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Synthesis and antitumor evaluation of acyclic 1-[ω-(N′-2-chloroethyl-N′-nitrosoureido)alkyl]thymidine nucleoside analogues

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In the preparation of acyclic thymidine nucleoside analogues, K2CO3 (or NaH) treated thymine in DMSO was alkylated with ω-chloroalkyl nitrite (Cl-(CH2)n-CN; n=1, 2, 3, 4) to provide an isomeric mixture of 1-(ω-cyanoalkyl)thymine (2a-d) and 1,3-bis(ω-cyanoalkyl)thymine in approximately 5∶1 ratios. Reduction of the cyano function2a-d with NaBH4/CoCl2·6H2O gave the corresponding 1-(ω-aminoalkyl)thymine (3a-d). The newly formed primary amino function in3a-d was directly reacted with 2-chloroethylisocyanate to afford the 1-[ω-(N′2-chloroethy-lureido) alkyl]thymine (4a-d) in good yields. Nitrosation of 1-[5-(N′-2-chloroethylureido)pentyl] thymine (4d) with glacial acetic acid and dry NaNO2 powder in anhydrous CH2Cl2 gave two types of regioisomeric nitrosoureas, 1-[5-(N′-2-chloroethyl-N′-nitrosoureido)pentyl]thymine (5d) and 1-[5-(N′-2-chloroethyl-N-nitrosoureido)pentyl]thymine in approximately 5∶1 ratios. The in vitro cytotoxicity of the synthesized compounds (2a-d, 3a-d, 4a-d and5a-d) against three cell lines (K-562, P-388 and FM-3A) are measured as IC50 values. Compounds3d and4c showed moderate activities against all three cell lines, and all other compounds were found to be not active.

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References Cited

  1. Carmichael, J., Degraff, W. G., Gazdar, A. F., Minna, J. D. and Mitchel, J. B., Evaluation of a Tetrazolium based Semiautomated Colorimetric Assay: Assessment of Chemosensitivity Testing.Cancer Res., 47, 936–938 (1987).

  2. Coates, J. A. V., Cammack, N. S., Jenkinson, H. J., Mutton, I. M., Pearson, B. A., Storer, R., Cameron, J. M. and Penn, C. R., The Separated Enantiomers of 2′-Deoxy-3′-Thiacytidine (BCH 189) Both Inhibit Human Immunodeficiency Virus Replication.In Vitro Antimicrob. Agents Chemother. 36, 202–205 (1992).

  3. Chu, C. K. and Cutter, S. J., Chemistry and Antiviral Activities of Acyclonucleosides.;J. Hererocycl. Chem., 23, 289–319 (1986).

  4. De Clercq, E. and Walker, R. T., Progress in Medicinal Chemistry; Ellis, G. P., West, G. B., Eds., Elsebvier, New York, 1986; Vol. 23, Chapter 5.

  5. Fisch, M. A., Richman, D. D. and Grieco, M. H., The Efficacy of Azidothymidine (AZT) in the Treatment of Patient with AIDS and AIDS-Related Complex: a Double-blind, Placebo-Controlled Trial.N. Engl. J. Med., 317, 185–192 (1987).

  6. Kametani, T., Kigasawa, K., Hiiragi, M., Wakisawa, K., Nakazato, K., Ichikawa, K., Fukawa, K., Irino, O., Nishimura, N. and Okada, T., Studies on the Synthesis of Chemotherapeutics. 12. Synthesis and Antitumor Activity of N-phthalidyl-5-Fluorouracil Derivatives.J. Med. Chem. 25, 1219–1222 (1982).

  7. Kelley, J. A., Kelsey, J. E., Hall, W. R., Krochmal, M. P. and Schaeffer, H. J., Pyrimidine Acyclic Nucleosides, 1-[2-(hydroxyethoxy)methyl]pyrimidines as Candidate Antivirals.J. Med. Chem., 24, 753 (1981).

  8. Kim, J. C., Dong, E. S., Kim, J. A., Kim, S. H., Park, J. I. and Kim, S. H., Synthesis and Antitumor Evaluation of Acyclic 5-Substituted Pyrimidine Nucleoside Analogues, Korean,J. Med. Chem., 4, 111–118 (1994a).

  9. Kim, J. C., Lim, Y. G., Min, B. T., and Park, J. I., Preparation of N′-substituted Anilino-N-Methyl-N′-Nitrosoureas as Candidate Antitumor Ageni,Arch. Pharm. Res., 420–423 (1994b).

  10. Kim, J. C., Han, S. H. Nitrosation Products of N-Acyl-N′-substituted phenylhydrazines.Bull. Kor. Chem. Soc. 15, 173–175 (1994c).

  11. Lambert, J. S., Sweglin, M., Reichman, R. C., Plank, C. S. and Dolin, R., 2′,3′-Dideoxyinosine(DDI) in patients with Acquired Immunodeficiency Syndrome or AIDS-Related Complex-a Phase I Study.N. Engl. J. Med., 332, 1333–1340 (1990).

  12. Larder, B. A., Darby, G. and Richman, D. D., HIV with Reduced Sensitivity to Zidovudine (AZT) Isolated During Proloned Therapy.Science, 243, 1731–1734 (1989).

  13. Mitsuya, H., Weinhold, K. J., Furman, P. A., St. Clair, M. H., Lehrman, S. N., Gallo, R. C., Bolognesi, D., Barry, D. W. and Broder, S., 3′-Azido-3′-deoxythymidine (BW A509U): Antiviral agent that inhibits the infectivity and cytopathic effect of Human T-lymphotropic virus type II/lympadenopathy associated virusin vitro.Proc. Natl. Acad. Sci. 82, 7096–7100 (1985).

  14. Mitsuya, H. and Boder, S., Inhibition of the in vitro infectivity and Cytopathic Effect of Human T-Lymphotrophic Virus (HTLV-III/LAV) by 2′,3′-dideoxynucleosides.Proc. Natl. Acad. Sci. U.S.A., 83, 1911–1915 (1986).

  15. Montgomery, J. A., Temple, C., The Alkylation of 5-Chloropurine.J. Am. Chem. Soc., 83, 630–635 (1961).

  16. Mosmann, T., Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxity Assay.J. Immunol. Methods, 65, 55–63 (1983).

  17. Nasr, M., Litterest and McGowan, J., Computer- Assisted Structure Activity Correlations of Dideoxynucleoside Analogs as Potential Anti-HIV Drugs.Antiviral Res., 14, 125–148 (1990).

  18. Norbeck, D. W., Spanton, S., Broder, S. and Mitsuya, H., (+)-Dioxolane-T((+)-1-[(2β,4β)-2 (hydroxymethyl-4-dioxolanyl]-thymine). A New 2′,3′-Dideoxynucleo-side Prototype within vitro Activity against HIV.Tetrahedron Lett., 30, 6263–6266 (1989).

  19. Schaeffer, H. J., Beauchamp, L., Miranda P., Elion, G. B., Bauer, D. J. and Collins P., 9-(2-Hydroxyethoxy-methyl) guanine Activity Against Viruses of the Herpes Group.Nature, 272, 583–585 (1987).

  20. Schinazi, R. F., Mead, J. F. and Feorino, P. M., Insights into HIV Chemotherapy.AIDS Res. Hum. Retroviruses, 8, 553–579 (1992).

  21. Urbina, J. A., Lazardi, K., Aguirre, M., Piras, M. M. and Piras, R., Antiproliferrative Effects and Mechanism of Action of ICI 195, 739, a novel Bis-triazol Derivative. Antimicrob.Agents Chemother., 35, 730–735 (1991).

  22. Yarchoan, R.; Thomas, R. V.; Allain, J. P.; McAtee, N.; Dubinsky, R.; Mitsuya, H.; Lawley, T. J.; Safai, B.; Myero, C. E.; Perno, C. F.; Klecker, R. W.; Wills, R. J.; Fischl, H. A.; McNeely, M. C.; Pluda, J. M.; Leuther, M.; Collins, J. M.; Broder, S.; Phase I Studies of 2′,3′-Dideoxycytidine in Severe Human Immunodeficiency Virus Infection as a Single Agent and Alternating with Zidovudine,Lancet, No. 76-80 (1988).

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Correspondence to Jack C. Kim.

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Kim, J.C., Kim, Y., Park, J.I. et al. Synthesis and antitumor evaluation of acyclic 1-[ω-(N′-2-chloroethyl-N′-nitrosoureido)alkyl]thymidine nucleoside analogues. Arch. Pharm. Res. 20, 259 (1997). https://doi.org/10.1007/BF02976154

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Key words

  • Acyclic thymidine nucleoside analogues
  • 1-[4-(N′-2-chloroethyl-N′-nitrosoureido) butyl]thymine
  • Regioisomeric nitrosoureas
  • In vitro cytotoxicity
  • Human chronic myelogenous leukemia cell
  • Mouse lymphoid neoplasma cell
  • Mouse mammary caruisoma cell
  • IC50