title: Molecular design and biological activities of protein-tyrosine phosphatase inhibitors.
abstract: Protein-tyrosine kinase (PTKase) and protein-tyrosine phosphatase (PTPase) regulate the intracellular signal transduction in various biological processes. PTPase often negatively regulates the intracellular protein-tyrosine phosphorylation. PTPases are considered to be involved in the etiology of diabetes mellitus and neural diseases, such as Alzheimer's disease and Parkinson's disease. Therefore, PTPase inhibitors should be useful tools to study the role of PTPases in these diseases and other biological phenomena, and they hopefully may be developed into chemotherapeutic agents. We first discovered a naturally occurring PTPase inhibitor, dephostatin, in 1993. Later, we developed stable and safe dephostatin analogues by a molecular design approach employing the concept of CH/pi interaction. We prepared Et-3,4-dephostatin as a stable analogue and found it to inhibit PTP-1B and SHPTP-1 PTPases selectively. Et-3,4-dephostatin increased the tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), with or without insulin, in differentiated 3T3-L1 mouse adipocytes. It also increased the phosphorylation and activation of Akt. The analogue also enhanced translocation of glucose transporter 4 (GLUT4) from the cytoplasm to the membrane and 2-deoxyglucose transport. It also showed an in vivo antidiabetic effect in terms of reducing the high blood glucose level in KK-Ay mice after oral administration. Since Et-3,4-dephostatin contains a nitrosamine moiety, we designed nitrosamine-free dephostatin analogues employing the concept of CH/pi interaction. Then, we synthesized methoxime- and hexyl-methoxime-3,4-dephostatin as nitrosamine-free analogues. These analogues also showed antidiabetic activity in vivo and illustrate the utility of the CH/pi interaction molecular design approach.
authors.affiliation: Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-0061, Japan. umezawa@applc.keio.ac.jp
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Mariko
authors.initials: M
authors.lastname: Kawakami
authors.forename: Takumi
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D002395:Catecholamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000188:drug therapy; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009603:Nitroso Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*
chemical_list: C432919:4-(ethyl)(nitroso)amino-3,4-benzenediol; D002395:Catecholamines; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D009603:Nitroso Compounds; D017027:Protein Tyrosine Phosphatases