ABSTRACT
Herein we report investigations into the p38alpha MAP kinase activity of trisubstituted imidazoles that led to the identification of compounds possessing highly potent in vivo activity. The SAR of a novel series of imidazopyridines is demonstrated as well, resulting in compounds possessing cellular potency and enhanced in vivo activity in the rat collagen-induced arthritis model of chronic inflammation.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Imidazoles/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Pyridines/pharmacology , Adenosine Triphosphate/analogs & derivatives , Adenosine Triphosphate/metabolism , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacokinetics , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Edema/drug therapy , ErbB Receptors/metabolism , Humans , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Mice , Mice, Inbred BALB C , Peptide Fragments/metabolism , Pyridines/chemistry , Pyridines/pharmacokinetics , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Two closely related diaryl acylsulfonamides were recently reported as potent antitumor agents against a broad spectrum of human tumor xenografts (colon, lung, breast, ovary, and prostate) in nude mice. Especially intriguing was their activity against colorectal cancer xenografts. In this paper, rapid parallel synthesis along with traditional medicinal chemistry techniques were used to quickly delineate the structure-activity relationships of the substitution patterns in both phenyl rings of the acylsufonamide anti-proliferative scaffold. Although the molecular target of the compounds remains unclear, we determined that the vascular endothelial growth factor-dependent human umbilical vein endothelial cells assay in combination with a soft agar disk diffusion assay allowed for optimization of potency in the series. The pharmacokinetic properties and in vivo activity in an HCT116 xenograft model are reported for representative compounds.
Subject(s)
Antineoplastic Agents/chemical synthesis , Sulfonamides/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Division/drug effects , Cell Line , Drug Screening Assays, Antitumor , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Female , Half-Life , Humans , In Vitro Techniques , Mice , Mice, Nude , Quantitative Structure-Activity Relationship , Rats , Rats, Inbred F344 , Sulfonamides/chemistry , Sulfonamides/pharmacology , Transplantation, Heterologous , Umbilical Veins/cytology , Vascular Endothelial Growth Factor A/pharmacology , Vascular Endothelial Growth Factor A/physiologyABSTRACT
The synthesis of new analogues of Arcyriaflavin A in which one indole ring is replaced by an aryl or heteroaryl ring is described. These new series of aryl[a]pyrrolo[3,4-c]carbazoles were evaluated as inhibitors of Cyclin D1-CDK4. A potent and selective D1-CDK4 inhibitor, 7a (D1-CDK4 IC(50)=45 nM), has been identified. The potency, selectivity profile against other kinases, and structure-activity relationship (SAR) trends of this class of compounds are discussed.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Carbazoles/chemistry , Carbazoles/chemical synthesis , Carbazoles/pharmacology , Cyclin D1/antagonists & inhibitors , Cyclin-Dependent Kinases/antagonists & inhibitors , Proto-Oncogene Proteins , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Cell Division/drug effects , Cell Line, Tumor , Cyclin-Dependent Kinase 4 , HumansABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Carbazoles/chemical synthesis , Carbazoles/pharmacology , Cyclin-Dependent Kinases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Cell Division/drug effects , Cell Line, Tumor , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Flow Cytometry , Humans , Molecular Conformation , Structure-Activity RelationshipABSTRACT
Novel substituted indolocarbazoles were synthesized, and their kinase inhibitory capability was evaluated in vitro. 6-Substituted indolocarbazoles 4 were found to be potent and selective D1/CDK4 inhibitors. 4d and 4h exhibited potent and ATP-competitive D1/CDK4 activities with IC50 values of 76 and 42 nM, respectively. Both compounds had high selectivity against the other kinases. These D1/CDK4 inhibitors inhibited tumor cell growth, arrested tumor cells at the G1 phase, and inhibited pRb phosphorylation.
