Synthesis and Antitumor and Antimetastatic Activity of 5-hydroxypyrimidine Derivatives

Abstract

2-Isobutyl-4,6-dimethyl-5-hydroxypyrimidine (SNK-411) and its salt (SNK-578) were synthesized. Antitumor and antimetastatic activity of the new derivative 5-hydroxypyrimidine SNK-578 were studied in tests on male C57BL/6 mice using the B16 melanoma model. The standard grafted dose was 5 × 10⁶ tumor cells mouse. SNK-578 was injected i.p. at doses of 10 and 25 mg/kg for two weeks from day 2 to day 15 of B16 melanoma development. Doxorubicin was injected to mice at a dose of 4 mg/kg on day 2 of tumor development to act as a positive control and to reveal an additive effect from combined single use of doxorubicin and injection of a course of SNK-578. The combination of i.p. injection of a course of SNK-578 at a dose of 10 mg/kg and a single i.p. injection of doxorubicin at a dose of 4 mg/kg revealed statistically significant tumor growth inhibition that was expressed as a decrease of tumor volume by 2.4, 1.9, and 1.5 times on day 11, 15, and 21 of the test as compared with the active control group that did not receive SNK-578. SNK-578 possessed pronounced antimetastatic activity at doses of 10 and 25 mg/kg for monotherapy and coadministration with doxorubicin at a dose of 4 mg/kg. The metastasis inhibition index (MII) after SNK-578 injection at a dose of 10 mg/kg was 75.8%; at 25 mg/kg, 92.3%. The most pronounced antimetastatic effect was observed after combined i.p. injection of SNK-578 at a dose of 10 mg/kg for 14 d and a single injection of doxorubicin at a dose of 4 mg/kg. Metastases were not observed in six of nine mice on day 21 of B16 melanoma development; the other three had 1, 2, and 3 very small metastases so that the MII was 98.9%.