Reduction of cisplatin-induced nephrotoxicity by pyrazolone compounds, derivatives of tetrahydroindazolonedicarboxylic acid (HIDA)

Filipović Marijić, Vlatka; Makarević, Janja; Stojković, Ranko; Kalinić, Lidija; Katalenić, Darinka; Radačić, Marko (2008) Reduction of cisplatin-induced nephrotoxicity by pyrazolone compounds, derivatives of tetrahydroindazolonedicarboxylic acid (HIDA). Methods and findings in experimental and clinical pharmacology, 30 (9). pp. 675-680. ISSN 0379-0355

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Abstract

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.

Item Type:	Article
Uncontrolled Keywords:	cisplatin; nephrotoxicity; pyrazolone derivatives of tetrahydroindazolonedicarboxylic acid (HIDA); blood urea nitrogen
Subjects:	NATURAL SCIENCES > Mathematics
Divisions:	Division for Marine and Enviromental Research
Projects:	Project title Project leader Project code Project type Novi terapijski modaliteti u liječenju malignih bolesti- Ranko Stojković 098-0982464-2390 MZOS Stanične promjene u vodnih organizama pobuđene metalima- Marijana Erk 098-0982934-2721 MZOS Samo-udruživanje u gelovima i sinteza funkcionalnih hibridnih materijala- Leo Frkanec 098-0982904-2912 MZOS
Depositing User:	Vlatka Filipović Marijić
Date Deposited:	03 Sep 2020 10:45
URI:	http://fulir.irb.hr/id/eprint/3287
DOI:	10.1358/mf.2008.30.9.1306328

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