The design, synthesis, and evaluation of two universal doxorubicin-linkers: Preparation of conjugates that retain topoisomerase II activity

Two universal DOX-linkers were synthesized, which in turn allowed the parallel preparation of DOX conjugates that retain topoisomerase II activity. The design, synthesis, and evaluation of two N-alkylmaleimide aldehydes have been achieved, which upon reductive alkylation with the C3′-amino group of...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2006, Vol.16 (1), p.104-107
Main Authors: Sun, Chengzao, Aspland, Simon E., Ballatore, Carlo, Castillo, Rosario, Smith, Amos B., Castellino, Angelo J.
Format: Article
Language:English
Subjects:
Aldehydes - chemistry
Aldehydes - metabolism
Anthracycline
Anthracyclines - pharmacology
Antibiotics, Antineoplastic - chemistry
Antibiotics, Antineoplastic - pharmacology
Antineoplastic Agents - pharmacology
Biological and medical sciences
Chemistry, Pharmaceutical - methods
Conjugate
DNA Topoisomerases, Type II - chemistry
DNA Topoisomerases, Type II - metabolism
Doxorubicin
Doxorubicin - chemistry
Doxorubicin - pharmacology
Drug Design
Drug Evaluation, Preclinical
Drug Screening Assays, Antitumor
Humans
K562 Cells
Magnetic Resonance Spectroscopy
Maleimide
Maleimides - chemistry
Medical sciences
Miscellaneous
Models, Chemical
Nitrogen - chemistry
Pharmacology. Drug treatments
Topoisomerase II
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Summary:Two universal DOX-linkers were synthesized, which in turn allowed the parallel preparation of DOX conjugates that retain topoisomerase II activity. The design, synthesis, and evaluation of two N-alkylmaleimide aldehydes have been achieved, which upon reductive alkylation with the C3′-amino group of doxorubicin (DOX) permits the preparation of DOX conjugates via Michael addition of thiol-containing vectors. This method enables the mild, facile, and high-throughput preparation of DOX conjugates that retain the basic C3′-nitrogen, a pre-requisite for topoisomerase II inhibition. Seven DOX–amino acid conjugates were prepared, each displaying similar inhibitory activity as the parent drug.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2005.09.046