title: Synthesis, activity and molecular modeling of a new series of chromones as low molecular weight protein tyrosine phosphatase inhibitors.
abstract: Protein tyrosine phosphatases (PTP) are crucial elements in eukaryotic signal transduction. Several reports suggested that the LMW-PTP family has oncogenic relevance. Moreover, LMW-PTP has been recognized as a negative regulator of insulin-mediated mitotic and metabolic signaling. Thus, inhibition of the LMW-PTP can be considered an attractive approach for the design of new therapeutic agents for the treatment of type II diabetes and for new antitumoral drugs. To date very few (and weak) inhibitors of LMW-PTP have been identified. On the basis of the reported weak activity of some flavonoids on phosphatases, we discovered a lead that originated a new class of highly active LMW-PTP inhibitors; these compounds inhibit also PTP-1B and are active in cellular assays. Docking experiments and SAR highlighted the possible binding mode of these compounds to the enzyme, putting the background for the future optimization of their inhibitory activity and selectivity towards the closely related enzyme PTP-1B.
authors.affiliation: Department of Chemistry, University of Modena and R.E., Via G. Campi 183, 41100 Modena, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Forghieri
authors.forename: Christian
authors.initials: C
authors.lastname: Laggner
authors.forename: Paolo
authors.initials: P
authors.lastname: Paoli
authors.forename: Thierry
authors.initials: T
authors.lastname: Langer
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Manao
authors.forename: Guido
authors.initials: G
authors.lastname: Camici
authors.forename: Lucia
authors.initials: L
authors.lastname: Bondioli
authors.forename: Fabio
authors.initials: F
authors.lastname: Prati
authors.forename: Luca
authors.initials: L
authors.lastname: Costantino
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003198:Computer Simulation; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases