Pharmaceutical Chemistry

Biography

Biography: Geronikaki Athina

Abstract

Phosphorylation-dephosphorylation is a predominant mechanism involved in the regulation of eukaryotic cell function. During the last decade, protein kinases and phosphatases have been extensively studied and members of both enzyme families have been proved to be related with various diseases. As a result drug research has been focused in specific kinase or phosphatase regulation. PTP1B is a protein tyrosine phosphatase, acting on insulin receptor. Interaction of insulin with its receptor results in changes in the intracellular structure of the receptor followed by the phosphorylation of three tyrosine residues. This is the first step of a cascade of intracellular events leading to glucose uptake. The cascade is terminated by the dephosphorylation of insulin receptor by PTP1B. Thus, PTP1B inhibition, resulting in prolonged maintenance of the phosphorylated state, practically enhances insulin effect. Consequently, effective and selective PTP1B inhibitors can be potent drugs for the treatment of type 2 diabetes and obesity. LAR, a receptor-like transmembrane PTP is also believed to be a target for insulin receptor signalling, as LAR inhibitors were found to dramatically potentiate insulin's effects. Moreover, it was found that it is concentrated in mature synapses in hippocampal neurons, and is believed to play a role in the development and maintenance of excitatory synapses. HSP-2 is one of the classical non-transmembrane PTPs. A mutation in the gene, making HSP-2 continuously active results in Noonan syndrome, a developmental disorder affecting 1 in 2500 newborns that may lead to a higher risk for certain cancers, including juvenile myelomonocytic leukaemia. Treatment with HSP-2 selective inhibitors could bring hope to Noonan Syndrom patients. Although, many compounds have been tested as PTP1B inhibitors, the race for finding a highly effective and absolutely selective inhibitor continues. Most inhibitors act on more than one protein phosphatases. In the present study, we synthesised a number of 3-((furan-2-yl)methyl)-2-phenyl thiazolidin-4-one derivatives and tested their PTP1B inhibitory activity as well as the structure – activity relationship. Many of the derivatives showed good inhibitory action. Moreover, we evaluated the specificity of the compounds by testing the inhibition of protein phosphatases LAR and SHP-2. All inhibitory actions were tested using human recombinant phosphatases. In all cases p-nitro-phenyl-phosphate was used as substrate.