Reduction of cisplatin-induced nephrotoxicity by pyrazolone compounds, derivatives of tetrahydroindazolonedicarboxylic acid.

The structural requirements relevant for protective efficacy against cisplatin-induced renal toxicity was studied for seven newly synthesized pyrazolone compounds. Since tetrahydroindazolonedicarboxylic acid (HIDA) has shown potential nephroprotective efficacy, our study involved HIDA derivatives with specific modifications of functional groups. Pyrazolone compounds comprised four types of structural modifications: an HIDA regioisomer derivative (compound 1), compounds with modifications at the pyrazolone ring (compounds 2, 3 and 4) or the dicarboxylic moiety (compounds 5 and 6), and a compound without a cyclohexane moiety (compound 7). The best nephroprotective efficacy was found for compound 1, as reflected in the lowering of cisplatin-induced levels of blood urea nitrogen (BUN) by 86.3-89.3%, depending on cisplatin administration time. The alicyclic pyrazolonedicarboxylic acid (compound 7), characterized by free rotation of attached moieties due to the lack of a cyclohexane moiety, also showed good protection (lowering of cisplatin-induced BUN levels by 29.5-81.7%, depending on cisplatin administration time). Lower nephroprotective activity was found for compounds 2 and 3, with N- and O-substituted pyrazolone rings, and for the cyano derivative 5, while compounds without a carboxylic and pyrazolone moiety (compounds 6 and 4, respectively) did not show a nephroprotective effect. Therefore, carboxylic and pyrazolone moieties play an important role in the interaction with cisplatin and represent relevant functional groups required for nephroprotective efficacy in pyrazolone compounds.

Synthesis and antitumor activity of 5-bromo-1-mesyluracil.

Large-scale preparation of 5-bromo-1-mesyluracil (BMsU) 4 has been optimized. BMsU was synthesized by condensation of silylated 5-bromouracil and MsCl in acetonitrile or by the reaction of 5-bromouracil with MsCl in pyridine. The same product was obtained by bromination of 1-mesyluracil. The purpose of this study was to elucidate the effects of BMsU on the biosynthetic activity of tumor cell enzymes involved in DNA, RNA and protein syntheses, and in de novo and salvage pyrimidine and purine syntheses. Investigations were performed in vitro on human cervix carcinoma cells (HeLa). BMsU displayed inhibitory effects on DNA and RNA syntheses in HeLa cells after 24 h of treatment. De nova biosynthesis of pyrimidine and purine was also affected. Antitumor activity of BMsU is closely associated with its inhibitory activity on the enzymes that play an important role in the metabolism of tumor cells. In vivo antitumor activity of BMsU was also investigated. The model used in investigations was a mouse anaplastic mammary carcinoma transplanted into the thigh of the right leg of CBA mice. Significant reduction in tumor growth time was achieved with BmsU administered at a dose of 50 mg/kg.

Antitumor activity of novel N-sulfonylpyrimidine derivatives on the growth of anaplastic mammary carcinoma in vivo.

PURPOSE: The purpose of this study was to investigate in vivo antitumor activity of newly synthesized N-sulfonylpyrimidine derivatives 1-(p-toluenesulfonyl)cytosine (4H), 1-(p-toluenesulfonyl)cytosine hydrochloride (4HxHCl) and zinc(II) complex of 1-(p-toluenesulfonyl)cytosine (4K). MATERIALS AND METHODS: In order to do that we have used mouse anaplastic mammary carcinoma (AMCa). Tumor cells (10(6)) in a volume of 0.02 ml were transplanted into the thigh of the right hind leg of CBA mice. All compounds were dissolved in distilled water immediately before injecting to animals. RESULTS: Antitumor effect of these compounds depends on drug doses and time interval between tumor transplantation and drug application. Further the efficacy of these compounds depends on number of drug injections, i. e. whether drug was given in single or in multiple doses. Multiple doses of 400 mg/kg of 1-(p-toluenesulfonyl)cytosine (4H) showed good antitumor effect when applied on day 1, 3, 5, 7 and 9 after tumor transplantation. Still good but slightly lower antitumor effect was also achieved when that compound was given in a single dose (1,200 mg/kg) on day 1 after tumor transplantation. The longest period of tumor growth time was obtained after application of 1-(p-toluenesulfonyl)cytosine hydrochloride (4HxHCl) given as a single dose (300 mg/kg) on day 1 or on day 6 after tumor implantation. However, antitumor effect of zinc(II) complex of 1-(p-toluenesulfonyl)cytosine (4K) was very strong when 300 mg/kg was given on day 1 or day 6, while this effect was slightly lower when drug (200 mg/kg/inj) was given on day 1, 3, 5, 7 and 9 or on day 6, 8, 10, 12 and 14. CONCLUSION: In this work it has been found that N-1-sulfonylcytosine derivatives have strong antitumor activity against mouse mammary carcinoma which is a good reason for further research of these compounds both in experimental and preclinical studies.