Abstract
Several new TOP1-targeting agents were prepared using as an intermediate the N,N,N-trimethyl quaternary ammonium salt 2 of ARC-111. Direct displacement of the quaternary ammonium group with hydroxide, cyclopropylamine, imidazole, 1H-1,2,3-triazole, alkylethylenediamines, ethanolamine, and polyhydroxylated alkylamines provides a convenient means for furthering insight into the structure-activity relationships within this series of non-camptothecin TOP1-targeting agents. The relative TOP1-targeting activities and cytotoxicities were evaluated in RPMI8402 and P388 cells and their camptothecin-resistant variants. Their potential to serve as substrates for the efflux transporters MDR1 and BCRP, which are associated with multidrug resistance, was also assessed.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
-
ATP Binding Cassette Transporter, Subfamily G, Member 2
-
ATP-Binding Cassette Transporters / metabolism
-
Animals
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / chemistry*
-
Antineoplastic Agents / pharmacology*
-
Camptothecin / pharmacology
-
Cell Line, Tumor
-
DNA Topoisomerases, Type I / metabolism*
-
Drug Resistance, Multiple / drug effects
-
Drug Resistance, Neoplasm / drug effects
-
Drug Screening Assays, Antitumor
-
Humans
-
Mice
-
Naphthyridines / chemical synthesis
-
Naphthyridines / chemistry*
-
Naphthyridines / pharmacology*
-
Neoplasm Proteins / metabolism
-
Structure-Activity Relationship
Substances
-
ABCG2 protein, human
-
ATP Binding Cassette Transporter, Subfamily B, Member 1
-
ATP Binding Cassette Transporter, Subfamily G, Member 2
-
ATP-Binding Cassette Transporters
-
Antineoplastic Agents
-
Naphthyridines
-
Neoplasm Proteins
-
topovale
-
DNA Topoisomerases, Type I
-
Camptothecin