Polyhydroxylated 3-(N-Phenyl) Carbamoyl-2-iminochromene Derivatives as Potent Inhibitors of Tyrosine Kinase p60c-src.

Abstract Several polyhydroxylated 3-(N-phenyl) carbamoly-2-iminochromene derivatives were synthesized and their inhibitory effects on tyrosine kinase p60 c-src were evaluated. The structure-activity relationship reveals that the positions of the hydroxylation on both the iminochromene ring and the N-phenyl-ring of the carbamoyl group strongly affect the potency of the compounds. Protein tyrosine kinases (PTK) play an important role in the signal transduction of normal and abnormal cells. 1–3 . They include transmembrane receptors for growth factors and intracellular mediators between receptors and target proteins. They mediate cell growth, mitogenic activities and cellular differentiation. Oncogenic kinases contain point mutations, deletions or fusion with other genes. Abnormal expression results in cellular transformation and carcinogenesis. 1–3 Increasing numbers of PTK inhibitors have recently been introduced as potential anticancer reagents. 4–7 They include isoflavones (genistein), 8 tyrphostins (erbstatin), 9 lavendustin analogues, 10 staurosporine analogues (dianilinophthalmides), 11 dithiobis (indole-alkanoic acid), 12 dihydroxyisoquinolines 13 and others. 4–7 For the purpose of obtaining highly specific inhibitors, bicyclic compounds as ring-constrained inhibitors of PTK have recently been introduced. 13 They are expected to interact with the flat, cleft-like catalytic cavity of the kinase domain with high specificity. Iminochromenes belong to this type of compound. 13 Several 3-carbamoyl-2-iminochromenes with weak PTK inhibitory activity toward p56 lck have been reported. 13 We have synthesized several novel polyhydroxylated 3-(N-phenyl) carbamoyl-2-iminochromenes. We found that several of them are strongly affect the potency of the compounds. The results presented here and other recent studies 21–23 support the hypothesis of Gazit 9 that it may be possible to prepare potent, specific inhibitors for various tyrosine kinases.