| ABSTRACT: |
|
The plant-derived natural product ellagic acid (1) has recently been
identified as a potent, though nonselective, inhibitor of the
tyrosine-specific protein kinase pp60src. This report details efforts
directed toward the identification of tricyclic structures related to
ellagic acid, with enhanced specificity for inhibition of pp60src over
other protein kinases. Phenanthridinone and carbazole core structures were
selected for investigation, since N-functionalization allows for the
synthesis of numerous analogs which can be utilized to probe
enzyme-inhibitor interactions. These ring systems were prepared via a
general sequence of biaryl bond formation followed by cyclization to form
the desired tricyclic ring systems. N-Alkylation, -acylation, or
-sulfonylation and deprotection with boron tribromide afford the target
tetraphenolic phenanthridinones 5 and carbazoles 9. Several analogs from
both of these series have potencies comparable to that of 1 and exhibit
substantially enhanced selectivities for inhibition of pp60src relative to
protein kinase A (PKA), a serine/threonine protein kinase. Carbazole-based
analogs 9j,m,p are submicromolar inhibitors of pp60src, with potency for
the target tyrosine kinase comparable to that of ellagic acid (1), however
with 2 orders of magnitude greater selectivity versus that for PKA. As
seen for ellagic acid, members of the phenanthridinone-based series (e.g.,
5a) exhibited inhibition of pp60src in a manner which is partial mixed
noncompetitive with respect to ATP, while analogs in the carbazole series
(e.g., 9a) inhibit pp60src in an ATP competitive manner. |