ABSTRACT
A series of C2-exo-fluorounsaturated pyrrolobenzodiazepines (PBDs) have been synthesized. These C2-exo-fluorounsaturated PBD dimers have exhibited remarkable DNA-binding affinity.
Subject(s)
Benzodiazepinones/chemistry , Benzodiazepinones/chemical synthesis , DNA/chemistry , Fluorine Compounds/chemical synthesis , Fluorine Compounds/pharmacology , Pyrroles/chemistry , Pyrroles/chemical synthesis , Benzodiazepines/chemical synthesis , Benzodiazepines/pharmacology , Benzodiazepinones/pharmacology , Binding Sites/drug effects , DNA/drug effects , Molecular Conformation , Pyrroles/pharmacology , Structure-Activity RelationshipABSTRACT
Two moieties of epipodophyllotoxin have been linked at C4-position to provide novel bisepipodophyllotoxin analogues. These have been evaluated for their anticancer potential and DNA-topoisomerase II poisoning activity. Most of these analogues have exhibited promising in vitro anticancer activity against different human tumour cell lines and interestingly 4(')-O-methylated analogues have shown increased cytotoxic activity. Similarly, the DNA-topo II poisoning activity tested for these compounds has not only exhibited the DNA cleavage potential comparable to etoposide, but for some compounds this cleavage potential is superior to etoposide. Further, an interesting structure-activity relationship of these epipodophyllotoxin dimers have been generated on the basis of GI(50) values. The equations indicated that GI(50) activity is strongly dependent on structural and thermodynamic properties. These QSAR results are discussed in conjunction with conformational analysis from molecular modelling studies. QSAR models developed in these studies will be helpful in the future to design novel potent bispodophyllotoxin analogues by minor structural modifications.
Subject(s)
Podophyllotoxin , Quantitative Structure-Activity Relationship , Cell Division/drug effects , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Humans , Molecular Conformation , Podophyllotoxin/analogs & derivatives , Podophyllotoxin/chemical synthesis , Podophyllotoxin/pharmacology , Topoisomerase II InhibitorsABSTRACT
C2-Fluoro substituted pyrrolobenzodiazepines (PBDs) have been synthesized that exhibit potential anticancer activity in a number of human tumour cell lines. These C2-fluoro substituted PBDs also exhibit significant DNA-binding ability.
