ABSTRACT
The synthesis and kinase inhibitory activity of a series of novel 1,7-annulated indolocarbazoles 6 and 16 is described. These compounds exhibited potent inhibitory activity against cyclin-dependent kinase 4 and good antiproliferative activity in a human colon carcinoma cell line.
Subject(s)
Carbazoles/chemistry , Cyclin-Dependent Kinases/antagonists & inhibitors , Indoles/chemistry , Protein Kinase Inhibitors/chemistry , Carbazoles/pharmacology , Cyclin D1/antagonists & inhibitors , Cyclin D1/metabolism , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinases/metabolism , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/metabolismABSTRACT
Synthesis of indolo[6,7-a]pyrrolo[3,4-c]carbazoles 1, a new class of cyclin D1/CDK4 inhibitors, by oxidation of the corresponding aryl indolylmaleimides 2, will be described. Two approaches to the synthesis of 2 were identified that required new methods for the synthesis of 7-substituted indole acetamides 3 and N-methyl (indol-7-yl)oxoacetates 6. The chemistry developed enabled introduction of functionality (-OR, NR(2)) at C(12) and N(13) facilitating structure-activity relationship (SAR) evaluation of this indolocarbazole platform.
Subject(s)
Antineoplastic Agents/chemical synthesis , Carbazoles/chemical synthesis , Cyclin D1/antagonists & inhibitors , Cyclin-Dependent Kinases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Indoles/chemistry , Proto-Oncogene Proteins , Pyrroles/chemistry , Acetamides/chemistry , Acetates/chemistry , Cyclin-Dependent Kinase 4 , Humans , Maleimides/chemistry , Oxidants/chemistry , Photochemistry , Structure-Activity RelationshipABSTRACT
Synthesis of aryl- and hetero[a]pyrrolo[3,4-c]carbazoles by photochemical oxidation and Heck cyclization are described. Photochemical oxidation of 2-naphthyl indolyl maleimide affords two different carbazole regioisomers, depending on the reaction conditions. The regiochemistry of the cyclization can be controlled using the Heck reaction.
