Optimization of the antitumor activity of sequence-specific pyrrolobenzodiazepine derivatives based on their affinity for ABC transporters.
Pyrrolobenzodiazepine (PBD) derivatives are highly potent sequence-specific DNA cross-linking agents. The present study aimed to identify key physicochemical properties influencing the interaction of a series of PBDs (four dimers and 12 monomers) with the three major human ATP-binding cassette (ABC) transporters (P-gp, ABCG2, and MRP1). Isogenic cell lines expressing P-gp and ABCG2, cell lines with acquired resistance to cytotoxic agents due to the high expression of ABC transporters, and specific inhibitors against P-gp, ABCG2, and MRP1 were used. P-gp and ABCG2 decreased the permeability of the PBD dimers across cell membranes and their interaction with DNA, reducing DNA damage and the overall cytotoxic effect. PBD monomer SG-2823 formed a conjugate with glutathione and interacted with MRP1, reducing its cytotoxic effect in A549 cells. Structure-activity relationship revealed that the interaction of PBDs with the transporters could be predicted considering the molecular weight, the lipophilicity, the number of (N + O) atoms and aromatic rings, the polar surface area, the hydrogen bonding energy, and electrophilic centers. A rational design of novel PBDs with increased potency and reduced interaction with the ABC transporters is proposed.
Kaliszczak
Maciej
M
University of Edinburgh Cancer Research Centre, UK. m.kaliszczak@imperial.ac.uk
Antonow
Dyeison
D
Patel
Katan I
KI
Howard
Philip
P
Jodrell
Duncan I
DI
Thurston
David E
DE
Guichard
Sylvie M
SM
D018528:ATP-Binding Cassette Transporters / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines