- Anti-cancer drug aldehyde conjugate drugs with enhanced cytotoxicity compounds, compositions and methods
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Monomeric and dimeric anti-cancer drug aldehyde conjugate compounds and pharmaceutically acceptable salts thereof. Specifically, monomeric and dimeric aldehyde conjugates of 1-2, dihetero-substituted anti-cancer drugs, including monomeric and dimeric aldehyde conjugates of anthracyclines, are provided. Also provided are pro-drugs which, after administration, release monomeric aldehyde conjugates. Further provided are pharmaceutical and therapeutic compositions containing anti-cancer drug aldehyde conjugates and methods of treating cancer using the aldehyde conjugates.
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Page/Page column 19; 20; 21; 22; 61
(2010/02/05)
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- Epidoxoform: A hydrolytically more stable anthracycline-formaldehyde conjugate toxic to resistant tumor cells
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The recent discovery that the formaldehyde conjugates of doxorubicin and daunorubicin, Doxoform and Daunoform, are cytotoxic to resistant human breast cancer cells prompted the search for hydrolytically more stable anthracycline-formaldehyde conjugates. Doxoform and Daunoform consist of two molecules of the parent drug bound together with three methylene groups, two forming oxazolidine rings and one binding the oxazolidines together at their 3'amino nitrogens. The 4'-epimer of doxorubicin, epidoxorubicin, reacts with formaldehyde at its amino alcohol functionality to produce a conjugate, Epidoxoform, in 59% yield whose structure consists of two molecules of epidoxorubicin bound together with three methylene groups in a 1,6-diaza- 4,9-dioxabicyclo[4.4.1]undecane ring system. The structure was established from spectroscopic data and is consistent with products from reaction of simpler vicinal trans-amino alcohols with formaldehyde. Epidoxoforrn hydrolyzes at pH 7.3 to an equilibrium mixture with dimeric and monomeric epidoxorubicin-formaldehyde conjugates without release of formaldehyde or epidoxorubicin. The hydrolysis follows the rate law (A mutually implies B) mutually implies C + D where A (Epidoxoform) is in rapid equilibrium with B, and B is in slow equilibrium with C and D. The forward rate constant for A/B going to C+D gives a half-life of approximately 2 h at 37 °C. At equilibrium the mixture is stable for at least 2 days. At pH 6.0, hydrolysis proceeds with first-order kinetics to epidoxorubicin and formaldehyde with a half- life of 15 min at 37 °C. Epidoxoform and epidoxorubicin plus formaldehyde react with the self-complementary DNA octamer (GC)4 to yield five drug-DNA adducts which have structures analogous to the doxorubicin-DNA adducts from reaction of Doxoform with (GC)4. Epidoxoform is 3-fold more toxic to MCF-7 human breast cancer cells and greater than 120-fold more toxic to MCF-7/ADR resistant cells than epidoxorubicin. Epidoxoform in equilibrium with its hydrolysis products is greater than 25-fold more toxic to resistant cells with respect to epidoxorubicin.
- Taatjes, Dylan J.,Fenick, David J.,Koch, Tad H.
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p. 1306 - 1314
(2007/10/03)
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- An EPR Study of a Model System for the Initial Oxygen Activation Process Caused by Adriamycin-Iron System
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1,4-Dihydroxyanthraquinone, a model compound for Adriamycin, is reduced by Fe2+-ADP complex to generate semiquinone, while by Fe2+-phosphate complex to hydroquinone.The difference is explained in terms of the higher redox potential of the latter reducing agent.Similar reduction reactions were observed in the case of the drug.
- Tachibana, Masahiko,Tero-Kubota, Shozo,Iwaizumi, Masamoto
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p. 933 - 936
(2007/10/02)
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