title: Benzamides and benzamidines as specific inhibitors of epidermal growth factor receptor and v-Src protein tyrosine kinases.
abstract: The benzamides 1 and the benzamidines 2 as well as the cyclic benzamidines 3 were designed and synthesized as the mimics of 4-anilinoquinazolines for an inhibitor of EGFR tyrosine kinase. The specific inhibitions of EGFR tyrosine kinase were observed in the benzamides 1c and 1d, and the benzamidine 2a, whereas the specific inhibitions of v-Src kinase were observed in the benzamide 1j and the benzamidine 2d at a 10microg/mL concentration of compounds. The cyclic benzamidines 3a and 3b showed potent kinase inhibition of EGFR at a 1.0microg/mL concentration. According to the docking simulation using the X-ray structure of EGFR kinase domain in complex with erlotinib, the LigScore2 scoring function value of erlotinib was calculated as 5.61, whereas that of the benzamide 1c was 5.05. In a similar manner, the LigScore2 value of the cyclic benzamidine 3a was calculated as 5.10.
authors.affiliation: Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8588, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Asano
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Taikou
authors.initials: T
authors.lastname: Usui
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Uehara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakamura
mesh_terms: D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001550:Benzamidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010766:Phosphorylation; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001549:Benzamides; D001550:Benzamidines; D004791:Enzyme Inhibitors; D008024:Ligands; D004815:Epidermal Growth Factor; C037689:benzamide; D066246:ErbB Receptors; D019061:src-Family Kinases; C032157:benzamidine