Design, synthesis and pharmacological evaluation of novel vanadium-containing complexes as antidiabetic agents

PLoS One. 2014 Jul 24;9(7):e100386. doi: 10.1371/journal.pone.0100386. eCollection 2014.

Abstract

Based on the data about structure and antidiabetic activity of twenty seven vanadium and zinc coordination complexes collected from literature we developed QSAR models using the GUSAR program. These QSAR models were applied to 10 novel vanadium coordination complexes designed in silico in order to predict their hypoglycemic action. The five most promising substances with predicted potent hypoglycemic action were selected for chemical synthesis and pharmacological evaluation. The selected coordination vanadium complexes were synthesized and tested in vitro and in vivo for their hypoglycemic activities and acute rat toxicity. Estimation of acute rat toxicity of these five vanadium complexes was performed using a freely available web-resource (http://way2drug.com/GUSAR/acutoxpredict.html). It has shown that the selected compounds belong to the class of moderate toxic pharmaceutical agents, according to the scale of Hodge and Sterner. Comparison with the predicted data has demonstrated a reasonable correspondence between the experimental and predicted values of hypoglycemic activity and toxicity. Bis{tert-butyl[amino(imino)methyl]carbamato}oxovanadium (IV) and sodium(2,2'-Bipyridyl)oxo-diperoxovanadate(V) octahydrate were identified as the most potent hypoglycemic agents among the synthesized compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Animals
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacology*
  • Drug Design
  • Epinephrine
  • Hyperglycemia / chemically induced
  • Hyperglycemia / drug therapy*
  • Hyperglycemia / metabolism
  • Hyperglycemia / pathology
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Inhibitory Concentration 50
  • Male
  • Mice
  • Molecular Structure
  • Primary Cell Culture
  • Quantitative Structure-Activity Relationship
  • Rats
  • Rats, Wistar
  • Vanadium / chemistry*

Substances

  • (2,2'-bipyridyl)oxodiperoxovanadate(V)
  • Coordination Complexes
  • Hypoglycemic Agents
  • bis(tert-butyl(amino(imino)methyl)carbamato)oxovanadium(IV)
  • Vanadium
  • Epinephrine

Grant support

This work was supported by Ministry of Education and Science of the Russian Federation on the main academic programs of higher professional education, program 1.2.1. (fcpk.ru). We also acknowledge the support of the Russian Foundation for Basic Research (http://www.rfbr.ru/rffi/ru/)in the payment of the license for using the Cambridge Structural Database, project no. 02-07-90322. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.