ABSTRACT
Benz[b]oxepines 4a-g and 12-oxobenzo[c]phenanthridines 5a-d were designed and synthesized as constrained forms of 3-arylisoquinolines through an intramolecular radical cyclization reaction. Radical cyclization of O-vinyl compounds preferentially led to the 7-endo-trig cyclization pathway to the benz[b]oxepines and 12-oxobenzo[c]phenanthridines through 6-exo-trig path as minor products. Among the synthesized compounds, benz[b]oxepine derivative 4e exhibited potent in vitro cytotoxicity against three different tumor cell lines, as well as topoisomerase 1 inhibitory activity. A Surflex-Dock docking study was performed to clarify the topoisomerase 1 activity of 4e.
Subject(s)
Benzoxepins/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Phenanthrenes/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzoxepins/pharmacology , Camptothecin/chemistry , Cell Line, Tumor , Chemistry, Pharmaceutical/methods , DNA Topoisomerases, Type I/chemistry , Drug Design , Drug Screening Assays, Antitumor , Enzyme Inhibitors/pharmacology , HeLa Cells , Humans , Models, Chemical , Molecular Conformation , Phenanthrenes/pharmacology , Protein Binding , Topoisomerase I InhibitorsABSTRACT
The total synthesis of the natural phenolic benzo[c]phenanthridine alkaloid, oxyterihanine, was accomplished via substituted 3-arylisoquinoline intermediate. The key reaction was a coupling between the o-toluamide 4 and the benzonitrile 5.
Subject(s)
Benzamides/chemistry , Nitriles/chemistry , Alkaloids/chemical synthesis , Alkaloids/chemistry , Cyclization , Indicators and Reagents , Magnetic Resonance Spectroscopy , Phenanthridines/chemistry , Spectrophotometry, Infrared , Zanthoxylum/chemistryABSTRACT
Induction of differentiation is a new and promising approach to cancer therapy, well illustrated by the treatment of acute myeloid leukemia with all-trans retinoic acid (ATRA). Using combination of ATRA and chemotherapy, adverse effects such as retinoic acid syndrome have decreased, and long-term survival has improved. In this study, we demonstrated that the indeno[1,2-c]isoquinolines markedly enhanced differentiation of human myeloid leukemia HL-60 and NB4 cells when simultaneously combined with a low dose of ATRA. Of the tested compounds, 6-(4-methoxybenzyl)-2,11-dimethyl-6H,11H-indeno[1,2-c]isoquinolin-5-one (IIQ-16), an indeno[1,2-c]isoquinoline derivative, showed the highest differentiation-enhancing activity via a pathway involved with protein kinase C, extracellular signal-regulated kinase, and c-Jun N-terminal kinase. The ability to enhance the differentiation potential of ATRA by IIQ-16 may improve outcomes in the therapy of acute promyelocytic leukemia.
Subject(s)
Cell Differentiation/drug effects , Indenes/chemistry , Isoquinolines/chemistry , Isoquinolines/pharmacology , Leukemia, Myeloid/pathology , Tretinoin/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Humans , Isoquinolines/chemical synthesis , Molecular Structure , Structure-Activity RelationshipABSTRACT
11-hydroxyindeno[1,2-c]isoquinolines 12a-c were prepared as constrained forms of 3-arylisoquinolines through an intramolecular cyclization reaction. Among the synthesized compounds, the 11-(i)butoxy analog 15l displayed potent in vitro cytotoxicity against four different tumor cell lines as well as topoisomerase 1 inhibitory activity. A FlexX docking study was performed to explain the topoisomerase 1 activity of 15l.
