Daunorubicin analogs with

In other applications, Anne et al. used electrochemical reduction to synthesize new daunorubicin analogs. Kano et al. studied the electrochemical properties of Adriamycin adsorbed on a mercury electrode, while Konse et al. studied the electrochemical properties of Adriamycin adsorbed on pyrolyte graphite electrodes modified by phospholipid membranes. This latter work has relevance to the interaction of Adriamycin with cell membranes. 

Idarubicin is a semisynthetic anthracycline glycoside analog of daunorubicin and is approved for use in combination with cytarabine for induction therapy of acute myeloid leukemia. When combined with cytarabine, idarubicin appears to be more active than daunorubicin in producing complete remissions and in improving survival in patients with acute myelogenous leukemia. 

A second important and practical improvement is the use of a compound that blocks the efflux of the fluorescent substrate. The measurement of the ratio of fluorescent probe accumulating in the cell with and without a Pgp blocker makes the obtained data less dependent on a number of parameters that may cause variation between cells and samples. We have chosen to use the cyclosporin analog PSC 833 as Pgp inhibitor, which, at a concentration of 2 iM, completely blocks the Pgp-mediated efflux of probes such as daunorubicin or rhodamine 123 in cells with a clinically relevant Pgp content (6,11,14). In addition, we have chosen to measure the practically more convenient cellular accumulation of probe instead of cellular retention after an efflux period, although the latter is theoretically more sensitive (15). In our experience, the use of rhodamine 123 as Pgp probe, combined with PSC 833 as Pgp inhibitor, offers a sensitive and reproducible Pgp functional assay in AML. Although we prefer to use fresh cells, appropriately frozen and thawed cells can be used for this assay, as extensively discussed previously (4,14). 

With the clinical introduction of the 4-demethoxy analog of daunorubicin (idarubicin, Idamycin, Fig. 4-19) in 1991 another set of improvements were achieved. These include higher antileukemic activity, higher potency, and lower cardiotoxicity than the parent compound daunorubicin. The approved indication is acute myelogenous leukemia. 

Idarubicin is an anthracycUne, which is a DNA-intercalating analog of daunorubicin, which has an inhibitory effect nucleic acid synthesis and interacts with the enzyme topo-isomerase II. 

Idarubicin is an analog of daunorubicin. It is indicated for use in combination with cytara-bine (Ara-C) for induction therapy of acute myelogenous leukemia (AML). 

A different type of dimeric product was prepared by Wandless and his colleagues, who coupled taxol with daunorubicin to prepare analogs of the general structure 13.2.7, where X is one of several alkyl and aryl linker units. None of the dimeric compounds were as cytotoxic as the individual monomeric compounds 425). 

A series of experiments showed that substitution at the C4 position has a major effect on biological activity, with increased potency correlating with increased hydrcq)hobicity deoxy (idarubicin) > hydroxy (carminomycin series) > methoxy (daunorubicin, doxoiU bicin, and analogs) (176,177). A major finding was that chemically synthesized 4 deinethoxy analogs of daunorubicin and doxorubicin exhibited 25 to lOO fold ainl 65- to 200-fold increases in potency, respectively, over the parental molecules, with altered physicochemical properties (175,177,178). One of these, idarubicin, has recently been approved for chemotherapy use in the United States (Table 2). 

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