ABSTRACT
The pyrrolobenzodiazepines (PBD) are naturally occurring antitumor antibiotics, and a PBD dimer (SJG-136, SG2000) is in phase II trials. Many potent PBDs contain a C2-endo-exo unsaturated motif associated with the pyrrolo C-ring. The novel compound SG2202 is a PBD dimer containing this motif. SG2285 is a water-soluble prodrug of SG2202 in which two bisulfite groups inactivate the PBD N10-C11 imines. Once the bisulfites are eliminated, the imine moieties can bind covalently in the DNA minor groove, forming an interstrand cross-link. The mean in vitro cytotoxic potency of SG2285 against human tumor cell lines is GI(50) 20 pmol/L. SG2285 is highly efficient at producing DNA interstrand cross-links in cells, but they form more slowly than those produced by SG2202. Cellular sensitivity to SG2285 was primarily dependent on ERCC1 and homologous recombination repair. In primary B-cell chronic lymphocytic leukemia samples, the mean LD(50) was significantly lower than in normal age-matched B and T lymphocytes. Antitumor activity was shown in several human tumor xenograft models, including ovarian, non-small cell lung, prostate, pancreatic, and melanoma, with cures obtained in the latter model with a single dose. Further, in an advanced-stage colon model, SG2285 administered either as a single dose, or in two repeat dose schedules, was superior to irinotecan. Our findings define SG2285 as a highly active cytotoxic compound with antitumor properties desirable for further development.
Subject(s)
Antibiotics, Antineoplastic/pharmacology , Prodrugs/pharmacology , Animals , Benzodiazepinones/pharmacology , CHO Cells , Cell Line, Tumor , Cricetinae , Cricetulus , Female , Humans , Mice , Neoplasms/drug therapy , Pyrroles/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
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
The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a class of DNA minor groove binding agents that react covalently with guanine bases, preferably at Pu-G-Pu sites. A series of three fluorescent PBD-coumarin conjugates with different linker architectures has been synthesized to probe correlations between DNA binding affinity, cellular localization and cytotoxicity. The results show that the linker structure plays a critical role for all three parameters.
