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

Bioorganic & Medicinal Chemistry Letters
Luke A MastersonDavid E Thurston

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.

References

Dec 19, 1998·Journal of Medicinal Chemistry·D Niculescu-DuvazC J Springer
Sep 22, 2000·Bioorganic & Medicinal Chemistry Letters·M J SagnouDavid E Thurston
Oct 16, 2001·European Journal of Medicinal Chemistry·W A Denny
Nov 15, 1996·The Journal of Organic Chemistry·David E ThurstonLaurence H. Hurley
Aug 29, 2002·Chemical Communications : Chem Comm·Nectaroula CooperDavid E Thurston

Citations

Dec 21, 2010·Chemical Reviews·Dyeison Antonow, David E Thurston
Apr 5, 2011·Expert Opinion on Investigational Drugs·John A Hartley
May 26, 2016·Biotechnology and Applied Biochemistry·Hui LiuXingyuan Ma
Jun 5, 2010·Organic & Biomolecular Chemistry·Alexander V ButinGennady D Krapivin
Oct 31, 2006·Expert Review of Anticancer Therapy·K D Bagshawe
Apr 26, 2019·Organic & Biomolecular Chemistry·Sk Asraf AliShubhankar Samanta
Jun 17, 2020·Expert Opinion on Biological Therapy·John A Hartley
Jan 28, 2020·Current Organic Synthesis·Muhammad A RashidMuhammad Faruq

Related Concepts

(((4-(bis(2-iodoethyl)amino)phenyl)oxy)carbonyl)glutamic acid
Pyrrolobenzodiazepine
Tumor Antigens
Antineoplastic Agents
Benzodiazepines
Cell Survival
Malignant Tumor of Colon
Dye Exclusion Assays, Antitumor
Nitrogen Mustard Compounds
Prodrugs

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