DOI QR코드

DOI QR Code

Synthesis and Antiviral Activity Evaluation of 5',5'-Difluoro-2'-methylapiosyl Nucleoside Phosphonic Acid Analogs

  • Hong, Joon Hee (BK-21 Project Team, College of Pharmacy, Chosun University)
  • 투고 : 2015.07.10
  • 심사 : 2015.09.25
  • 발행 : 2015.09.30

초록

Racemic synthesis of novel 5',5'-difluoro-2'-methyl-apiose nucleoside phosphonic acid analogs was achieved as potent antiviral agents. Phosphonation was performed by direct displacement of triflate intermediate with diethyl (lithiodifluoromethyl) phosphonate to give the corresponding (${\alpha},{\alpha}$-difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor with persilylated bases to yield the nucleoside phosphonate analogs. Deprotection of diethyl phosphonates provided the target nucleoside analogs. An antiviral evaluation of the synthesized compounds against various viruses such as HIV, HSV-1, HSV-2 and HCMV revealed that the pyrimidine analogs (cytosine, uracil, and thymine) have weak anti-HIV or HCMV activity.

키워드

참고문헌

  1. D. Vina, T. Wu, M. Renders, G. Laflamme, and P. Herdewijn, "Synthesis of 3'-O-phosphonomethyl nucleosides with an adenine base moiety", Tetrahedron, Vol. 63, pp. 2634-2646, 2007. https://doi.org/10.1016/j.tet.2007.01.032
  2. E. I. Kodama, S. Kohgo, K. Kitano, H. Machida, H. Gatanaga, S. Shigeta, M. Matsuoka, H. Ohrui, and H. Mitsuya, "4'-Ethynyl nucleoside analogs: potent inhibitors of multidrug-resistant human immunodeficiency virus variants in vitro", Antimicrob. Agents Chemother., Vol. 45, pp. 1539-1546, 2001. https://doi.org/10.1128/AAC.45.5.1539-1546.2001
  3. S. G. Dumbre, M.-Y. Jang, and P. Herdewijn, "Synthesis of ${\alpha}$-L-threose nucleoside phosphonates via regioselective sugar protection", J. Org. Chem., Vol. 78, pp. 7137-7144, 2013. https://doi.org/10.1021/jo400907g
  4. U. Pradere, E. C. Garnier-Amblard, S. J. Coats, F. Amblard, and R. F. Schinazi, "Synthesis of nucleoside phosphate and phosphonate prodrugs", Chem. Rev., Vol. 114, pp. 9154-9218, 2014 https://doi.org/10.1021/cr5002035
  5. R. Engel, "Phosphonates as analogues of natural phosphates", Chem. Rev., Vol. 77, pp. 349-367, 1977 https://doi.org/10.1021/cr60307a003
  6. O. Baszczy ski, and Z. Janeba, "Medicinal chemistry of fluorinated cyclic and acyclic nucleoside phosphonates", Med. Chem. Rev., Vol. 33, pp. 1304-1344, 2013
  7. E. De Clercq, "The holy trinity: the acyclic nucleoside phosphonates", Adv. Pharmacol., Vol. 67, pp. 293-316, 2013. https://doi.org/10.1016/B978-0-12-405880-4.00008-1
  8. G. M. Blackburn, and D. E. Kent, "Synthesis of ${\alpha}$- and ${\gamma}$-fluoroalkylphosphonates", J. Chem. Soc., Perkin Trans. 1, pp. 913-917, 1986
  9. G. R. J. Thatcher, and A. S. Campbell, "Phosphonates as mimics of phosphate biomolecules: ab initio calculations on tetrahedral ground states and pentacoordinate intermediates for phosphoryl transfer", J. Org. Chem., Vol. 58, pp. 2272-2281, 1993 https://doi.org/10.1021/jo00060a050
  10. T. R Jr. Burke, M. S. Smyth, A. Otaka, M. Nomizu, M.; P. P. Roller, G. Wolf, R. Case, and S. E. Shoelson, "Nonhydrolyzable phosphotyrosyl mimetics for the preparation of phosphatase-resistant SH2 domain inhibitors", Biochemistry, Vol. 33, pp. 6490-6494, 1994. https://doi.org/10.1021/bi00187a015
  11. R. D. Chambers, R. Jaouhari, and D. O'Hagan, "The preparation of difluoromethylenephosphonate analogues of glycolytic phosphates. Approaching an isosteric and isoelectronic phosphate mimic", Tetrahedron, Vol. 45, pp. 5101-5108, 1989 https://doi.org/10.1016/S0040-4020(01)81089-9
  12. D. B. Berkowitz, H. J. Eggen, Q. Shen, and R. K. Shoemaker, "Ready access to fluorinated phosphonate mimics of secondary phosphates. Synthesis of the (${\alpha},{\alpha}$-difluoroalkyl) phosphonate analogues of L-phosphoserine, L-phosphoallothreonine, and L-phosphothreonine", J. Org. Chem., Vol. 91, pp. 4666-4675, 1996
  13. D. J. Burton, Z.-Y. Yang, and W. Qiu, "Fluorinated ylides and related compounds", Chem. Rev., Vol. 96, pp. 1641-1715, 1996. https://doi.org/10.1021/cr941140s
  14. S. Halazy, A. Ehrhard, and C. Danzin, "(9-(Difluorophosphonoalkyl)guanines as a new class of multisubstrate analogue inhibitors of purine nucleoside phosphorylase", J. Am. Chem. Soc., Vol. 113, pp. 315-317, 1991. https://doi.org/10.1021/ja00001a045
  15. S. G. Levy, D. B. Wasson, D. A. Carson, and H. B Cottam, "Synthesis of 2-chloro-2',5'-dideoxy-5'-(phosphinyldifluoromethyl)adenosine: A nonhydrolyzable isosteric, isopolar analog of 2-chlorodeoxyadenosine monophosphate", Synthesis, Vol. 7, pp. 843-846, 1996.
  16. D. A. Fort, T. J. Woltering, A. M. Alker, and T. Bach, "Photochemical reactions of prop-2-enyl and prop-2-ynyl substituted 4-aminomethyl- and 4-oxymethyl-2(5H)-furanones", Heterocycles, Vol. 88, pp. 1079-1100, 2004.
  17. E. J. Corey, and A.Venkateswarlu, "Protection of hydroxyl groups as t-butyldimethylsilyl derivatives", J. Am. Chem. Soc., Vol. 94, pp. 6190-6172, 1972. https://doi.org/10.1021/ja00772a043
  18. G. Rassu, F. Zanardi, L. Battistini, E. Caetani, and G. Casirsghi, "Expeditious synthesis of sugarmodified nucleosides and collections thereof exploiting furan-, pyrrole-, and thiophen-based dienes", J. Med. Chem., Vol. 40, pp. 168-180, 1997. https://doi.org/10.1021/jm960400q
  19. D. B. Berkowitz, M. Eggen, Q. Shen, and D. G. Sloss, "Synthesis of (${\alpha},{\alpha}$,-difluoroalkyl) phosphonates by displacement of primary triflates", J. Org. chem., Vol. 58, pp. 6174-6176, 1993. https://doi.org/10.1021/jo00075a005
  20. K. Walczak, J. Lau, and E. B. Pedesen, "2,3,6-Trideoxy-5-O-(4-nitrobenzoyl)-3-trifluoroacetamido-L-ribo-hexofuranosyl bromide - A suitable furanoid ristosamine glycosylation reagent", Synthesis, pp. 790-792, 1993.
  21. H. Vorbruggen, "Nucleoside analogs, Chemistry", Biology and Medical Applications, NATO ASI Series A 26; Plenum Press: New Tork, pp. 35, 1980.
  22. D. Hockova, A. Holy, M. Masojidkova, D. T. Keough, J. De Jersey, and L. W. Guddat, "Synthesis of branched 9-[2-(2-phosphonoethoxy)ethyl]purines as a new class of acyclic nucleoside phosphonates which inhibit Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase", Bioorg. Med. Chem., Vol. 17, pp. 6218-6232, 2009; https://doi.org/10.1016/j.bmc.2009.07.044
  23. J. Matulic-Adamic, P. Haeberli, and N. Usman, "Synthesis of 5'-deoxy-difluoromethyl phosphonate nucleoside analogs", J. Org. Chem. Vol. 60, pp. 2563-2569, 1995. https://doi.org/10.1021/jo00113a040
  24. M. J. Robins, and B. Uznanski, "Non-aqueous diazotization with t-butyl nitrite. Introduction of fluorine, chlorine, and bromine at C-2 of purine nucleoside", Can. J. Chem. Vol. 59, pp. 2608-2611, 1981. https://doi.org/10.1139/v81-375
  25. J. Montgomery, and K. Hewson, "Nucleosides of 2-fluoroadenine", J. Med. Chem., Vol. 12, pp. 498-504, 1969. https://doi.org/10.1021/jm00303a605
  26. G. L. Tong, K. J. Ryan, W. W. Lee, E. M. Acton, and L. Goodman, "Nucleosides of thioguanine and other 2-amino-6-substituted purines from 2-acetamido-5-chloropurine", J. Org. Chem., Vol. 32, pp. 859-862, 1967. https://doi.org/10.1021/jo01278a095
  27. A. Holy, I. Votruba, A. Merta, J. Cerny, J. Vesely, J. Vlach, K. Sediva, I. Rosenberg, M. Otmar, H. Hrebabecky, M. Travniekb, V. Vonkac, R. Snoeck, and E. De Clercq, "Acyclic nucleotide analogues: synthesis, antiviral activity and inhibitory effects on some cellular and virus-encoded enzymes in vitro", Antiviral Res., Vol. 13, pp. 295-311, 1990. https://doi.org/10.1016/0166-3542(90)90014-X
  28. O. H. Ko, and J. H. Hong, "Synthesis and biological evaluation of novel 2',3'-4'-triply branched carbocyclic nucleosides as potential antiviral agents", Arch. Pharm. Pharm. Med. Chem., Vol. 337, pp. 579-586, 2004. https://doi.org/10.1002/ardp.200400918