Synthesis and biological evaluation of novel pyrrolo[2,1- c][1,4]benzodiazepine prodrugs for use in antibody-directed enzyme prodrug therapy

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 2; pp. 252 - 256
• Main Authors: Masterson, Luke A., Spanswick, Victoria J., Hartley, John A., Begent, Richard H., Howard, Philip W., Thurston, David E.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.01.2006; Elsevier
• Subjects: ADEPT; Antibodies - chemistry; Antibodies - therapeutic use; Antigens, Neoplasm - drug effects; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Benzodiazepines - chemical synthesis; Benzodiazepines - pharmacology; Benzodiazepines - therapeutic use; Biological and medical sciences; Cell Line, Tumor; Cell Survival - drug effects; Colonic Neoplasms - drug therapy; CPG2; Drug Design; Drug Screening Assays, Antitumor; gamma-Glutamyl Hydrolase - chemistry; gamma-Glutamyl Hydrolase - therapeutic use; General aspects; Humans; Inhibitory Concentration 50; Medical sciences; Molecular Structure; Nitrogen Mustard Compounds - chemistry; Nitrogen Mustard Compounds - pharmacology; Nitrogen Mustard Compounds - therapeutic use; PBD; Pharmacology. Drug treatments; Prodrug; Prodrugs - chemical synthesis; Prodrugs - pharmacology; Prodrugs - therapeutic use; Pyrroles - chemical synthesis; Pyrroles - pharmacology; Pyrroles - therapeutic use; Pyrrolo[2,1- c][1,4]benzodiazepines; Structure-Activity Relationship; Time Factors; PBD; Prodrug; Pyrrolo[2,1- c][1,4]benzodiazepines; ADEPT; CPG2; Antineoplastic agent; Angular nitrogen heterocycle; Lactam; Cytotoxicity; Organic carbamate; Pyrrolo[2,1-c][1,4]benzodiazepines; Structure activity relation; Targeted drug; Ureas; Aromatic compound; Colon; Chemical synthesis; Glutamate carboxypeptidase; Tumor cell; Human; Enzyme; Gut; Antibody directed enzyme prodrug therapy; Tricyclic compound; Substrate; Peptidases; Cell line; Hydrolases; Dimer; Metallocarboxypeptidases

Four novel pyrrolo[2,1- c][1,4]benzodiazepine prodrugs ( 1a, b and 2a, b) have been synthesized for potential use in carboxypeptidase G2 (CPG2)-based ADEPT therapy. The urea prodrugs ( 1b and 2b) are relatively unstable but the carbamate prodrugs ( 1a and 2a) are both stable in an aqueous environmen...