Abstract
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.
MeSH terms
-
Aldehydes / chemistry*
-
Aldehydes / metabolism
-
Anthracyclines / pharmacology
-
Antibiotics, Antineoplastic / chemistry
-
Antibiotics, Antineoplastic / pharmacology
-
Antineoplastic Agents / pharmacology*
-
Chemistry, Pharmaceutical / methods*
-
DNA Topoisomerases, Type II / chemistry
-
DNA Topoisomerases, Type II / metabolism*
-
Doxorubicin / chemistry*
-
Doxorubicin / pharmacology
-
Drug Design*
-
Drug Evaluation, Preclinical
-
Drug Screening Assays, Antitumor
-
Humans
-
K562 Cells
-
Magnetic Resonance Spectroscopy
-
Maleimides / chemistry*
-
Models, Chemical
-
Nitrogen / chemistry
Substances
-
Aldehydes
-
Anthracyclines
-
Antibiotics, Antineoplastic
-
Antineoplastic Agents
-
Maleimides
-
Doxorubicin
-
DNA Topoisomerases, Type II
-
Nitrogen