ABSTRACT
Merkel cell carcinoma is a rare, aggressive, highly metastatic, often fatal, primary neuroendocrine tumor typically located on sun-exposed skin. It is frequently found in white males aged 60 to 70 years. The somewhat typical benign clinical appearance of the lesion can result in a delayed diagnosis, leading to a less than optimal outcome.
Subject(s)
Carcinoma, Merkel Cell/diagnosis , Skin Neoplasms/diagnosis , Aged , Carcinoma, Merkel Cell/surgery , Humans , Middle Aged , Skin Neoplasms/surgerySubject(s)
Botany , Online Systems , Publishing , Access to Information , Online Systems/economics , Publishing/economicsABSTRACT
Palladium catalyzed cross-coupling reactions were used to synthesize two key intermediates 3 and 5 that resulted in the synthesis of novel series of macrocyclic bis-7-azaindolylmaleimides. Among the three series of macrocycles, the oxygen atom and thiophene containing linkers yielded molecules with higher inhibitory potency at GSK-3 beta (K(i)=0.011-0.079 microM) while the nitrogen atom containing linkers yielded molecules with lower potency (K(i)=0.150->1 microM). Compound 33 and 36 displayed 1-2 orders of magnitude selectivity at GSK-3 beta against CDK2, PKC beta II, Rsk3 and little or no inhibitions to the other 62 protein kinases. Compound 46 was at least 100-fold more selective towards GSK-3 beta than PKC beta II, and it had little or no activity against a panel of 65 protein kinases, almost behaved as a GSK-3 beta 'specific inhibitor'. All three compounds showed good potency in GS assay. Molecular docking studies were conducted in an attempt to rationalize the GSK-3 beta selectivity of azaindolylmaleimides. The high selectivity, inhibitory potency and cellular activities of these non-crown-ether typed molecules may provide them as a valuable pharmacological tools in elucidating the complex roles of GSK-3 beta in cell signaling pathways and the potential usage for the treatment of elevated level of GSK-3 beta involved diseases.
