title: Dinuclear Cyclam Complex as a Non-Cytotoxic, Anti-Hyperurecemic Lead: In vitro to In vivo Studies.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
authors.forename: Humaira
authors.initials: H
authors.lastname: Zafar
authors.affiliation: Engineering Laboratory of Organometallic and Molecular Materials "LIMOM", (CNRST - URAC 19), Faculty of Sciences Dhar El Mahraz, University Sidi Mohamed Ben Abdellah, Po. Box 1796 (Atlas), 30000 Fez, Morocco.
authors.forename: Najlae
authors.initials: N
authors.lastname: Hamdi
authors.affiliation: Engineering Laboratory of Organometallic and Molecular Materials "LIMOM", (CNRST - URAC 19), Faculty of Sciences Dhar El Mahraz, University Sidi Mohamed Ben Abdellah, Po. Box 1796 (Atlas), 30000 Fez, Morocco.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Lachkar
authors.affiliation: Engineering Laboratory of Organometallic and Molecular Materials "LIMOM", (CNRST - URAC 19), Faculty of Sciences Dhar El Mahraz, University Sidi Mohamed Ben Abdellah, Po. Box 1796 (Atlas), 30000 Fez, Morocco.
authors.forename: Brahim
authors.initials: B
authors.lastname: El Bali
authors.affiliation: Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad, Pakistan.
authors.forename: Ajmal
authors.initials: A
authors.lastname: Khan
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
authors.forename: Muhammad I
authors.initials: MI
authors.lastname: Choudhary
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002417:Cattle; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D033461:Hyperuricemia / Q000188:drug therapy* / Q000201:enzymology; D007700:Kinetics; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
chemical_list: D006571:Heterocyclic Compounds; C024560:cyclam; D014969:Xanthine Oxidase
keywords: Dinuclear cyclam complex; gout; hyperuricemia; purine metabolism; uric acid; xanthine oxidase inhibition