title: Synthesis, characterization and anti-diabetic therapeutic potential of novel aminophenol-derivatized nitrilotriacetic acid vanadyl complexes.
abstract: In the present work, we synthesized three novel aminophenol-derivatized nitrilotriacetic acid vanadyl complexes (VOohpada, VOmhpada, VOphpada) using the strategy of rational incorporation of antioxidant groups in ligand in order to balance the side effects with the therapeutic properties. The complexes were characterized by IR, UV-VIS, ESI-MS and elemental analysis. The biological evaluations in vitro revealed that the position of the hydroxyl group of aminophenol moiety regulated the antioxidant activity of the complexes as well as the cytotoxicity on HK-2 cells. The vanadyl complex of p-hydroxyl aminophenol derivative (VOphpada) exhibited better antioxidant activity and lower cytotoxicity than other analogs. In type II diabetic db/db mice, VOphpada (0.1 mmol/kg/day) effectively reduced blood glucose level, improved glucose tolerance, and alleviated stresses induced by hyperglycemia and hyperlipidemia. VOphpada treatment significantly increased expression of PPARα and γ, activated Akt, and inactivated JNK in muscle and adipose tissues. The insulin enhancement effects of VOphpada were observed more potent than BMOV. Moreover, VOphpada decreased the level of kidney injury molecule-1 marker (KIM-1), suggesting a potentially lower renal toxicity. In overall, the present results suggest VOphpada as a novel hypoglycemic agent with improved efficacy-over-toxicity index.
authors.affiliation: State Key Laboratories of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.affiliation: State Key Laboratories of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, PR China.
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratories of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, PR China.
authors.forename: Xia
authors.initials: X
authors.lastname: Niu
authors.affiliation: State Key Laboratories of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, PR China. Electronic address: xyang@bjmu.edu.cn.
authors.forename: Xiaoda
authors.initials: X
authors.lastname: Yang
mesh_terms: D000627:Aminophenols / Q000737:chemistry*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009571:Nitrilotriacetic Acid / Q000737:chemistry*; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D014639:Vanadium / Q000737:chemistry*
chemical_list: D000627:Aminophenols; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D009942:Organometallic Compounds; D014639:Vanadium; D009571:Nitrilotriacetic Acid
keywords: Aminophenol; Diabetes; PPARα; PPARγ; Vanadium