Self-Immolative Anthracycline Prodrugs for Suicide Gene Therapy
- 11 June 1999
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 42 (13) , 2485-2489
- https://doi.org/10.1021/jm980696v
Abstract
Four novel potential prodrugs derived from daunorubicin (8, 10) and doxorubicin (12, 14) were designed and synthesized. They are self-immolative prodrugs for suicide gene therapy activation by the enzyme carboxypeptidase G2 (CPG2) subsequently releasing the corresponding anthracyclines, by a 1,6-elimination mechanism. A mammary carcinoma cell line (MDA MB 361) was engineered to express CPG2 intracellularly (CPG2*) or extracellularly, tethered to the outer cell membrane (stCPG2(Q)3). The prodrugs derived from doxorubicin showed prodrug/drug cytotoxicity differentials of 21-fold (compound 12) and 23-fold (compound 14). Prodrug 12 underwent an 11-fold activation when assayed in the cell line expressing externally surface-tethered CPG2.Keywords
This publication has 22 references indexed in Scilit:
- Self-Immolative Nitrogen Mustard Prodrugs for Suicide Gene TherapyJournal of Medicinal Chemistry, 1998
- Gene-Directed Enzyme Prodrug TherapyBioconjugate Chemistry, 1998
- A cell surface tethered enzyme improves efficiency in gene-directed enzyme prodrug therapyNature Biotechnology, 1997
- New Mustard Prodrugs for Antibody-Directed Enzyme Prodrug Therapy: Alternatives to the Amide LinkJournal of Medicinal Chemistry, 1996
- Optimization of Alkylating Agent Prodrugs Derived from Phenol and Aniline Mustards: A New Clinical Candidate Prodrug (ZD2767) for Antibody-Directed Enzyme Prodrug TherapyJournal of Medicinal Chemistry, 1995
- Expression of the bacterial nitroreductase enzyme in mammalian cells renders them selectively sensitive to killing by the prodrug CB1954European Journal Of Cancer, 1995
- Synthesis of novel targeted pro-prodrugs of anthracyclines potentially activated by a monoclonal antibody galactosidase conjugate (part 1)Bioorganic & Medicinal Chemistry Letters, 1992
- Novel prodrugs which are activated to cytotoxic alkylating agents by carboxypeptidase G2Journal of Medicinal Chemistry, 1990
- Activation of prodrugs by antibody‐enzyme conjugates: a new approach to cancer therapyThe FASEB Journal, 1990
- Anthracycline analogs The past, present, and futureCancer Chemotherapy and Pharmacology, 1986