TYROSINE KINASE INHIBITORS .11. SOLUBLE ANALOGS OF PYRROLOQUINAZOLINES AND PYRAZOLOQUINAZOLINES AS EPIDERMAL GROWTH-FACTOR RECEPTOR INHIBITORS - SYNTHESIS, BIOLOGICAL EVALUATION, AND MODELING OF THE MODE OF BINDING

Citation
Bd. Palmer et al., TYROSINE KINASE INHIBITORS .11. SOLUBLE ANALOGS OF PYRROLOQUINAZOLINES AND PYRAZOLOQUINAZOLINES AS EPIDERMAL GROWTH-FACTOR RECEPTOR INHIBITORS - SYNTHESIS, BIOLOGICAL EVALUATION, AND MODELING OF THE MODE OF BINDING, Journal of medicinal chemistry, 40(10), 1997, pp. 1519-1529
Citations number
27
Categorie Soggetti
Chemistry Medicinal
ISSN journal
00222623
Volume
40
Issue
10
Year of publication
1997
Pages
1519 - 1529
Database
ISI
SICI code
0022-2623(1997)40:10<1519:TKI.SA>2.0.ZU;2-3
Abstract
A new route to N-1-substituted pyrazolo- and pyrroloquinazolines has b een developed from the known quinazolones 19 and 23, via conversion to the corresponding thiones, S-methylation to the thioethers, N-1-alkyl ation, and coupling with 3-bromoaniline. C-S-Substituted pyrroloquinaz olines were prepared by Mannich base chemistry. A series of compounds bearing solubilizing side chains at these positions has been prepared and evaluated for inhibition of the tyrosine kinase activity of the is olated epidermal growth factor receptor (EGFR) and of its autophosphor ylation in EGF-stimulated A431 cells. Several analogues, particularly C-3-substituted pyrroloquinazolines, retained high potency in both ass ays. A model for the binding of the general class of 4-anilinoquinazol ines to the EGFR was constructed from structural information (particul arly for the catalytic subunit of the cAMP-dependent protein kinase) a nd structure-activity relationships (SAR) in the series. In this model , the pyrrole ring in pyrroloquinazolines (and the 6- and 7-positions of quinazoline and related pyridopyrimidine inhibitors) occupies the e ntrance of the ATP binding pocket of the enzyme, with the pyrrole nitr ogen located at the bottom of the cleft and the pyrrole C-3 position p ointing toward a pocket corresponding to the ribose binding site of AT P. This allows considerable bulk tolerance for C-3 substituents and le sser but still significant bulk tolerance for N-1 substituents. The ob served high selectivity of these compounds for binding to EGFR over ot her similar tyrosine kinases is attributed to the 4-anilino ring bindi ng in an adjacent hydrophobic pocket which has an amino acid compositi on unique to the EGFR. The SAR seen for inhibition of the isolated enz yme by the pyrazolo- and pyrroloquinazolines discussed here is fully c onsistent with this binding model. For the N-1-substituted compounds, inhibition of autophosphorylation in A431 cells correlates well with i nhibition of the isolated enzyme, as seen previously for related pyrid opyrimidines. However, the C-S-substituted pyrroloquinazolines show un expectedly high potencies in the autophosphorylation assay, making the m of particular interest.