Abstract
Recently, 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one, 1, was identified as a TOP1-targeting agent with pronounced antitumor activity. In the present study, the effect on activity of substituting a single nitro or amino group in the A-ring in lieu of the methylenedioxy moiety of 1 was evaluated. The presence of either a nitro or amino substituent at the 4-position had a pronounced adverse affect on both TOP1-targeting activity and cytotoxicity. To a lesser extent, derivatives with a nitro or amino substituent at the 1-position were also less active than 1. Replacement of the methylenedioxy moiety of 1 with either a nitro or amino substituent at either the 2- and 3-position did result in analogues with potent TOP1-targeting activity and cytotoxicity.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Amination
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology
-
Antineoplastic Agents / toxicity
-
Cell Line, Tumor
-
DNA / metabolism
-
DNA Topoisomerases, Type I / metabolism*
-
Enzyme Inhibitors / chemical synthesis
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / pharmacology
-
Enzyme Inhibitors / toxicity
-
Humans
-
Inhibitory Concentration 50
-
Molecular Conformation
-
Molecular Structure
-
Naphthyridines / chemical synthesis
-
Naphthyridines / chemistry*
-
Naphthyridines / pharmacology*
-
Naphthyridines / toxicity
-
Nitrogen / chemistry*
-
Static Electricity
-
Topoisomerase I Inhibitors*
Substances
-
Antineoplastic Agents
-
Enzyme Inhibitors
-
Naphthyridines
-
Topoisomerase I Inhibitors
-
benzonaphthyridone
-
DNA
-
DNA Topoisomerases, Type I
-
Nitrogen