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
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.10.017

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 environment and are good substrates for CPG2. The design, synthesis and evaluation of four novel pyrrolo[2,1- c][1,4]benzodiazepine (PBD) prodrugs ( 1a, b and 2a, b; Fig. 1) 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.