ABSTRACT
For the development of novel anticancer agents, we designed and synthesized hydroxylated 2,4-diphenyl indenopyridines, and evaluated their topoisomerase inhibitory activity as well as their antiproliferative activities against several human cancer cell lines. The structure-activity relationship study showed that indenopyridines with hydroxyl group at meta or para positions of 2- or 4-phenyl ring displayed selective and significant topoisomerase IIα (topo IIα) inhibitory activity and potent antiproliferative activity. Positive correlation between topo IIα inhibition and antiproliferative activity was observed for compounds 15, 16, 18-20, 22, 23, 25 and 26. The mode of action of compound 16 was further evaluated to be a non-intercalative topo IIα catalytic inhibitor.
Subject(s)
Antineoplastic Agents/pharmacology , DNA-Binding Proteins/antagonists & inhibitors , Indenes/pharmacology , Pyridines/pharmacology , Topoisomerase II Inhibitors/pharmacology , Antigens, Neoplasm/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Biocatalysis , Cell Line, Tumor , Cell Proliferation/drug effects , DNA Topoisomerases, Type II/metabolism , DNA-Binding Proteins/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Hydroxylation , Indenes/chemical synthesis , Indenes/chemistry , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/chemistryABSTRACT
For the development of potential anticancer agents, we designed and synthesized 30 new 2,4-diaryl-5H-indeno[1,2-b]pyridine derivatives containing aryl moiety such as furyl, thienyl, pyridyl, and phenyl at 2- and 4-position of 5H-indeno[1,2-b]pyridine. They were evaluated for topoisomerase I and II inhibitory activity, and cytotoxicity against several human cancer cell lines. Among prepared 30 compounds, 7, 8, 9, 10, 12, 14, 16, 19, 20, 22, and 23 with 2- or 3-furyl and/or 2- or 3-thienyl either at 2- or 4-position of central pyridine showed the significant or moderate topoisomerase II inhibitory activity. Compounds 7, 8, 11, 12, 13, and 22 with 2-furyl, 2-thienyl or 3-thienyl at 2-position of central pyridine showed the significant or moderate topoisomerase I inhibitory activity. Especially, compound 12 with strong topoisomerase II inhibitory activity at 100 µM and 20 µM, and moderate topoisomerase I inhibitory activity displayed strong cytotoxicity against several human cancer cell lines.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Topoisomerase I Inhibitors/chemistry , Topoisomerase I Inhibitors/pharmacology , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Drug Design , Humans , Pyridines/chemical synthesis , Structure-Activity Relationship , Topoisomerase I Inhibitors/chemical synthesisABSTRACT
Twelve dihydroxylated 2,4,6-triphenyl pyridines were designed and synthesized which contain hydroxyl groups at ortho, meta or para position of 2- and 6-phenyl, or 2- and 4-phenyl rings attached to the central pyridine. They were evaluated for topoisomerase I and II inhibitory activity, and cytotoxicity against several human cancer cell lines for the development of novel anticancer agents. Generally, dihydroxylated 2,4,6-triphenyl pyridines exhibited stronger topoisomerase II inhibitory activity, and cytotoxicity compared to those of monohydroxylated 2,4,6-triphenyl pyridines. The concrete structure-activity relationship was observed that dihydroxylated 2,4,6-triphenyl pyridines with hydroxyl group at meta or para position of 2-phenyl ring displayed significant topoisomerase II inhibitory activity as well as cytotoxicity. Positive correlation between topoisomerase II inhibitory activity and cytotoxicity was observed for compounds 10, 12, 13, 17-20 and 22.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Topoisomerase Inhibitors/chemistry , Topoisomerase Inhibitors/pharmacology , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Cell Survival/drug effects , DNA Topoisomerases, Type I/metabolism , DNA Topoisomerases, Type II/metabolism , Humans , Neoplasms/drug therapy , Neoplasms/enzymology , Pyridines/chemical synthesis , Topoisomerase Inhibitors/chemical synthesisABSTRACT
Designed and synthesized thirty-two 2,4-diaryl-5,6-dihydro-1,10-phenanthroline and 2,4-diaryl-5,6-dihydrothieno[2,3-h] quinoline derivatives as rigid analogs of 2,4,6-trisubstituted pyridines 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 [2,2';6',2"]-terpyridine skeleton is important for the cytotoxicity against several human cancer cell lines.
Subject(s)
DNA Topoisomerases, Type II/chemistry , DNA Topoisomerases, Type I/chemistry , Phenanthrolines/chemistry , Quinolines/chemistry , Topoisomerase I Inhibitors/chemistry , Topoisomerase II Inhibitors/chemistry , Cell Line, Tumor , Cell Survival/drug effects , DNA Topoisomerases, Type I/metabolism , DNA Topoisomerases, Type II/metabolism , Drug Screening Assays, Antitumor , Enzyme Activation/drug effects , Humans , Phenanthrolines/chemical synthesis , Phenanthrolines/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Structure-Activity Relationship , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/pharmacology , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacologyABSTRACT
Epidermal growth factor (EGF) is a well-known neurotrophic factor regulating the development of various neuronal cells, including dopaminergic neurons, and dysfunction of EGF signals has been demonstrated as a risk factor for schizophrenia. Recently, several researchers have investigated associations including age at onset (AAO) with EGF A61G functional polymorphism, but the results of these studies have been controversial. Thus, we investigated whether A61G plays a role in predisposition to schizophrenia and its effects on AAO. Our subjects included 190 patients with schizophrenia and 347 controls. We assessed three different points of AAO: age at first occurrence of positive psychotic symptoms, medication, and hospitalization as a patient with schizophrenia. We found no differences in allele and genotype frequencies between patients and controls or associations between A61G and AAOs across stratified points in the entire sample and in each gender. However, we found significant gender differences in patients with the AA genotype in all stratified points of AAOs. Subset analyses of G allele distribution between clinical subsets with an AAO cutoff of 20 years revealed that male patients with early onset schizophrenia were more likely to exhibit the common AA homozygote than male patients with adulthood onset schizophrenia. In conclusion, although we were unable to support an association between EGF A61G and schizophrenia, the AA genotype might play a disease-modifying role differentially according to gender.