ABSTRACT
A comprehensive SAR investigation of the C2-position of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) monomer antitumor agents is reported, establishing the molecular requirements for optimal in vitro cytotoxicity and DNA-binding affinity. Both carbocyclic and heterocyclic C2-aryl substituents have been studied ranging from single aryl rings to fused ring systems, and also styryl substituents, establishing across a library of 80 analogues that C2-aryl and styryl substituents significantly enhance both DNA-binding affinity and in vitro cytotoxicity, with a correlation between the two. The optimal C2-grouping for both DNA-binding affinity and cytotoxicity was found to be the C2-quinolinyl moiety which, according to molecular modeling, is due to the overall fit of the molecule in the DNA minor groove, and potential specific contacts with functional groups in the floor and walls of the groove. This analogue (14l) was shown to delay tumor growth in a HCT-116 (bowel) human tumor xenograft model.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzodiazepines/chemistry , Benzodiazepines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Base Sequence , Benzodiazepines/chemical synthesis , Benzodiazepines/metabolism , Cattle , Cell Line, Tumor , DNA/chemistry , DNA/genetics , DNA/metabolism , Female , Humans , Imines/chemistry , Mice , Models, Molecular , Nucleic Acid Conformation , Nucleic Acid Denaturation/drug effects , Pyrroles/chemical synthesis , Pyrroles/metabolism , Stereoisomerism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
A prodrug form (17) of a novel C2/C2'-aryl-substituted pyrrolobenzodiazepine (PBD) dimer (16) has been synthesized by introducing sodium bisulfite groups to the C11/C11'-positions of the parent bis-imine. The prodrug form is highly water soluble, stable in aqueous conditions, and the rate of DNA cross-link formation is much slower compared to the parent bis-imine.
Subject(s)
Benzodiazepinones/chemical synthesis , DNA/drug effects , Drug Resistance, Neoplasm/drug effects , Prodrugs , Pyrroles/chemical synthesis , Animals , Benzodiazepines/pharmacology , Benzodiazepinones/chemistry , Benzodiazepinones/pharmacology , Cell Line, Tumor , Computer Simulation , DNA/metabolism , Drug Design , Drug Screening Assays, Antitumor , Epoxy Compounds/pharmacology , Humans , Models, Molecular , Pyrroles/chemistry , Pyrroles/pharmacology , Solubility/drug effects , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A 66-member C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine (PBD) library has been successfully synthesized in parallel via Suzuki coupling using PS-PPh3Pd (catalyst) and PS-DEAM (scavenger) under microwave radiation. Library members were obtained in sufficient yield (up to 91%) and purity (85-98% crude) for biological evaluation.
Subject(s)
Benzodiazepines/chemical synthesis , Combinatorial Chemistry Techniques/methods , Benzodiazepines/chemistry , Benzodiazepines/radiation effects , Catalysis , Microwaves , Molecular Structure , Organometallic Compounds/chemistry , Palladium/chemistry , StereoisomerismABSTRACT
Three novel C2-aryl substituted pyrrolobenzodiazepines (PBDs) have been synthesised and evaluated in a number of cell lines revealing selective cytotoxicity at the sub-nanomolar level towards melanoma and ovarian cancer cell lines.
