ABSTRACT
We have designed and synthesized a series of 2,4,6-triaryl pyridine derivatives containing chlorophenyl and phenolic moeity at 2- and 4- position of the central pyridine, respectively, resulting in a total of 42 compounds. They were evaluated for topoisomerase I and II inhibitory activities as well as cytotoxicities against several human cancer cell lines. Most compounds showed better topoisomerase II inhibitory activity compared to topoisomerase I inhibitory activity. Compounds 19, 20, 26-28, and 47-50 especially showed stronger topo II inhibitory activity than etoposide.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Chemistry Techniques, Synthetic , Drug Design , Phenols/chemistry , Pyridines/chemistry , Pyridines/pharmacology , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , DNA Topoisomerases, Type I/chemistry , DNA Topoisomerases, Type I/metabolism , DNA Topoisomerases, Type II/chemistry , DNA Topoisomerases, Type II/metabolism , Humans , Models, Molecular , Protein Conformation , Pyridines/chemical synthesisABSTRACT
Designed and synthesized were a series of 5H-chromeno[4,3-b]pyridines with substitution at 2- and 4-positions with various 5- or 6-membered heteroaromatics as antitumor agents. They were evaluated for topoisomerase I and II inhibitory activities as well as cytotoxicities against several human cancer cell lines. Structure-activity relationship study showed that 2-furyl or 2-thienyl at 2- or 4-position of central pyridine is crucial in displaying topo I or II inhibitory activity and cytotoxicity.
Subject(s)
Antigens, Neoplasm/metabolism , Benzopyrans/chemical synthesis , Cell Proliferation/drug effects , DNA Topoisomerases, Type II/metabolism , DNA Topoisomerases, Type I/metabolism , DNA-Binding Proteins/metabolism , Neoplasms/enzymology , Pyridines/chemical synthesis , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzopyrans/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Female , Humans , Male , Neoplasms/drug therapy , Neoplasms/pathology , Pyridines/pharmacology , Structure-Activity Relationship , Topoisomerase I Inhibitors/pharmacology , Topoisomerase II Inhibitors/pharmacologyABSTRACT
A series of 2-(thienyl-2-yl or -3-yl)-4-furyl-6-aryl pyridine derivatives were designed, synthesized, and evaluated for their topoisomerase I and II inhibition and cytotoxic activity against several human cancer cell lines. Compounds 10-19 showed moderate topoisomerase I and II inhibitory activity and 20-29 showed significant topoisomerase II inhibitory activity. Structure-activity relationship study revealed that 4-(5-chlorofuran-2-yl)-2-(thiophen-3-yl) moiety has an important role in displaying topoisomerase II inhibition.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Pyridines/pharmacology , Topoisomerase I Inhibitors , Topoisomerase II Inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , DNA Topoisomerases, Type I/chemistry , DNA Topoisomerases, Type I/metabolism , DNA Topoisomerases, Type II/chemistry , DNA Topoisomerases, Type II/metabolism , Drug Design , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Stereoisomerism , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
For the development of novel antitumor agents, 2,6-dithienyl-4-furyl pyridine derivatives were prepared and evaluated for their topoisomerase I and II inhibitory activity as well as cytotoxicity against several human cancer cell lines. Among the 21 prepared compounds, compound 24 exhibited strong topoisomerase I inhibitory activity. In addition, a docking study with topoisomerase I and compound 24 was performed.
