Article
Full Access
C-2 Arylamino substituted purine ara-carbocyclic nucleosides as potential anti-cytomegalovirus agents
Masakazu Koga,
Stewart W. Schneller,
Masakazu Koga
Department of Chemistry, University of South Florida, Tampa, FL 33620-5250
Search for more papers by this authorStewart W. Schneller
Department of Chemistry, University of South Florida, Tampa, FL 33620-5250
Search for more papers by this authorMasakazu Koga,
Stewart W. Schneller,
Masakazu Koga
Department of Chemistry, University of South Florida, Tampa, FL 33620-5250
Search for more papers by this authorStewart W. Schneller
Department of Chemistry, University of South Florida, Tampa, FL 33620-5250
Search for more papers by this authorAbstract
There are reports in the literature that placement of an arylamino side chain at the C-2 position of purine nucleosides produces compounds capable of inhibiting DNA polymerase. To evaluate the potential of this class of compounds as antiviral agents that act by inhibiting viral DNA polymerase, ara-carbocyclic purine nucleosides possessing a 4-(l-butyl)phenylamino and a 3,5-dichlorophenylamino substituent at C-2 were chosen as the prototype structures and have been prepared from 2,4,6-trichloropyrimidine in 6 steps. For the antiviral analysis, human cytomegalovirus served as the principal virus since it expresses a virally specific DNA polymerase. None of the compounds showed activity towards this virus, but they were found to display some toxicity towards one or more cell lines.
References and Notes
- 1 D. J. Jeffries, J. Antimicrob. Chemother., 23 (Supplement E), 1 (1989).
- 2a See, for example, J. Boryski, B. Golankiewicz and E. De Clercq, J. Med. Chem., 34, 2380 (1991); b J. A. Secrist, III, K. N. Tiwari, J. M. Riordan and J. A. Montgomery, J. Med. Chem., 34, 2361 (1991); c E. De Clercq, M. Cools, J. Balzarini, R. Snoeck, G. Andrei, M. Hosoya, S. Shigeta, T. Ueda, N. Minakawa and A. Matsuda, Antimicrob. Agents Chemother., 35, 679 (1991); d P. Wigerinck, R. Snoeck, P. Claes, E. De Clercq and P. Herdewijn, J. Med. Chem., 34, 1767 (1991); e G. S. Bisacchi, A. Braitman, C. W. Cianci, J. M. Clark, A. K. Field, M. E. Hagen, D. R. Hockstein, M. F. Malley, T. Mitt, W. A. Slusarchyk, J. E. Sundeen, B. J. Terry, A. V. Tuomari, E. R. Weaver, M. G. Young and R. Zahler, J. Med. Chem., 34, 1415 (1991); f D. P. C. McGee, J. C. Martin, D. F. Smee and J. P. H. Verheyden, Nucleosides Nucleotides, 9, 815 (1990); g N. K. Saxena, L. A. Coleman, J. C. Drach and L. B. Town-send, J. Med. Chem., 33, 1980 (1990); h C. U. Kim, B. Y. Luh and J. C. Martin, J. Med. Chem., 33, 1797 (1990); i D. W. Norbeck, E. Kern, S. Hayashi, W. Rosenbrook, H. Sham, T. Herrin, J. J. Planner, J. Erickson, J. Clement, R. Swanson, M. Shipkowitz, D. Hardy, K. Marsh, G. Arnett, W. Shannon, S. Broder and H. Mitusya, J. Med. Chem., 33, 1281 (1990); j J. J. Bronson, I. Ghazzouli, M. J. M. Hitchcock, R. R. Webb, II and J. C. Martin, J. Med. Chem., 32, 1457 (1989); k Y. Nishiyama, N. Yama-moto, K. Takahash and N. Shimada, Antimicrob. Agents Chemother., 32, 1053 (1988); l K. Harada, J. Matulic-Adamic, R. W. Price, R. F. Schinazi, K. A. Watanabe and J. J. Fox, J. Med. Chem., 30, 226 (1987); m S. Suzuki, H. K. Misra, L. I. Wiebe, E. E. Knaus and D. L. J. Tyrrell, Mol. Pharmacol, 31, 301 (1987); n S. R. Turk, C. Shipman, Jr., R. Nassiri, G. Genzlinger, S. H. Krawczyk, L. B. Townsend and J. C. Drach, Antimicrob. Agents Chemother., 31, 544 (1987).
- 3a R. J. Suhadolnik, Nucleosides as Biological Probes, Wiley, New York, 1979, pp 217–233; b R. Dolin, Science, 227, 1296 (1985); c T.-W. Chang and D. R. Snydman, Drugs, 18, 354 (1979); d S. C. Marker, R. J. Howard, K. E. Groth, A. R. Mastri, R. L. Simmons and H. H. Balfour, Jr., Arch. Intern. Med., 140, 1441 (1980).
- 4a J. C. Drach, Abstracts 185th American Chemical Society Meeting, Seattle, WA, March 20-25, 1983, CARB-24; b J. A. Montgomery, Med. Res. Rev., 2, 271 (1982); c L. L. Bennett, Jr., P. W. Allan, S. C. Shaddix, W. M. Shannon, G. Arnett, L. Westbrook, J. C. Drach and C. M. Reinke, Biochem. Pharmacol., 30, 2325 (1981).
- 5 W. M. Shannon, L. Westbrook, G. Arnett, S. Daluge, H. Lee and R. Vince, Antimicrob. Agents Chemother., 24, 538 (1983).
- 6 R. Vince and S. Daluge, J. Med. Chem., 20, 612 (1977).
- 7 R. Vince, S. Daluge, H. Lee, W. M. Shannon, G. Arnet, T. W. Schafer, T. L. Nagabhushan, P. Reichert and H. Tsai, Science, 221, 1405 (1983).
- 8 H. Lee and R. Vince, J. Pharm. Sci., 69, 1019 (1980).
- 9 G. E. Wright and N. C. Brown, Pharmacol. Therap., 47, 447 (1990).
- 10 N. N. Khan, G. E. Wright, L. W. Dudycz and N. C. Brown, Nucleic Acids Res., 12, 3695 (1984).
- 11 F. Focher, C. Hildebrand, S. Freese, G. Ciarrocchi, T. Noonan, S. Sangalli, N. Brown, S. Spadari and G. Wright, J. Med. Chem., 31, 1496 (1988).
- 12
M. Koga and
S. W. Schneller,
Nucleosides Nucleotides,
8,
1085
(1989).
10.1080/07328318908054291 Google Scholar
- 13 R. Vince, J. Brownell and S. Daluge, J. Med. Chem., 27, 1358 (1984).
- 14a G. W. Kenner, B. Lythgoe, A. R. Todd and A. Topham, J. Chem. Soc., 388 (1943); b W. Traube, Ann., 64, 331 (1904).
- 15 H. King and I. M. Tonkin, J. Chem. Soc., 1063 (1946).
- 16 F. Seela, W. Bussmann, A. Götze and H. Rosemeyer, J. Med. Chem., 27, 981 (1984).
- 17a D. J. Brown, The Pyrimidines, Supplement II, Wiley, New York, 1985, pp 187–188; b G. D'atari, P. Gomarasca, G. Resnati, G. Tronconi, C. Scolastico and C. R. Sirtori, J. Med. Chem., 27, 1621 (1984).
- 18 W. M. Dankner, D. Scholl, S. C. Stanat, M. Martin, R. L. Sonke and S. A. Spector, J. Virological Methods, 28, 293 (1990).
- 19 When 4a and 5a were evaluated against HSV-1 (KOS) [20], HSV2 (186) [20], and VZV [18], no activity was found up to 100 μM. Also, neither 4b nor 5b demonstrated anti-HSV-1 or HSV-2 [20] potential up to 25 μM. In an anti-HIV assay (versus strain 3B in MT4 cells) [21] 5a demonstrated no activity [21] whereas 4a displayed a 12% inhibition at 40 μM. With 4b and 5b anti-HIV activity [21] was found to be 6% at 100 μM(4b) and 38% at 100 μM(5b).
- 20 C. McLaren, M. N. Ellis and G. A. Hunter, Antiviral Res., 3, 223 (1983).
- 21 D. R. Averett, J. Virological Methods, 23, 263 (1989).
