| Abstract
| - A new route to N-1-substituted pyrazolo- and pyrroloquinazolineshas been developed fromthe known quinazolones 19 and 23, via conversionto the corresponding thiones, S-methylationto the thioethers, N-1-alkylation, and coupling with 3-bromoaniline.C-3-Substituted pyrroloquinazolines were prepared by Mannich base chemistry. A series ofcompounds bearingsolubilizing side chains at these positions has been prepared andevaluated for inhibition ofthe tyrosine kinase activity of the isolated epidermal growth factorreceptor (EGFR) and of itsautophosphorylation in EGF-stimulated A431 cells. Severalanalogues, particularly C-3-substituted pyrroloquinazolines, retained high potency in both assays.A model for the bindingof the general class of 4-anilinoquinazolines to the EGFR wasconstructed from structuralinformation (particularly for the catalytic subunit of thecAMP-dependent protein kinase) andstructure−activity relationships (SAR) in the series. In thismodel, the pyrrole ring inpyrroloquinazolines (and the 6- and 7-positions of quinazoline andrelated pyridopyrimidineinhibitors) occupies the entrance of the ATP binding pocket of theenzyme, with the pyrrolenitrogen located at the bottom of the cleft and the pyrrole C-3position pointing toward a pocketcorresponding to the ribose binding site of ATP. This allowsconsiderable bulk tolerance forC-3 substituents and lesser but still significant bulk tolerance forN-1 substituents. Theobserved high selectivity of these compounds for binding to EGFR overother similar tyrosinekinases is attributed to the 4-anilino ring binding in an adjacenthydrophobic pocket whichhas an amino acid composition unique to the EGFR. The SAR seen forinhibition of the isolatedenzyme by the pyrazolo- and pyrroloquinazolines discussed here is fullyconsistent with thisbinding model. For the N-1-substituted compounds, inhibition ofautophosphorylation in A431cells correlates well with inhibition of the isolated enzyme, as seenpreviously for relatedpyridopyrimidines. However, the C-3-substitutedpyrroloquinazolines show unexpectedly highpotencies in the autophosphorylation assay, making them of particularinterest.
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