ABSTRACT
New 1,6-dihydropyrazolo[4,3-c]carbazoles and 3,6-dihydropyrazolo[3,4-c]carbazoles were prepared and evaluated for their Pim kinase inhibitory potencies as well as their antiproliferative activities toward two prostatic cancer cell lines. Pyrazolocarbazole 15a was found to be a potent Pim kinase modulator with inhibitory potency toward the three isoforms. Compound 6c strongly inhibited Pim-3 with weaker effect toward Pim-1 and Pim-2, and thus could be used as an interesting molecular tool to study Pim-3 biological functions.
Subject(s)
Carbazoles/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Carbazoles/chemical synthesis , Carbazoles/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Inhibitory Concentration 50 , Male , Models, Molecular , Prostatic Neoplasms/drug therapy , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacologyABSTRACT
The synthesis of quinoline derivatives, designed to interact with Bcl-x(L), and to inhibit its interaction with pro-apoptotic partners, is described and their biological effects investigated. We showed that 5 out of 28 synthetized compounds restored cell death of 3T3 cells overexpressing Bcl-x(L) following serum starvation. Active compounds were further characterized for their binding capacity to the anti-apoptotic member of the Bcl-2 family, Bcl-x(L) as well as Bcl-2, Bfl-1 and Mcl-1, and for their pro-apoptotic activities toward lymphoid tumor cells and peripheral blood mononuclear cells. Altogether our results indicate that dimeric, rather than trimeric quinoline derivatives, represent a new attractive class of BH3 mimetics for cancer therapy.
Subject(s)
Antineoplastic Agents/chemical synthesis , Gene Expression/drug effects , Leukocytes, Mononuclear/drug effects , Quinolines/chemical synthesis , bcl-2-Associated X Protein/metabolism , bcl-X Protein/metabolism , 3T3 Cells , Animals , Antineoplastic Agents/pharmacology , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Bcl-2-Like Protein 11 , Cell Death/drug effects , Cell Survival/drug effects , Dimerization , Humans , Inhibitory Concentration 50 , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Minor Histocompatibility Antigens , Myeloid Cell Leukemia Sequence 1 Protein , Protein Binding , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Quinolines/pharmacology , bcl-2-Associated X Protein/genetics , bcl-X Protein/geneticsABSTRACT
Development of potent and selective Pim kinase inhibitors has recently emerged as an important field for the design of new anti-cancer drugs. We report the synthesis of new N-10-substituted pyrrolo[2,3-a]carbazole derivatives and their evaluation as Pim kinase inhibitors. Moreover, in vitro antiproliferative activity of these compounds was evaluated toward a human fibroblast primary culture and three human solid cancer cell lines (PA1, PC3 and DU145). Compounds 3, 7 and 10 showed inhibitory potencies toward Pim-1 and Pim-3 in the nanomolar range. Additionally, dimethylamino analog 10 also demonstrated interesting sub-micromolar antiproliferative activities toward the cell lines tested.
Subject(s)
Antineoplastic Agents/chemistry , Carbazoles/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Carbazoles/chemical synthesis , Carbazoles/pharmacology , Cell Proliferation/drug effects , Cells, Cultured , Humans , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/metabolismABSTRACT
Di- and trimeric quinoline derivatives have been recently described as potential modulators of Bcl-2 family protein interactions. However, only a few trimeric compounds have been described so far and an enlargement of the number of analogs of this class is needed to expand the structure-activity relationship study. Therefore, the synthesis of six new trimeric quinoline derivatives is reported. Moreover molecular modeling experiments were performed to study the conformational arrangement of compound 36 in Bak binding site of Bcl-x(L), showing that these compounds could be potential ligands for Bcl-x(L).
Subject(s)
Models, Molecular , Quinolines/chemistry , Quinolines/chemical synthesis , Binding Sites , Polymerization , Proto-Oncogene Proteins c-bcl-2/chemistry , Proto-Oncogene Proteins c-bcl-2/metabolism , Structure-Activity Relationship , bcl-2 Homologous Antagonist-Killer Protein/chemistry , bcl-2 Homologous Antagonist-Killer Protein/metabolism , bcl-X Protein/metabolismABSTRACT
The synthesis of new pyrazolo[3,4-g]quinoxaline derivatives, as well as their Pim kinases (Pim-1, Pim-2, Pim-3) inhibitory potencies and in vitro antiproliferative activities toward a human fibroblast primary culture and three human solid cancer cell lines (PA1, PC3 and DU145) are described. The results obtained in this preliminary structure-activity relationship study have pointed out that most of the compounds in this series exhibited interesting in vitro Pim-3 kinase inhibitory potencies. Moreover, some of the tested compounds have demonstrated favorable antiproliferative potencies.
