ABSTRACT
Various 5-amino group-substituted indeno[1,2-c]isoquinolines 7a-f were synthesized based on the previous QSAR study as rigid structures of 3-arylisoquinolines. Amino group-substituted compounds, especially 5-piperazinyl indeno[1,2-c]isoquinoline 7f, displayed potent topoisomerase I inhibitory activity as well as cytotoxicities against five different tumor cell lines. A Surflex-Dock docking model of 7f was also studied.
Subject(s)
DNA Topoisomerases, Type I/chemistry , Isoquinolines/chemistry , Piperazines/chemical synthesis , Topoisomerase I Inhibitors/chemical synthesis , Binding Sites , Cell Line, Tumor , Computer Simulation , DNA Topoisomerases, Type I/metabolism , Drug Design , Humans , Isoquinolines/chemical synthesis , Isoquinolines/toxicity , Piperazines/chemistry , Piperazines/toxicity , Quantitative Structure-Activity Relationship , Topoisomerase I Inhibitors/chemistry , Topoisomerase I Inhibitors/toxicityABSTRACT
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.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Isoquinolines/chemical synthesis , Topoisomerase I Inhibitors , Cell Line, Tumor , DNA Topoisomerases, Type I/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Hydrogen Bonding , Isoquinolines/chemistry , Isoquinolines/pharmacology , Models, Molecular , Molecular StructureABSTRACT
An intramolecular radical cyclization reaction of 4-bromo-3-arylisoquinolines 11a-c allowed the efficient synthesis of 11-methylindenoisoquinolines 2a-c. 5-(2-Aminoethylamino)indeno[1,2-c]isoquinolin-11-one 4 was also prepared in the convenient manner. The synthesized compounds were tested in vitro for cytotoxicity and DNA-topoisomerase 1 (top 1) inhibitory activity. The dramatic enhancement of top 1 inhibitory activity of 4 was explained by a docking study using the FlexX program.
