ABSTRACT
A series of novel 7-alkoxyl substituted indolizinoquinoline-5,12-dione derivatives were synthesized. The cholinesterase inhibition assays indicated that most synthesized compounds exhibited good activity for acetylcholinesterase (AChE) and high selectivity index of AChE over butyrylcholinesterase (BuChE). Compound 12b exhibited the most potent AChE inhibitory activity with an IC(50) value of 0.068 µM and the highest selectivity index of 144. Kinetic study of AChE indicated that a mixed type of inhibition pattern existed for these indolizinoquinoline-5,12-dione derivatives. Molecular docking study indicated that compound 12b could bind to both the catalytically active site and the peripheral anionic site of AChE.
Subject(s)
Cholinesterase Inhibitors/pharmacology , Indolizines/pharmacology , Quinolines/pharmacology , Acetylcholinesterase , Binding Sites , Butyrylcholinesterase , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Indolizines/chemical synthesis , Indolizines/chemistry , Inhibitory Concentration 50 , Models, Molecular , Quinolines/chemical synthesis , Quinolines/chemistry , Structure-Activity RelationshipABSTRACT
In the title mol-ecule, C(18)H(11)FN(2)O(4), the fused four- ring system is essentially planar, with an r.m.s. deviation of 0.032â Å. In the crystal, mol-ecules are connected by π-π stacking inter-actions [centroid-centroid distances = 3.5684â (9) and 3.8247â (9)â Å] into chains along [100].
ABSTRACT
DNA topoisomerase I (Top1) is an essential nuclear enzyme and a validated target for anticancer agent screening. In a previous study, we found that indolizinoquinoline-5,12-dione derivatives show significant biological activity against several human cancer cell lines. To understand their mechanism of inhibition of cancer cell growth, one indolizinoquinoline-5,12-dione derivative, CY13II, was further studied as lead. Our present results indicate that CY13II shows more potent antiproliferative activity against K562 cells than camptothecin. Additionally, K562 cells were arrested in G2/M, and their growth rate decreased after treatment with CY13II at micromolar concentration. Biochemical Top1 assays indicate that CY13II exhibits a different inhibitory mechanism from camptothecin. Unlike camptothecin, CY13II specifically inhibits the catalytic cleavage activity of Top1 instead of forming the drug-enzyme-DNA covalent ternary complex.
Subject(s)
DNA Topoisomerases, Type I/metabolism , Indolizines/pharmacology , Quinolones/pharmacology , Topoisomerase I Inhibitors/pharmacology , Camptothecin/pharmacology , Cell Division/drug effects , Cell Proliferation/drug effects , Humans , K562 CellsABSTRACT
Two new metabolites, 3R,5R-Sonnerlactone (1) and 3R,5S-Sonnerlactone (2), were isolated from the mangrove endophytic fungus Zh6-B1 obtained from the South China Sea. Their structures were elucidated by MS and NMR. The absolute configuration of compound 1 was determined by single-crystal X-ray analysis using Cu Kalpha radiation. The absolute configuration of compound 2 was determined by NOESY analysis and comparing circular dichroism spectroscopy with compound 1. The antiproliferative activity of compound 1 and 2 against the multi-drug resistant human oral floor carcinoma cells (KV) was evaluated.
Subject(s)
Fungi/metabolism , Lythraceae/chemistry , Cell Line, Tumor , Circular Dichroism , Crystallography, X-Ray , Humans , Lythraceae/microbiology , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , Seawater , Spectrometry, Mass, Electrospray IonizationABSTRACT
A series of 9-bromo-substituted indolizinoquinoline-5,12-dione derivatives was synthesized. Antimicrobial activity assessment indicates that compounds 1, 26, 27 and 28 exhibit strong activity against gram-positive bacterial strains, including Beta-hemolytic streptococcus CMCC32210, Staphylococcus aureus ATCC25923, Staphylococcus epidermidis ATCC12228, Enterococcus faecalis ATCC29212 and methicillin-resistant S. aureus ATCC43300 (MRSA). Compound 27 shows the best anti-MRSA activity with an MIC value of 0.031 µg/ml. To assess the mechanism of action, the inhibitory activities of compound 1 against DNA gyrase and DNA topoisomerase IV were also measured. The results indicate that compound 1 has strong inhibitory effects on the Escherichia coli DNA gyrase supercoiling activity and S. aureus Topo IV relaxing activity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Anti-Bacterial Agents/chemistry , Enzyme Inhibitors/pharmacology , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Models, Molecular , Quinolines/chemistry , Spectrometry, Mass, Electrospray IonizationABSTRACT
A series of novel indolizinophthalazine-5,12-dione derivatives were designed and synthesized by the reaction of 6,7-dichlorophthalazine-5,8-dione with active methylene reagents (AMR) and pyridine derivatives. Some of synthesized compounds exhibited significant in vitro antiproliferative activity at micromolar level toward four human tumor cell lines, including lung adenocarcinoma cell, large-cell lung carcinoma cell, breast carcinoma cell and ardriamycin-resistance breast carcinoma cell. The DNA topoisomerase IB inhibitory assay indicated that DNA topoisomerase IB might be a biological target of the synthesized compounds.