Abstract
Ten, heretofore unreported, 5′-methyl-5′-[2-(5-substituted uracil-1-yl)ethyl)]-2′-oxo-3′-methylenetetrahydrofurans (H, F, Cl, Br, I, CH3, CH3, CH2CH3, CH=CH2, SePh) (7a-j) were synthesized and evaluated against four cell lines (K-562, FM-3A, P-388 and U-937). For the preparation of α-methylene-γ-butyrolactone-linked to 5-substituted uracils (7a-j), the convenient Reformasky type reaction was employed which involves the treatment of ethyl α-(bromomethyl)acrylate and zinc with the respective 1-(5-substituted uracil-1-yl)-3-butanone (6a-j). The 5-substituted uracil ketones (6a-j) were directly obtained by the respective Michael type reaction of vinyl methyl ketone with the K2CO3 (or NaH)-treated 5-substituted uracils (5a-j) in the presence of acetic acid in the DMF solvent. The α-methylene-γ-butyrolactone compounds showing the most significant antitumor activity are7e, 7f, 7h and7j (inhibitory concentration (IC50) ranging from 0.69 to 2.9 μg/ml), while7b, 7g and7i have shown moderate to significant activity. The compounds7a, 7c and7d were found to be inactive. The synthetic intermediate compounds6a-j were also screened and found marginal to moderate activity where compounds6b and6g showed significant activity (IC50:0.4∼2.8 μg/ml).
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References Cited
Carmichael, J., DeGraff, W. G., Gazdar, A. F., Minna, J. D. and Mitchell, J. B., Evaluation of a Tetrazolium-based Semiautomated Colorimetric Assay;Assessment of Chemosensitivity Testing, Cancer 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).
Farina, V., Hauck, S. I., Palladium-Catalyzed Approach to 5-Substituted Uracil and Uridine Derivatives,Synlett., 157–159 (1991).
Ferris, A. F., The Action of Mineral acid on Diethyl bis(hydroxymethyl) malonate.J. Org. Chem., 20, 780–787 (1955).
For part 1., See Kim, J. C., Kim, J. A., Kim, S. H., Park, J. I., Kim, S. H., Choi, S. K. and Park, W. O., Synthesis and Antitumor Evaluation of α-methylene-γ-butyrolactone-Linked to 5-Substituted Uracil Nucleic Acid Bases.Arch. Pham. Res., 19, 235–239 (1996).
Fursteer, A., Recent Advancements in the Reformatsky Reaction. Synthesis, 571–589 (1989).
Gammill, R. B., Wilson, C. A., Bryson, T. A., Synthesis of α-Methylene-γ-butyrolactons.Synthetic Communication, 5, 245–268 (1975).
Goudgaon, N. H., Nafuib, F. N. H., el Kouni, M. H., Schinazi, R. F., Phenyselenenyl-and Phenylthio-Substituted Pyrimidines as Inhibitors of Dihydrouracil Dehydrogenase and Uridine Phosphorylase,J. Med. Chem. 36, 4250–4254 (1993).
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. and Han, S. H., Nitrosation Products ofN-Acyl-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 andIn Vitro Cytotoxicity of Homologous Series of 9-ω-(N′-methyl-N′-nitrosoueido)alkyl] purines.Korean J. 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., 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).
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., Lim, Y. G., Min, B. T. and Park, J. I. Preparation ofN-Substituted Anilino-N-Methyl-N-Nitrosoureas as Candidate Antitumor Agents.Arch. Pharm. Res., 17, 420–423 (1994e).
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-oxa-zaphorinane.Bull. Korean Chem. Soc., 14, 318–319 (1993b).
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., 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).
Kupchan, S. M., Hemingway R. J., Werner, D., Karim, A., Tumor Inhibitors. VI. Verlepin, a Novel Sesquiterpene Dilactone Tumor Inhibitor from Vernonia-hymenolepis A. Rich,J. Org. Chem., 34, 3903–3908 (1969b).
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.
Montgomery, J. A., Temple, C., The Alkylation of 5-Chloropurine.J. Am. Chem. Soc., 83, 630–635 (1961).
Mosmann, T., Rapid Colorimetric Assay for Cellular Growth and Survival; Application to Proliferaton and Cytotoxicity Assays.J. Immunol. Methods, 65, 55–63 (1983).
Ohler, E., Reining, K., Schmidt, U., A Simple Sythesis of α-Methylene-γ-lactones.Angew. Chem. Internat. Ed., 9, 457–459 (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).
Schinazi, R., Arbiser. J., Lee, J., Kalman, T., Prusoft. W., Sythesis and Biological Activity of 5-Phenyl Substituted Pyrimidine Nucleosides,J. Med. Chem., 1293–1295 (1986).
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Kim, J.C., Kim, JA., Park, J.I. et al. Potential antitumor α-methylene-ψ-butyrolactone-bearing nucleic acid bases. 2. Synthesis of 5′-methyl-5′-[2-(5-substituted uracil-1-yl)ethyl]-2′-oxo-3′-methylenetetrahydrofurans. Arch. Pharm. Res. 20, 253–258 (1997). https://doi.org/10.1007/BF02976153
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DOI: https://doi.org/10.1007/BF02976153
Key words
- 5′-Methyl-5′-[2-(5-substituted uracil-1-yl)ethyl)-2′-oxo-3′-methylenetetra-hydrofuran
- 1-(5-Substituted uracil-1-yl)-3-butanone
- Stille coupling reaction
- Tris(dibenzylidenacetonyl)bispalladium (Pd2dba3)
- Tri(2-furyl)phosphine
- Antitumor activity
- IC50
- Reformatsky reaction
- Human chronic myelogenous (K-562)
- Mouse lymphoid neoplasma (P-388)
- Mouse mammary carcinoma (FM-3A)
- Human histiocytic lymphoma (U-937)