83310-79-6Relevant academic research and scientific papers
Synthetic (N, N-Dimethyl)doxorubicin Glycosyl Diastereomers to Dissect Modes of Action of Anthracycline Anticancer Drugs
Wander, Dennis P. A.,Van Der Zanden, Sabina Y.,Vriends, Merijn B. L.,Van Veen, Branca C.,Vlaming, Joey G. C.,Bruyning, Thomas,Hansen, Thomas,Van Der Marel, Gijsbert A.,Overkleeft, Herman S.,Neefjes, Jacques J. C.,Codée, Jeroen D. C.
, p. 5757 - 5770 (2021/05/04)
Anthracyclines are effective drugs in the treatment of various cancers, but their use comes with severe side effects. The archetypal anthracycline drug, doxorubicin, displays two molecular modes of action: DNA double-strand break formation (through topoisomerase IIα poisoning) and chromatin damage (via eviction of histones). These biological activities can be modulated and toxic side effects can be reduced by separating these two modes of action through alteration of the aminoglycoside moiety of doxorubicin. We herein report on the design, synthesis, and evaluation of a coherent set of configurational doxorubicin analogues featuring all possible stereoisomers of the 1,2-amino-alcohol characteristic for the doxorubicin 3-amino-2,3-dideoxyfucoside, each in nonsubstituted and N,N-dimethylated forms. The set of doxorubicin analogues was synthesized using appropriately protected 2,3,6-dideoxy-3-amino glycosyl donors, equipped with an alkynylbenzoate anomeric leaving group, and the doxorubicin aglycon acceptor. The majority of these glycosylations proceeded in a highly stereoselective manner to provide the desired axial α-linkage. We show that both stereochemistry of the 3-amine carbon and N-substitution state are critical for anthracycline cytotoxicity and generally improve cellular uptake. N,N-Dimethylepirubicin is identified as the most potent anthracycline that does not induce DNA damage while remaining cytotoxic.
NEW DERIVATIVES OF EPIRUBICIN, THEIR MEDICINAL APPLICATION AND PHARMACEUTICALY ACCEPTABLE FORMS OF DRUGS
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Page/Page column 9, (2008/06/13)
The present invention relates to novel derivatives of epirubicin, pharmaceutical composition comprising these derivatives, and uses of epirubicin and its derivative for treating HCV.
NEW DERIVATIVES OF EPIRUBICIN, THEIR MEDICINAL APPLICATION AND PHARMACEUTICALS ACCEPTABLE FORMS OF DRUGS
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Page/Page column 5, (2010/11/27)
New derivatives of 7-O-(3'amino-2',3',6'-trideoxy-α,β,L- arabinoheksopiranosyl)-adriamycinone (epirubicin) presented at Formula 1, where R1, R2, R3 and R4 are the same and indicate hydrogen atom, alkyl group, isopropyl, alkenyl or alkinyl, especially acetyl or alkylcarbonyl group, all with alkyl chain containing 1 to 5 carbon atoms or dimethylformamidinyl group, at which if R1 and R4 indicate simultaneously hydrogen atom, then R3 indicates dimethylformamidinyl group. According to the invention, medical application of novel epirubicin derivatives is characterized by the fact, that derivatives presented at Formula 1 are used as active substances potently inhibiting hepatitis C virus (HCV) replication. Pharmaceutically acceptable form of the drug against hepatitis C virus (HCV) infections as active substance contains epirubicin derivatives presented at Formula (1), where R1, R2, R3 and R4 have above mentioned indications, eventually in the form of hydrochloride. According to invention, form of the drug ensures simultaneously low toxicity in Huh 7 and PBMC cells, therapeutic index (TI) better than for epirubicin, and lower than for epirubicin acute toxicity in vivo.
