Synthesis and biological evaluation of novel pyrrolo[2,1-c][1,4]benzodiazepine prodrugs for use in antibody-directed enzyme prodrug therapy.
The design, synthesis and evaluation of four novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD) prodrugs (1a,b and 2a,b; ) for potential use in carboxypeptidase G2 (CPG2)-based antibody-directed enzyme prodrug therapy (ADEPT) is reported. Although all four prodrugs were shown to be less cytotoxic than the released parent PBDs 3 and 4, the urea prodrugs 1b and 2b were found to be too unstable for use in ADEPT, whereas carbamates 1a and 2a are both stable in an aqueous environment and are good substrates for CPG2.
Masterson
Luke A
LA
CR-UK Gene Targeting Drug Design Research Group, School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1 1AX, UK.
Spanswick
Victoria J
VJ
Hartley
John A
JA
Begent
Richard H
RH
Howard
Philip W
PW
Thurston
David E
DE
D000906:Antibodies / Q000737:chemistry / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000187:drug effects; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009588:Nitrogen Mustard Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013997:Time Factors; D011623:gamma-Glutamyl Hydrolase / Q000737:chemistry / Q000627:therapeutic use*
D000906:Antibodies; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; D011758:Pyrroles; C097602:ZD 2767; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines; D011623:gamma-Glutamyl Hydrolase