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.
Marijic
Vlatka Filipovic
VF
Division of Marine and Environmental Research, Ruder Boskovic Institute, Zagreb, Croatia. vfilip@irb.hr
Makarevic
Janja
J
Stojkovic
Ranko
R
Kalinic
Lidija
L
Katalenic
Darinka
D
Radacic
Marko
M
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects*; D007191:Indazoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D047069:Pyrazolones / Q000494:pharmacology*
D000970:Antineoplastic Agents; D007191:Indazoles; D047069:Pyrazolones; C051797:4,5,6,7-tetrahydro-3-oxo-2H-indazole-5,5-dicarboxylic acid; D002945:Cisplatin