The design, synthesis, and evaluation of two universal doxorubicin-linkers: preparation of 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.
Sun
Chengzao
C
Acidophil, LLC, Suite 250, 10835 Road to the Cure, San Diego, CA 92121, USA. csun@acidophil.com
Aspland
Simon E
SE
Ballatore
Carlo
C
Castillo
Rosario
R
Smith
Amos B
AB
Castellino
Angelo J
AJ
D000447:Aldehydes / Q000737:chemistry* / Q000378:metabolism; D018943:Anthracyclines / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism*; D004317:Doxorubicin / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020014:K562 Cells; D009682:Magnetic Resonance Spectroscopy; D008301:Maleimides / Q000737:chemistry*; D008956:Models, Chemical; D009584:Nitrogen / Q000737:chemistry
D000447:Aldehydes; D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D008301:Maleimides; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II; D009584:Nitrogen