title: The design, synthesis, and evaluation of two universal doxorubicin-linkers: preparation of conjugates that retain topoisomerase II activity.
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.
authors.affiliation: Acidophil, LLC, Suite 250, 10835 Road to the Cure, San Diego, CA 92121, USA. csun@acidophil.com
authors.forename: Chengzao
authors.initials: C
authors.lastname: Sun
authors.forename: Simon E
authors.initials: SE
authors.lastname: Aspland
authors.forename: Carlo
authors.initials: C
authors.lastname: Ballatore
authors.forename: Rosario
authors.initials: R
authors.lastname: Castillo
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.forename: Angelo J
authors.initials: AJ
authors.lastname: Castellino
mesh_terms: 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
chemical_list: D000447:Aldehydes; D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D008301:Maleimides; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II; D009584:Nitrogen