, 100, 2047-60; W.Wu, D.E.Bergstrom, V.J.Davisson, J Org Chem2003, 68, 3860-510.1021 / jo020745i]

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