| 摘要 |
A process for the synthesis of high affinity irreversible inhibitors of epidermal growth factor receptor (EGFR) having fluorescent properties and significant anti- proliferative activity is described. More specifically, the mechanism of action of ZR2002, a chimeric aminoquinazoline designed to possess mixed EGFR tyrosi ne kinase (TK) inhibitory and DNA targeting properties, was compared with those of ZR01, a reversible inhibitor of the same class and PD168393, a known irreversible inhibitor of EGFR. ZR2002 was shown to exhibit 4-fold stronger EGFR TK inhibitory activity than its structural homologue ZR01 but was approximately 3-fold less active than the 6-acrylamidoquinazoline PD168393. It preferentially blocked EGF and TGF.alpha.-induced cell growth over PDGF and serum. It also inhibited signal transduction in heregulin-stimulated breast tumour cells, indicating that it does not only block EGFR but also its closely related erb B2 gene product. In contrast to its structural homologues, ,ZR2002 was capable of inducing significant levels of DNA strand breaks in MDA-MB-468 cells after a short 2 h drug exposure and at a concentration as low as 10 mM.
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