Design, synthesis and evaluation of PD176252 analogues for ameliorating cisplatin-induced nephrotoxicity

Abstract

Cisplatin is a clinical chemotherapy drug for cancers; however, its remarkably high kidney toxicity and other toxicities pose a danger to patients. As the small molecule inhibitor of GRPR, PD176252 can inhibit the growth and proliferation of various cancer cells, but the characteristics of high toxicity and poor water solubility has limited its use as a drug. When we studied PD176252 for the reduction of toxicity of cisplatin, we modified its structure to synthesize 16 analogues. Surprisingly, the analogues showed reduced cisplatin-induced renal toxicity, and unlike PD176252, the analogues 5d and 5m were almost non-toxic to the normal HK2 cells. Furthermore, the analogue 5d and PD176252 were subjected to cisplatin-induced inflammatory response in vitro. The results showed that 5d was able to better prevent this condition by effectively inhibiting its inflammatory response. Thus, this study will help in clinically reducing the side effects of cisplatin.