Abstract
A series of indolo[2,3-a]pyrrolo[3,4-c]carbazoles and their bis-indolylmaleimides precursors have been prepared in order to compare their activity as D1-CDK4 inhibitors. Both enzymatic and antiproliferative assays have shown that the structurally more constrained indolo[2,3-a]pyrrolo[3,4-c]carbazoles are consistently more active (8-42-fold) in head-to-head comparison with their bis-indolylmaleimides counterparts. Cell-cycle analysis using flow cytometry have also shown that the indolocarbazoles are selective G1 blockers while the bis-indolylmaleimides arrest cells in the G2/M phase.
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology*
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Carbazoles / chemical synthesis*
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Carbazoles / pharmacology*
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Cell Division / drug effects
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Cell Line, Tumor
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Crystallography, X-Ray
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology*
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Flow Cytometry
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Humans
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Molecular Conformation
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Pyrroles / chemical synthesis*
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Pyrroles / pharmacology*
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Carbazoles
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Enzyme Inhibitors
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Pyrroles
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Cyclin-Dependent Kinases