Abstract
Six, heretofore undescribed, 5′-Methyl-5′-(5-Substituted uracil-1-ylmethyl)-2′-oxo-3′-methylenetetrahydrofurans (F, Cl, Br, I, CH3, H) (6a-f) were synthesized and evaluated against three cell lines (FM-3A, P-388 and U-937). For the preparation of α-methylene-γ-butyrolactone bearing 5-substituted uracils (6a-f), the efficient Reformatsky type reaction was employed which involves the treatment of ethyl α-(bromomethyl) acrylate and zinc with the respective 5-substituted uracil-1-ylacetones (5a-f). The acetone derivatives (5a-f) were directly obtained by the respective alkylation reaction of 5-substituted uracils with chloroacetone in the presence of K2CO3 (or NaH). These lactone compounds6a-f exhibited moderate to significant activity in all of the three cell lines, and6b, 6c and6e showed significant antitumor activities (inhibitory concentrations (IC50) ranged from 1.3–3.8 μg/ml).
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References Cited
Carmichael, J., DeGraff, W. G., Gazdar, A. F., Minna, J. D., Mitchell, J. B., Evaluation of a Tetrazoliumbased Semiautomated Colorimetric Assay; Assessment of Chemosensitivity Testing.Canceer Res., 47, 936–940 (1987).
Cassady, J. M., Bryn, S. R., Stamos, I. K., Evans, S. M., McKenzie, A., Potential Antitumor Agents. Synthesis, Reactivity and Cytotoxicity of α-Methylene Carbonyl Compounds.J. Med. Chem., 21, 815–819 (1978).
Dehal, S. S., Marples, B. A., Stretton, R. J., Traynor, J. R., Steroidal α-Methylenes as Potential Antitumor Agents.J. Med. Chem., 23, 90–92 (1980).
Fursteer, A., Recent Advancements in the Reformatsky Reaction.Synthesis, 571–589 (1989).
Ferris, A. F., The Action of Mineral acid on Diethyl bis(hydroxymethyl) malonate.J. Org. Chem., 20, 780–787 (1955).
Gammill, R. B., Wilson, C. A., Bryson, T. A., Synthesis of α-Methylene-γ-butyrolactons.Synthetic Communication, 5, 245–268 (1975).
Grieco, P. A., Methods for the Synthesis of α-Methylene Lactones.Synthesis, 67–77 (1975).
Hall, I. H., Lee, K-H, Mar, E. C., Starnes, C. O., Waddel, T. G., Antitumor Agents. 21. A Proposed Mechanism for Inhibition of Cancer Growth by Tenulin and Helenalin and Related Cyclopentenones.J. Med. Chem., 20, 333–337 (1977).
Heindel, N. D., Minatelli, J. A. Synthesis and Antibacterial and Anticancer Evaluations of α-Methylene-γ-butyrolactones.J. Pharm. Sci., 70, 84–86 (1981).
Kim, J. C., Lee, Y. H. Synthesis and Evaluation of Uracil-6-carboxaldehyde Schiff Base as Potential Antitumor Agents.Korean J. Med. Chem., 2, 64–69 (1992).
Kim, J. C., Park, J. I., Hur, T. H., Synthesis of 4-Azacholestane Derivatives Containing Nitrosoureido Function as Antitumor Activity.Bull. Korean Chem. Soc., 14, 176–178 (1993a).
Kim, J. C., Peak, H. D., Moon, S. H., Kim, S. H. Synthesis of Steroidal Cyclophosphamide, 2-bis(2-chloroethyl) amino-2-oxo-6-(5α-cholestanyl)-1,3, 2-oxazaphorinane.Bull. Korean Chem. Soc., 14, 318–319 (1993b).
Kim, J. C. and Han, S.H. Nitrosation Products of N-Acy-N′-Substituted Phenyl Hydazines.Bull. Korean Chem. Soc., 15, 173–176 (1994a).
Kim, J. C., Bae, S. S., Kim, S. H. and Kim, S. H., Synthesis and In Vitro Cytotoxicity of Homologous Series of 9-[ω-(N′-methyl-N′-nitrosoueido) alkyl] purines. KoreanJ. Med. Chem., 4, 66–72 (1994b).
Kim, J. C., Dong, E. S., Ahn, J. W., Kim S. H., Synthesis and Evaluation of Antitumor Activity of a Homologous Series of 1-(ω-cyanoalkyl) and 1,3-bis (ω-cyanoalkyl)uracil Nucleoside Analogues.Arch. Pharm. Res., 17, 135–138 (1994c).
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 (1994d).
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 Agents.Arch. Pharm. Res., 17, 420–423 (1994e).
Kim, J. C., Dong, E. S., Park, J. I., Bae, S. D. and Kim, S. H. 5-Substituted Pyrimidine Acyclic Nucleoside Analogues. 1-Cyanomethyl- and 1-(4-Cyanobutyl)-5-Substituted Uracils as Candidate Antitumor Agents.Arch. Pharm. Res., 17, 480–482 (1994f).
Kim, J. C., Kim, M. Y., Kim, S. H., Choi, S. H. Synthesis of a Series of cis-Diamminedichloroplatinum (II) Complexes Linked to Uracil and Uridine as Candidate Antitumor Agents.Arch. Pharm. Res., 18, 449–453 (1995).
Kupchan, S. M., Aynehchi, Y., Cassady, J. M., Schones, H. K., Burlingaame, A. L., Tumor Inhibitions XL. The Isolation and Structural Elucidation of Elephantin and Elephantopin, Two Novel Sequiterpenoid Tumor Inhibitors from Elephantopus Elatus.J. Org. Chem., 34, 3867–3875 (1969a).
Kupchan, S. M., Hemingway R. J., Werner, D., Karim, A., Tumor Inhibitors. XLVI. Verlepin, a Novel Sesquiterpene Dilactone Tumor Inhibitor from Vernoniahymenolepis A. Rich.J. Org. Chem., 34, 3903–3908 (1969b).
Kupchan, S. M., Giacobbe, T. J., Krull, I. S., Thomas, A. M., Eakin, M. A., Fessler, D. C., Reaction of Endocyclic α,β-Unsaturated γ-Lactones with Thiols.J. Org. Chem., 35, 3539–3542 (1970).
Lee, K-H., Furukawa, H., Huang, E-S.,J. Med. Chem., 15, 6009–611 (1972).
Lee, K-H., Ibuka, T., Kim, S.H., Vestal, B.R., Hall, I.H. Antitumor Agents 16. Steroidal α-Methylene-γ-lactones.J. Med. Chem., 18, 812–817 (1975).
Lee, K-H., Imakura, Y., Sims, D., McPail, A.T., Onan, K.D.,J. Chem. Soc., Commun., 341, 1976.
8Mosmann, T., Rapid Colorimetric Assay for Cellular Growth and Survival; Application to Proliferaton and Cytotoxicity Assays.J. Immunol. Methods, 65, 55–63 (1983).
Montgomery, J. A., Temple, C., The Alkylation of 5-Chloropurine.J. Am. Chem. Soc., 83, 630–635 (1961).
Ohler, E., Reining, K., Schmidt, U. A Simple Sythesis of α-Methylene-γ-lactones.Angew. Chem. Internat. Ed., 9, 458–459 (1970).
Rosowsky, A., Papathanasopoulos, N., Lazarus, H., Foley, G. E., Modest, E. J.,J. Med. Chem., 17, 672–676 (1974).
Sanyal, U., Mitra, S., Pal, P., Chakraborti, S. K., New α-Methylene-γ-Lactone Derivatives of Substituted Nucleic Acid Bases as Potential Anticancer Agents.J. Med. Chem., 29, 595–599 (1986).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kim, J.C., Kim, JA., Kim, SH. et al. Synthesis and antitumor evaluation of α-methylene-γ-butyrolactone-linked to 5-Substituted uracil nucleic acid bases. Arch. Pharm. Res. 19, 235–239 (1996). https://doi.org/10.1007/BF02976897
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF02976897