• Elena Welchinska Bogomolets National Medical University, Kiev, Ukraine
Keywords: 5-methyluracile, halothane, anti-tumor, synthesis, toxicity


The synthesis was performed using 5-methyluracil mono-and bis-derivatives with the halogen-containing pharmacophore groups in the composition of molecules; their physiochemical and biological properties were studied. These reactions are a typical example of substitution reactions on heteroatom N(1) of uracil molecule using as the second component the reaction of halothane—the known inhaled anesthetic.  The reactions were carried out in a solvent system: benzene-dimethyl formamide and diethyl ether, under conditions of phase transfer catalysis DB-18-crown-6-complex (alkaline medium), by heating from 2 to 11 hours, followed by purification, and drying of the resulting products.  

The structure of the synthesized compounds was confirmed by elemental analysis, IR and 1HNMR spectra.  The purity was controlled by the methods of thin-layer and gas-liquid chromatography. Chromatography, IR and 1HNMR spectra of the final products were identified in comparison with the chromatograms, IR and 1HNMR spectra of the initial compounds. Variation of the reaction conditions and changes in methods of synthesis enabled to receive the synthesized compounds of high purity and to increase their practical output up to 43-80%.  Molecular complex of Bacterial lectin and 5-methyluracil bis-derivative was obtained.  

The toxicity and anti-tumor activity of some of the synthesized compounds were investigated. We have found that the new molecular complex of Bacterial lectin and 5-methyluracil bis-derivative has high anti-tumor activity in Limphosarcoma Plissa—62.8% (activity criterion >50%), which allows us to consider the synthesized compound as a physiologically active compound with the prospect for further study as a potential vehicle for anti-tumoral treatment in patients. 


Adjei, A. A. (1999). Review of pharmacology and clinical activity of new chemotherapy agents for the treatment of colorectal cancer. Clinical Pharmacology, 48, 265-277.

Abou-Gharbia, M., & Patel-Usha, R. (Eds.). (1988). Polycyclic aryl- and heteroarylpiperazinyl imides as 5-HT1A receptor ligands and potential anxiolytic agents: synthesis and structure-activity relationship studies. Journal of Medical Chemistry, 31(7), 1382-1385.

Аlоnso, R., Shaw, G., & Wright, D. (1984). Thermal addition of heterocycles to bicyclic reagents. Journal Chemical Society Perkin Translation, 1(12), 2795-2799.

Anderson, N., & Lokich, J. (1992). Controversial issues in 5-fluorouracil infusion use. Dose intensity, treatment duration, and cost comparisons. Cancer, 70, 998-1002.

Anttila, M. I., Sotaniemi, E. A., & Kairaluoma, M. I. (Eds.). (1983). Pharmacokinetics of ftorafur after intravenous and oral administration. Cancer Chemotherapy and Pharmacology, 10, 150–153.

Au, J. L., Wu, A. T., & Friedman, M. A. (Eds.). (1979). Pharmacokinetics and metabolism of ftorafur in man. Cancer Treatment Report, 63, 343–350.

Baba, H., Kohnoe, S., & Endo, K. (Eds.). (2000). State of the treatment for gastrointestinal cancer. Gan To Kagaku Ryoho, 27, 1233-1246.

Barlow, R. (1959). Vvedenie v himicheskyy farmacologiy [Introduction to chemical pharmacology].. Moscow, Russia: Foreign literature.

Benz, C., Tills, T., & Tattelman, E. (Eds.). (1982). Optimal schedule of methotrexate and 5-fluorouracil in human breast cancer. Cancer Research, 42, 2081-2086.

Blohin, N. N., & Perevodchikova, N.I. (1984). Himioterapia rakovih zabolevaniy [Chemistry therapy of tumor’s illnesses]. Moscow, Russia: Medicine.

Brody, G. L., & Sweet, R. B. (1963). Halothane anesthesia as a possible cause of massive hepatic necrosis. Anesthesiology, 24, 29–37. doi: 10.1097/00000542-196301000-00005

Brown, B. R., & Sipes, I. G. (1977). Biotransformation and hepatotoxicity of halothane. Biochemical Pharmacology, 26, 2091–2094. doi: 10.1016/0006-2952(77)90256-8

Perevodchikova, N. I. (Ed.) (2005). Chimioterapia rakovih zabolevaniy [Chemotherapy of cancerous diseases] (2nd ed.). Moscow, Russia: Practical medicine.

Kovalenko, E. A. (1990). Vnekletochnie lektini bakteriy [Extracellular bacterial lectins]. Microbiol. Zhurn., 5(3), 92-99.

Longley, D. B., & Harkin, D. P. (2004). Mechanisms of action of 5-fluorouracil. Nature Revues Cancer, 4, 230-238.

Noordhuis, P., & Holwerda, U. (2004). 5-fluorouracil incorporation info RNA and DNA in relation to thymidilate synthetase inhibition human colorectal cancer. Annals of oncology, 15, 1025-1032. doi: 10.1093/annonc/mdh264. PMid:15205195

Prozorovskiy, V. B., Prozorovskiy, V. P., & Demchenko, V. М. (1978). Ekspress-metod opredeleniya sredney effektivnosty dozy i ego oshibka [Express - method of middle effective dose determination and its mistake]. Pharmacology and toxicology, 41(4), 407-509.

Sophyina, Z. P., Sophyina, A. B., Goldin, A., & Kmein, A. (Eds.) (1979). Eksperimentalnaya otsenka protivoopuholevyh preparatov v SSSR i SShA [The experimental value of the antitumour drugs in USSR and USA]. Moscow, Russia: Medicine.

Welchinskaya, H., Kuzmenko, I., & Ilchenko, A. (1997). Geterotsikliceskie soedineniya s farmakofornimy galogenzameshenimy grupamy [Heterocyclic compounds with pharmacophore halogensubstituted groups]. Journal of Heterocyclic Chemistry, 7, 967-971.

Yagupolskiy, L. M. (1988). Aromaticheskie I geterocyklicheskie soedineniya s ftorsoderjashimy zamestitelyamy [Aromatic and heterocyclic compounds with fluoro-containing substitutes]. Kiev, Ukraine: Naukova dumka.