ABSTRACT
A novel series of (7-aryl-1,5-naphthyridin-2-yl)ureas was discovered as dual ERK2 and Aurora B kinases inhibitors. Several analogues were active at micromolar and submicromolar range against ERK2 and Aurora B, associated with very promising antiproliferative activity toward various cancer cell lines. Synthesis, structure activity relationship and docking study are reported. In vitro ADME properties and safety data are also discussed.
Subject(s)
Antineoplastic Agents/pharmacology , Aurora Kinase B/antagonists & inhibitors , Drug Discovery , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Urea/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Aurora Kinase B/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HCT116 Cells , Humans , Mitogen-Activated Protein Kinase 1/metabolism , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemistryABSTRACT
As part of our research projects to identify new chemical entities of biological interest, we developed a synthetic approach and the biological evaluation of (7-aryl-1,5-naphthyridin-4-yl)ureas as a novel class of Aurora kinase inhibitors for the treatment of malignant diseases based on pathological cell proliferation. 1,5-Naphthyridine derivatives showed excellent inhibitory activities toward Aurora kinases A and B, and the most active compound, 1-cyclopropyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]urea (49), displayed IC50 values of 13 and 107â nM against Aurora kinases A and B, respectively. In addition, the selectivity toward a panel of seven cancer-related protein kinases was highlighted. In vitro ADME properties were also determined in order to rationalize the difficulties in correlating antiproliferative activity with Aurora kinase inhibition. Finally, the good safety profile of these compounds imparts promising potential for their further development as anticancer agents.
Subject(s)
Aurora Kinase A/antagonists & inhibitors , Aurora Kinase B/antagonists & inhibitors , Protein Kinase Inhibitors/analogs & derivatives , Urea/analogs & derivatives , Animals , Aurora Kinase A/genetics , Aurora Kinase A/metabolism , Aurora Kinase B/genetics , Aurora Kinase B/metabolism , Caco-2 Cells , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Evaluation, Preclinical , HCT116 Cells , Half-Life , Humans , Mice , Microsomes, Liver/metabolism , Naphthyridines/chemistry , Protein Binding , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Structure-Activity Relationship , Urea/pharmacokinetics , Urea/pharmacologyABSTRACT
A novel series of 2,3-diarylimidazo[1,2-a]pyridines was synthesized and evaluated for their antileishmanial activities. Four derivatives exhibited good activity against the promastigote and intracellular amastigote stages of Leishmania major, coupled with a low cytotoxicity against the HeLa human cell line. The impact of compound lipophilicity on antiparasitic activities was investigated by Log D comparison. Although LmCK1 could be the parasitic target for three compounds (13, 18, 21), the inhibition of another target is under study to explain the antileishmanial effect of the most promising compounds.
Subject(s)
Antineoplastic Agents/pharmacology , Antiprotozoal Agents/pharmacology , Leishmania major/drug effects , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Casein Kinase I/antagonists & inhibitors , Casein Kinase I/metabolism , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Leishmania major/enzymology , Models, Molecular , Molecular Structure , Parasitic Sensitivity Tests , Protein Kinase C/antagonists & inhibitors , Protein Kinase C/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
The synthesis and study of the structure-activity relationships of cytotoxic compounds based on N-pyridinyl or N-aryl-2-(1-benzylindol-3-yl)glyoxamide skeleton, represented by the lead structures D-24241 and D-24851, are described. The presence of N-(pyridin-4-yl) moiety was crucial for activity and 2-[1-(4-chloro-3-nitrobenzyl)-1H-indol-3-yl]-2-oxo-N-(pyridin-4-yl)acetamide (55), the most potent derivative, showed IC(50)=39 nM, 51 nM and 11 nM against HeLa/KB (human cervix carcinoma), L1210 (murine leukemia) and SKOV3 (human ovarian carcinoma) cell lines proliferation assay, respectively, as active as the lead compounds.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Indoles/chemistry , Indoles/pharmacology , Sulfonylurea Compounds/chemistry , Sulfonylurea Compounds/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Carcinoma/drug therapy , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Female , HeLa Cells , Humans , Indoles/chemical synthesis , Leukemia/drug therapy , Ovarian Neoplasms/drug therapy , Structure-Activity Relationship , Sulfonylurea Compounds/chemical synthesis , Uterine Cervical Neoplasms/drug therapyABSTRACT
New series of analogues of N-(pyridin-4-yl)-2-[1-(4-chlorobenzyl)-indol-3-yl]glyoxamide D-24851 were synthesized, characterized and tested for their in vitro anticancer properties. In the first series, an amino acid spacer was introduced in the glyoxamide chain of D-24851. In the second series, the glyoxamide chain was moved to positions 4 and 5 of indole skeleton. These new compounds were tested on four cancer cell lines (KB, SK-OV-3, NCI-H460 and SF-268), with promising activity for the glycine derivative.