RU2111750C1 - Modifying agent for antitumor therapy - Google Patents

Abstract

FIELD: pharmacy, oncology. SUBSTANCE: invention proposes new agent for oncological sicknesses treatment. Agent is a complex of organocobalt (III) with Schiff's tridentate bases of the general formula (I)

Description

 The invention relates to medicine, namely to the treatment of cancer.

 The following chemical agents (substances) are known as modifiers of antitumor therapy.

 1. Hypoxic radiosensitizers - derivatives of 2-nitroimidazole (metronidazole, misonidazole, ethanidazole, pimonidazole), which, simulating the effects of molecular oxygen, enhance the cytotoxic effect of ionizing radiation and thus increase the effectiveness of radiation therapy of tumors [1 and 2]; under hypoxic conditions, these substances are also able to increase the cytotoxicity of certain alkylating antitumor drugs [3 and 4].

 Recently, a new hypoxic radiosensitizer AK-2123, a derivative of 3-nitrotriazole, possessing both radio- and chemosensitizing activity was synthesized and tested in experiment and clinic [5 and 6].

 2. Glucose, by intravenous infusion of which a state of hyperglycemia is artificially created, allows you to selectively intensify the process of glycolysis in the tumor and thereby reduce the intratumoral pH; artificial hyperglycemia significantly improves the results of radiation and chemotherapy [7 and 8].

 3. Hydralazine (1-hydrazinephthalazine hydrochloride) is a hypotensive drug that, by lowering blood pressure, can inhibit local blood flow in the tumor, which increases the effectiveness of a number of antitumor drugs and local hyperthermia [9 and 10].

4. Amiloride (3,5-diamino-6-chloro-N- (diaminomethylene) pyrazinecarboxamide) is a diuretic that inhibits Na ⁺ / H ⁺ antiport and thereby reduces intracellular pH, increasing the effectiveness of thermochemotherapy [11 and 12].

 5. Nigericin is an antibiotic that promotes the exchange of intracellular potassium for extracellular hydrogen, which leads to a decrease in intracellular pH, and thereby enhances the antitumor effect of alkylating drugs active at low pH [13].

 6. Pentoxifylline (trental, 3,7-dimethyl-1- (5-oxohexyl) xanthin) is a vasoactive drug that can improve the oxygenation of tumor tissue and thereby increase the antitumor effect of radiation therapy [14 and 15], while it was also shown that pentoxifylline enhances the antitumor effect of a number of alkylating drugs [16].

 7. Nicotinamide improves the oxygenation of tumor tissue, thereby increasing the effectiveness of radiation therapy [17], while it has also been shown that nicotinamide increases the sensitivity of the tumor to chemotherapeutic drugs [18].

 8. Verapamil (isoptin, 5 - [(3,4-dimethoxyphenethyl) methylamino] -2- (3,4-dimethoxyphenyl) -2-isopropylvaleronitrile hydrochloride) is a vasodilator and antiarrhythmic drug; it inhibits the activity of P-glycoprotein, which enhances the resistance of tumors to chemotherapeutic drugs; due to this property, verapamil is able to increase the effectiveness of antitumor chemotherapy [19].

 9. SR-4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide) - a substance that has a cytotoxic effect on cells in a state of hypoxia; it increases the antitumor effect of a number of alkylating drugs [20-22].

As modifiers of antitumor therapy, physical effects (methods) are also used, namely
(10) hyperthermia - local, consisting in increasing the temperature of the tumor tissue to 42 - 43 ^o C, and general, consisting in increasing the body temperature of the patient to 41 - 41.5 ^o C [23 and 24].

 Closest to the proposed modifier according to the principle of action and effectiveness of amiloride (p. 4).

 A common disadvantage of known means and methods of modifying antitumor therapy, with the exception of artificial hyperglycemia, is that their effect on the tumor is not selective. In addition, all of them have individual flaws. In particular, amiloride (prototype) causes hyperkalemia and can lead to the development of megaloblastic anemia [25], and artificial hyperglycemia is contraindicated in diabetes mellitus, grade III hypertension and renal failure.

 The objective of the invention is the search for new effective modifiers of antitumor therapy, exhibiting their effect selectively, at a relatively low pH, which is inherent in the tumor and can be further reduced with high selectivity using artificial hyperglycemia.

где
R - алкил, в том числе функционально замещенный. Общие формулы предлагаемых модификаторов I-VIII приведены ниже.The essence of the invention lies in the fact that, as a modifier of antitumor therapy, complexes (chelates) of organocobalt (III) with tridentate Schiff bases, a schematic formula, are used.

Where
R is alkyl, including functionally substituted. The general formulas of the proposed I-VIII modifiers are given below.

 Complexes of this type were first obtained in [26–28]. Earlier it was proposed to use some of them as initiators of emulsion polymerization [28].

Таким образом, они являются pH-зависимыми источниками алкильных свободных радикалов, которые, как известно, способны повреждать или расщеплять биомолекулы, такие как углеводы и нуклеиновые основания и кислоты [30]. Вероятно, что модифицирующий эффект этих комплексов осуществляется путем повреждения структуры ДНК опухолевых клеток и (или) ингибирования репарации молекул ДНК, поврежденных в результате действия известного противоопухолевого препарата или излучения высокой энергии.It was found that these complexes decompose under the influence of protons under very mild conditions: in slightly acidic solutions (at pH <7) and ordinary temperatures (0 - 40 ^o C), effectively generating free radicals [29]

Thus, they are pH-dependent sources of alkyl free radicals, which are known to damage or break down biomolecules, such as carbohydrates and nucleic bases and acids [30]. It is likely that the modifying effect of these complexes is carried out by damaging the DNA structure of tumor cells and (or) inhibiting the repair of DNA molecules damaged as a result of the action of a known antitumor drug or high-energy radiation.

The authors showed that organocobalt complexes not only inhibit the restoration of single-stranded DNA breaks caused by cis-platinum (platidiam), but they themselves can damage DNA. The study was conducted on Guerin's carcinoma (tumor volume 1.0 cm ³ ). The determination of the number of single strand DNA breaks was carried out using the alkaline elution method. The results are shown in table. 1. These data suggest that the modifying effect of organocobalt (III) complexes with Schiff tridentate bases is due to their ability to cause single-stranded DNA breaks and inhibit the recovery of single-stranded DNA breaks resulting from exposure to cytotoxic agents.

 Examples.

 The list of organocobalt complexes in the examples is given in table. 2.

Cancer models:
transplanted Guerin's carcinoma in rats,
transplanted sarcoma 45 in rats,
transplanted L1210 leukemia in mice.

Therapy regimens:
1) injected a solution of the complex;
2) injected a solution of the complex and infused a 20% glucose solution;
3) a solution of the complex was administered in combination with chemotherapy (platidiam);
4) injected a solution of the complex and carried out local hyperthermia;
5) a solution of the complex was administered in combination with thermochemotherapy, i.e. chemotherapy (platidiam) and local hyperthermia;
6) a complex solution was administered and radiation therapy was performed.

 The test results, in each of which several groups of animals were used, are summarized in the form of a table. 3 - 6. They show that the proposed modifiers significantly enhance the antitumor effect of known cytostatic agents. The use of these complexes can significantly reduce the dose of a chemotherapeutic drug - platidiam, or the intensity of the physical effect - local hyperthermia without loss of treatment effectiveness, and in some cases even with its increase. Thus, it is possible to reduce the general toxic effect of these cytostatic agents on the body.

 With the introduction of the considered complexes in doses that have a modifying effect, no side effects were observed that would require the cessation of the use of these modifiers or the entire treatment regimen.

 Thus, the use of the proposed modifiers significantly increases the effectiveness of known methods of antitumor therapy and can significantly reduce the dosage of cytostatic drugs or the intensity of physical effects.

 Literature.

 1. J. Overgaard et al., Int. J. Radiat. Oncol. Biol. Phys., 1989, 16, 1065-1068.

 2. G. Adams et al., Radiotherapy and Oncology, 1991, Suppl. 20, 85-91.

 3. I. Tannock, Br. J. Cancer, 1980, 42, 861-870.

 4. S. Fujimoto et al., Br. J. Cancer, 1988, 58, 42-45.

 5. A. Garcia-Angulo et al., Int. J. Radiat. Oncol. Biol. Phys., 1992, 22, 589-591.

 6. S.P. Osinsky et al., Exp. Oncology, 1994, 16, 61-66.

 7. M. von Ardenne. Krebs-Mehrschritt-Therapie. Berlin, 1970.

 8. Javrid E.A. Hyperthermia and hyperglycemia in oncology. - Kiev: Naukova Dumka, 1987.

 9. M. Horsman et al., Int. J. Hyperthermia, 1989, 5, 123-126.

 10. P. Quinn et al., Br. J. Cancer, 1992, 66, 323-330.

 11. J. Miyakoshi et al., Cancer Res., 1986, 46, 1840-1843.

 12. S. Kim et al. Int. J. Radiat. Oncol. Biol. Phys., 1991, 20, 541-549.

 13. E. Jahde et al., Cancer Chemother. Pharmacol., 1991, 27, 440-444.

 14. D. Honess et al., Radiotherapy and Oncology, 1993, 28, 208-218.

 15. S. Kim et al., Int. J. Radiat. Oncol. Biol. Phys., 1993, 25, 61-65.

 16. B. Dezube et al., Cancer Res., 1990, 50, 6806-6810.

 17. M. Horsman, Radiotherapy and Oncology, 1991, 23, 79-80.

 18. S. Masunaga et al., Int. J. Radiat. Oncol. Biol. Phys., 1993, 27, Suppl. 1, 306.

 19. J. Ford et al., Pharmacol. Rev. 1990, 42, 155-199.

 20. T. Herman et al., Cancer Res., 1990, 50, 5055-5059.

 21. S. Holden et al., J. Natl. Cancer Inst., 1992, 84, 187-193.

 22. L. Skarsgard et al., Br. J. Cancer, 1993, 68, 681-683.

 23. J. Overgaard et al., Int. J. Radiat. Oncol. Biol. Phys., 1989, 16, 535-549.

 24. Proc. of the 6th Congress on Hypothermic Oncology. 1992, vol. one; 1993, vol. 2.

 25. Braunwald E. et al. Internal Medicine. - M.: Medicine, 1995, v. 5, p. 403.

 26. I. Ya. Levitin et al., J. Organometal. Chem., 1987, 330,161-178.

 27. I. Ya. Levitin et al., Inorg. Chim. Acta, 1985, 100, 65-77.

 28. RF patent for application N 4939599/04 of 05/29/1991, I.Ya. Levitin and etc.

 29. Levitin I.Ya. and others, Organometallic chemistry, 1990, 3, 865-875.

 30. C. G. Riordan et al., J. Amer. Chem. Soc., 1994, 116, 2189-2190 and cit. there work.

Claims (1)

The use of organocobalt (III) complexes with Schiff's tridentate bases of the general formulas I - VIII

where R, R ² is alkyl, including functionally substituted;
R ¹ is H or alkyl, including functionally substituted;
R ³ is H or alkyl or aryl, including functionally substituted;
R ⁴ is alkyl or aryl, including functionally substituted;
X are substituents, including functional groups;
Z is a two or three link aliphatic chain, including with alkyl or aryl side groups, including functionally substituted ones;
L, L ¹ , L ² - neutral monodentate ligand, for example, a nitrogenous base;
A is a singly charged anionic monodentate ligand, for example hydroxyl, halide or rhodanide ion;
L - L '- neutral bidentate chelating ligand, for example diamine;
L - A is a singly charged anionic bidentate chelating ligand, for example, an anion from an amino acid, peptide or β aldehyde or ketoenol;
Y is a counterion (singly charged anion), for example a halide or acetate ion,
as modifiers for antitumor therapy.

Images