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

Luke A Masterson; Victoria J Spanswick; John A Hartley; Richard H Begent; Philip W Howard; David E Thurston

doi:10.1016/j.bmcl.2005.10.017

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

Bioorg Med Chem Lett. 2006 Jan 15;16(2):252-6. doi: 10.1016/j.bmcl.2005.10.017. Epub 2005 Nov 15.

Authors

Luke A Masterson¹, Victoria J Spanswick, John A Hartley, Richard H Begent, Philip W Howard, David E Thurston

Affiliation

¹ CR-UK Gene Targeting Drug Design Research Group, School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1 1AX, UK.

PMID: 16290933
DOI: 10.1016/j.bmcl.2005.10.017

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies / chemistry
Antibodies / therapeutic use*
Antigens, Neoplasm / drug effects
Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Benzodiazepines* / chemical synthesis
Benzodiazepines* / pharmacology
Benzodiazepines* / therapeutic use
Cell Line, Tumor
Cell Survival / drug effects
Colonic Neoplasms / drug therapy*
Drug Design
Drug Screening Assays, Antitumor
Humans
Inhibitory Concentration 50
Molecular Structure
Nitrogen Mustard Compounds / chemistry
Nitrogen Mustard Compounds / pharmacology
Nitrogen Mustard Compounds / therapeutic use
Prodrugs* / chemical synthesis
Prodrugs* / pharmacology
Prodrugs* / therapeutic use
Pyrroles* / chemical synthesis
Pyrroles* / pharmacology
Pyrroles* / therapeutic use
Structure-Activity Relationship
Time Factors
gamma-Glutamyl Hydrolase / chemistry
gamma-Glutamyl Hydrolase / therapeutic use*

Substances

Antibodies
Antigens, Neoplasm
Antineoplastic Agents
Nitrogen Mustard Compounds
Prodrugs
Pyrroles
ZD 2767
pyrrolo(2,1-c)(1,4)benzodiazepine
Benzodiazepines
gamma-Glutamyl Hydrolase