Syntheses and biological activities of 3'-azido disaccharide analogues of daunorubicin against drug-resistant leukemia

Journal of Medicinal Chemistry
Guisheng ZhangDuxin Sun

Abstract

Anthracyclines, such as daunorubicin (DNR) and doxorubicin (Dox), are widely used for cancer therapy but are limited by drug resistance and cardiotoxicity. To overcome drug resistance, we synthesized a novel class of disaccharide analogues of DNR against drug-resistant leukemia. In these disaccharide analogues (1-6) the first (inner) sugar in the carbohydrate chain is a 3-azido-2,3,6-trideoxy-L-lyxo-alpha-hexopyranose; the second (outer) sugars that are linked via alpha(1-->4) to the first sugar are a series of uncommon sugars. Their cytotoxicities were examined in drug-sensitive leukemia cells K562 and doxorubicin-resistant K562/Dox cells by MTS assay. In drug-sensitive cells, compounds 1-6 were found to be active against leukemia K562 cells with IC50 in the nanomolar range (200-1100 nM), while compounds 2-5 with 2,6-dideoxy sugars showed better activity than compounds 1 and 6 with 2,3,6-trideoxy sugars. In doxorubicin-resistant K562/Dox cells, compounds 1, 3, and 5 exhibited much better activities (with IC50 between 0.29 and 2.0 microM) than DNR (with IC50 > 5 microM). Compound 3 emerged as the most active compound, showing at least 17-fold higher activity against drug-resistant cells than parent compound DNR. The IC50 values...Continue Reading

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Citations

Nov 1, 2006·Expert Opinion on Drug Discovery·Janos Nadas, Duxin Sun
Jun 2, 2007·Expert Opinion on Drug Metabolism & Toxicology·Donal P McLornanDaniel B Longley
Feb 2, 2008·The Journal of Pharmacy and Pharmacology·Song-Qiang XieBian-Sheng Ji
Dec 20, 2011·Veterinary Parasitology·Juliana de Araujo PortesSergio Henrique Seabra
Aug 26, 2016·Beilstein Journal of Organic Chemistry·Mei-Yuan HsuCheng-Chung Wang
Jan 10, 2009·The Journal of Organic Chemistry·Jianjun Zhang, Cheng-Wei Tom Chang
Jul 14, 2011·ACS Medicinal Chemistry Letters·Elinor Breiner-GoldsteinMicha Fridman
Nov 15, 2018·Organic Letters·Manas Jana, Clay S Bennett
Jun 29, 2018·Chemical Reviews·Clay S Bennett, M Carmen Galan
Oct 7, 2006·Carbohydrate Research·Derek Horton, Anakshi Khare

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