ABSTRACT
Dual inhibitors of protein phosphotyrosine phosphatase 1B (PTP1B)/T-cell protein phosphotyrosine phosphatase (TC-PTP) based on the 3-(hydroxymethyl)-4-oxo-1,4-dihydrocinnoline scaffold have been identified. Their dual affinity to both enzymes has been thoroughly corroborated by in silico modeling experiments. The compounds have been profiled in vivo for their effects on body weight and food intake in obese rats. Likewise, the effects of the compounds on glucose tolerance, insulin resistance, as well as insulin and leptin levels, have been evaluated. In addition, the effects on PTP1B, TC-PTP, and Src homology region 2 domain-containing phosphatase-1 (SHP1), as well as the insulin and leptin receptors gene expressions, have been assessed. In obese male Wistar rats, a five-day administration of all studied compounds led to a decrease in body weight and food intake, improved glucose tolerance, attenuated hyperinsulinemia, hyperleptinemia and insulin resistance, and also compensatory increased expression of the PTP1B and TC-PTP genes in the liver. The highest activity was demonstrated by 6-Chloro-3-(hydroxymethyl)cinnolin-4(1H)-one (compound 3) and 6-Bromo-3-(hydroxymethyl)cinnolin-4(1H)-one (compound 4) with mixed PTP1B/TC-PTP inhibitory activity. Taken together, these data shed light on the pharmacological implications of PTP1B/TC-PTP dual inhibition, and on the promise of using mixed PTP1B/TC-PTP inhibitors to correct metabolic disorders.
Subject(s)
Insulin Resistance , Rats , Male , Animals , Protein Tyrosine Phosphatase, Non-Receptor Type 2/metabolism , Rats, Wistar , T-Lymphocytes/metabolism , Insulin/metabolism , Obesity/metabolism , Glucose , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Enzyme Inhibitors/pharmacologyABSTRACT
A new convenient approach to the synthesis of useful N-heterocyclic carbene complexes of group 13 metals was successfully developed. We demonstrate that air-stable copper(i) diaminocarbene complexes are excellent carbene transfer reagents for the synthesis of (IMes or IPr)MCl3 with high yields (M = Al, Ga). Use of this simple method allowed for the first time to obtain (IPr)AlCl3, inaccessible via a free carbene route. In contrast to copper complexes, under the same conditions the more commonly used silver analog (IPr)AgCl reacts with MCl3 (M = Al, Ga, In) yielding only the homoleptic cationic complexes [(IPr)2Ag]+MCl4-.
ABSTRACT
Well-defined diazotates are scarce. Here we report the synthesis of unprecedented homoleptic palladium(II) diazotate complexes. The palladium(II)-mediated nitrosylation of 2-aminopyridines with NaNO2 results in the formation of metal-stabilized diazotates, which were found to be cytotoxic to human ovarian cancer cells.
