Design, synthesis, and biological evaluation of aminoboronic acids as growth-factor receptor inhibitors of EGFR and VEGFR-1 tyrosine kinases.
A series of aminoboronic acids was synthesized based on the structure of lavendustin pharmacophore 1. Their inhibitory activities against the epidermal growth-factor receptor (EGFR) and vascular endothelial growth-factor receptor-1 (VEGFR-1, Flt-1) protein tyrosine kinases, and various protein kinases, PKA, PKC, PTK, and eEF2K were evaluated. Selective inhibition activities were observed in a series of aminoboronic acids. 4-Methoxy-3-((2- methoxyphenylamino)methyl)phenylboronic acid 10 inhibited EGFR tyrosine kinase, whereas 4-(2,5-dihydroxybenzylamino)phenylboronic acid 12 inhibited Flt-1 protein kinase, although lavendustin pharmacophore 1 inhibited both EGFR and Flt-1 kinases at a compound concentration of 1.0 microg mL(-1). The selective inhibition of EGFR by 10 is considered to be due to the substitution of the dihydroxy groups on the benzyl moiety for a boronic acid group at the para position, whereas the selective inhibition of Flt-1 by 12 is due to the substitution of the carboxyl group on the aniline moiety in the lavendustin pharmacophore 1 for a boronic acid group.
Asano
Toru
T
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan.
Nakamura
Hiroyuki
H
Uehara
Yoshimasa
Y
Yamamoto
Yoshinori
Y
D000586:Amination; D000818:Animals; D001897:Boronic Acids / Q000737:chemistry* / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry; D002460:Cell Line; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D001897:Boronic Acids; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D040281:Vascular Endothelial Growth Factor Receptor-1