Dinuclear Cyclam Complex as a Non-Cytotoxic, Anti-Hyperurecemic Lead: In vitro to In vivo Studies.

Abstract

Uric acid is the end product of purine metabolism in humans and its increased level in serum leads to hyperuricemia. Among the different regulatory factors to control the level of uric acid in humans, xanthine oxidase (XO) is a well-established pharmacological target, as it is directly involved in uric acid production. The aim of the study was to present a systematic approach to analyze the xanthine oxidase inhibition studies from in vitro leading to in vivo. Initially, dinuclear cyclam complex 1 was evaluated for in-vitro XO inhibitory activity using a spectrophotometric assay. Significant results were obtained in XO inhibition assay (IC50 = 3.70 ± 0.07 μM), in comparison to the standard drug, allopurinol (IC50 = 2.00 ± 0.01 μM). Complex 1 showed a non-competitive type of inhibition in kinetic studies. Complex 1 was also found to be non-cytotoxic in MTT assay, as it did not affect the viability of 3T3-cell line. Based on these results, compound 1 was further evaluated for the in-vivo xanthine oxidase inhibitory activity. An in-vivo model was used to evaluate the XO inhibitory activity in plasma samples of male Wistar rats. Complex 1 showed a significant inhibition of xanthine oxidase activity (50%), in comparison to the standard inhibitor allopurinol (100%). Therefore, non-cytotoxic compound 1 could be considered as an anti-hyperurecemic lead for further studies. Our studies concluded that complex 1 is a non-cytotoxic inhibitor that decreases the activity of XO in a non-competitive manner. It can serve as a potential anti-hyperurecemic lead after further pre-clinical and clinical studies.