Резюме
Вельчинська О.В. Новий хіміко-біологічний аддукт на основі 1,1-біс-(5-бромопіримідин-2’,4’-діон-1’-іл)-2-бромо-2-хлороетилену та протипухлинного бактерійного лектину Bacillus polymyxa.
Дослідження антиметаболітів піримідинового обміну, які виступають у якості преформованих сполук в низці біосинтетичних процесів та гальмують пухлинний рост, є найбільш успішним напрямком пошуку нових протипухлинних засобів. З метою отримання нових потенційних протипухлинних засобів синтезовано нове біс-похідне 5-бромоурацилу, створено оригінальний хіміко-біологічний аддукт на основі 1,1-біс-(5-бромопіримідин-2’,4’-діон-1’-іл)-2-бромо-2-хлороетилену та протипухлинного бактерійного лектину Bacillus polymyxa. Встановлено, що хіміко-біологічний аддукт біс-похідного 5-бромоурацилу та бактерійного лектину, є малотоксичним (ЛД50: 635 мг/кг) та виявляє значний протипухлинний ефект на Саркомі 45 (% гальмування пухлинного росту 82,0). Це свідчить про те, що новий хіміко-біологічний аддукт є перспективним для подальшого вивчення як малотоксична речовина з високою протипухлинною активністю на Саркомі 45.
Ключові слова: 5-бромоурацил, протипухлинна активність, лектин.
Резюме
Вельчинская Е.В. Новый химико-биологический аддукт на основе 1,1-бис-(5-бромопиримидин-2’,4’-дион-1’-ил)-2-бромо-2-хлороэтилена и противоопухолевого бактериального лектина Bacillus polymyxa.
Исследования антиметаболитов пиримидинового обмена, которые выступают в качестве преформированных соединений в цепочке биосинтетических процессов и тормозят опухолевый рост, являются наиболее успешным направлением поиска новых противоопухолевых средств. С целью получения новых потенциальных противоопухолевых средств синтезировано новое бис-производное 5-бромоурацила, создан оригинальный химико-биологический аддукт на основе 1,1-бис-(5-бромопиримидин-2’,4’-дион-1’-ил)-2-бромо-2-хлороэтилена и противоопухолевого бактериального лектина Bacillus polymyxa. Установлено, что химико-биологический аддукт бис-производного 5-бромоурацила и бактериального лектина, является матотоксичным (ЛД50: 635 мг/кг) и проявляет значительный противоопухолевый эффект на Саркоме 45 (% торможения опухолевого роста 82,0). Это свидетельствует о том, что новый химико-биологический аддукт является перспективным для дальнейшего изучения как малотоксичное вещество с высокой противоопухолевой активностью на Саркоме 45.
Ключевые слова: 5-бромоурацил, противоопухолевая активность, лектин.
Summary
Welchinska E.V. New chemical-biological adduct on the base of 1,1-bis-(5-bromopyrimidine-2’,4’-diono-1’-il)-2-bromo-2-chloroethylene and antitumoure bacterial lectin Bacillus polymyxa.
Investigation of the antimetabolites of pyrimidin’s change which forwards as preformed compounds at the link of biosynthetic processes and brakes tumour’s growth is more successful finding direction of new antitumour preparations. With a purpose of new potential antitumour preparation the new bis-derivative of 5-bromouracile was synthesised, the chemical-biological adduct on the base of 1,1-bis-(5-bromopyrimidine-2’,4’-diono-1’-il)-2-bromo-2-chloroethylene and antitumour bacterial lectin Bacillus polymyxa was produced. It was discovered that chemical-biological adduct of bis-derivative of 5-bromouracile and bacterial lectin applies to a little toxic preparation (LD50: 635 mg/kg) and demonstrates considerable antitumour effect upon to 82,0% on Sarcoma 45 tumour. It confirms that new chemical-biological adduct is perspective for the future investigation as substance with a little toxicity and high antitumour activity on the Sarcoma 45.
Key words: 5-bromouracile, antitumour activity, lectin.

Рецензент: д.фарм.н., проф. М.М. Слободянюк

УДК 547.745

Національний медичний університет імені О.О. Богомольця (Київ)

Национальный медицинский университет имени А. А. Богомольца Киев,

O.O. Bogomolets National medical university Kyiv

elena_wwu@ukr.net

The aim of research. One of the more successful finding direction of new antitumour preparations is investigations of the antimetabolites of pyrimidin’s and purin’s change which forwards as preformed compounds at the link of biosynthetic processes (DNA, RNA, specific proteins) and brakes tumour’s growth. Investigation of the antimetabolites of pyrimidin’s change which forwards as preformed compounds at the link of biosynthetic processes and brakes tumour’s growth is more successful finding direction of new antitumour preparations. With a purpose of new potential antitumour preparation the new bis-derivative of 5-bromouracile was synthesised, the chemical-biological adduct on the base of 1,1-bis-(5-bromopyrimidine-2’,4’-diono-1’-il)-2-bromo-2-chloroethylene and antitumour bacterial lectin Bacillus polymyxa was produced. A purpose of the work is explaining of preformed heterocycles as pyrimidines, investigation of its antitumour activity. Molecular complexes of 1,1-bis-(5-bromopyrimidine-2’,4’-diono-1’-il)-2-bromo-2-chloroethylene and bacterial lectin Bacillus polymyxa  received. 

Materials and methods.  Objects of investigations are new bis-derivative which synthesised on the base of 5-bromopyrimidine and halothane. Investigation of critical toxicity of new compounds was carried out at Institute of Pharmacology and Toxicology of National Academy of Medical Sciences of Ukraine. The lectin’s preparations were obtained by treatment of culture Liquid of saprophytic strain Bacillus from Ukrainian Collection of Microorganisms of Institute of Microbiology and Virology (IMV): B. polymyxa 102 KGU; in future:  lectine 102) clarified by treatment with ammonium sulfate (70% concentration of a saturated solution). The white imbredical mice and experimental model of tumor growth—cancer Sarcoma 45, were used following published procedures in Prozorovskiy (1978).  The experimental tumors used for our investigation were obtained from Strain Bank of Oncological Centre of Russian Academy of Medical Sciences.  The experimental tumors were used for passage on experimental animals, and program freezing.  Afterward, these would be preserved in Strain Bank of Institute of Pharmacology and Toxicology of National Academy of Medical Sciences of Ukraine.  The quantity of animals in each group was six.  Minimum weight of mice body was 17.0±2.0 g and 22,0±2,0 g,  of rats body was 160,0+20,0 g.  Percentage of primary recovery and destruction is “0.”  Method of killing was decapitation and ethyl ester overdose.  The method of the experimental tumors removal was surgery.   There were six introductions of the physiological solutions of molecular complexes every day.  The dosage of the preparations corresponded to 1/4-1/6 of the LD₅₀.  The efficiency parameter (% of tumor growth relaxation [volume and mass]) is > 50% in case of cancer Sarcoma 45.  The main control data are: average weight of the tumor in the control animals (g), average weight of the tumor in experimental animals (g), % of growth relaxation of the tumor, index of effectiveness, and spleen ratio.  The considerable criterion is > 50.0% of growth relaxation of the tumor.  Preparation of standard was 5-flurouracil (5-FU).  The results were assessed by standard methods of statistical analysis. Molecular complex of bis-adduct and bacterial lectin was obtained by mixing two components at physiological solution, 1:1.

Results. It was discovered that molecular complexes of bis-derivative of 5-bromouracile and bacterial lectin applies to a little toxic preparation (LD₅₀: 635 mg/kg). It has been established that molecular complexe of Bacillus polymyxa 102 KGU and bis-derivative of 5-bromouracile shows an anti-tumor activity on cancer Sarcoma 45:  82,0%  growth braking in cancer growth (considerable criteria is > 50.0% of tumor growth relaxation). 

Conclusion. Anti-tumor activity of molecular complex of bis-derivative of 5-bromouracile and bacterial lectin permits us to consider it as physiological active with a perspective investigation as a potential antitumor drug for future treatment in people.  It confirms that new chemical-biological adduct is perspective for the future investigation as substance with a little toxicity and high antitumour activity on the Sarcoma 45. The construction of the principle of new medical preparations, on the basis of the saprophytic strains bacterial lectins and heterocyclic bis-adducts, is very possible.

Література

1. Клецкий М.Е. Структура и реакционная способность производных ура­цила / М.Е. Клецкий, Е.Б. Цупак, Д.А. Назаров // ХГС. – 2002. – № 8. – С. 1106-1108.
2. Кудрявцева І.Г. Сучасний стан пошуку і вивчення ФАР з проти пух­лин­ною дією серед похідних кислот фосфору / І.Г. Кудрявцева, Н.І. Шари­кіна // Ліки. – 2004. – № 1-2. – С. 31-40.
3. Прозоровский В.Б. Экспресс метод определения средней эффективности дозы и ее ошибки / В.Б. Прозоровский, В.П. Прозоровский, В.М. Демченко // Фармакол. и токсикол. – 1978. – Т. 41, № 4. – С. 407-509.
4. Экспериментальная оценка противоопухолевых препаратов в СССР и США / Под ред. Софьиной З.П., Сыркина А.Б., Голдина А., Кляйна А. – М.: Медицина, 1979. – 296 с.
5. Adjei A.A. Review of pharmacology and clinical activity of new chemotherapy agents for the treatment of colorectal cancer / A.A. Adjei // Clin. Pharmacol. – 1999. – Vol. 48. – P. 265-277.
6. Anderson N. Controversial issues in 5-fluorouracil infusion use. Dose intensity, treatment duration, and cost comparisons / N. Anderson, J. Lokich // Cancer. – 1992. – Vol. 70. – P. 998-1002.
7. Anttila M. I. Pharmacokinetics of ftorafur after intravenous and oral administration / M.I. Anttila, E.A. Sotaniemi, M.I. Kairaluoma // Cancer Chemother. and Pharmacol. - 1983. – Vol. 10. – P. 150–153.
8. Baba H. State of the treatment for gastrointestinal cancer / H. Baba, S. Kohnoe, K. Endo // Gan To Kagaku Ryoho. - 2000. – Vol. 27. – P. 1233-1246.
9. Longley D.B. Mechanisms of action of 5-fluorouracil / D.B. Longley, D.P. Harkin // Nature Rev. Cancer. – 2004. – Vol. 4. – P. 230-238.
10. Noordhuis P. 5-fluorouracil incorporation info RNA and DNA in relation to thymidilate synthetase inhibition human colorectal cancer / P. Noordhuis, U. Holwerda // Annals. of oncol. – 2004. – Vol. 15. – P. 1025-1032.

References

1. Kletskiy, M.E., Tsupak, E.B. & Nazarov, D.A. (2002). Struktura i reaktsionnaya sposobnost proizvodnikh uratcila [Structure and reactive ability of derivatives of uracile]. Chemistry of heterocyclic compounds, 8, рр. 1106-1108. (Russian).
2. Kudriyvtseva, I.G., Sharikina, N.I. (2004). Suchacniy stan poshuku i vivchenniy FAR z protypukhlinnoy diey sered pokhidnikh kislot fosforu [Modern situation of finding and learning of PhAS with antitumour action besides derivatives of phosphorus’s acids]. Liki, 1-2, рр. 31-40. (Ukrainian).
3. 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), рр. 407-509. (Russian).
4. 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.
5. Adjei, A. A. (1999). Review of pharmacology and clinical activity of new chemotherapy agents for the treatment of colorectal cancer. Clinical Pharmacology, 48, рр. 265-277.
6. Anderson, N., & Lokich, J. (1992). Controversial issues in 5-fluorouracil infusion use. Dose intensity, treatment duration, and cost comparisons. Cancer, 70, рр. 998-1002.
7. Anttila, M. I., Sotaniemi, E. A., & Kairaluoma, M. I. (Eds.). (1983). Pharmacokinetics of ftorafur after intravenous and oral administration. Cancer Chemotherapy and Pharmacology, 10, рр. 150–153.
8. Baba, H., Kohnoe, S., & Endo, K. (Eds.). (2000). State of the treatment for gastrointestinal cancer. Gan To Kagaku Ryoho, 27, 1233-1246.
9. Longley, D.B., Harkin, D.P. (2004). Mechanisms of action of 5-fluorouracil. Nature Rev. Cancer, 4, рр. 230-238.
10. Noordhuis, P., Holwerda, U. (2004). 5-fluorouracil incorporation info RNA and DNA in relation to thymidilate synthetase inhibition human colorectal cancer. Annals. of oncol., 15, рр. 1025-1032.