Design and tumor targeting of anthracyclines able to overcome multidrug resistance: A double-advantage approach

Interaction of doxorubicin and its derivatives with DNA: Elucidation by resonance Raman and surface-enhanced resonance Raman spectroscopy

“…9,10 The efficiency and toxicity of these derivatives depend to The antitumor activity of the widely used anthraa great extent on their pattern of peripheral subcycline antibiotics [1][2][3] has been attributed to the stitution; even slight changes in substituents formation of intercalation complexes between the within the anthracycline drug structure have anthracycline antibiotics and DNA base pairs. 4,5 been shown to cause significant changes in the The intercalation of antitumor drugs is underantitumor activity.…”

Synthesis of the Sugar Moieties

“…Relative stability of the glycosidic bond is also recognized as a pos-sible determinant of clinical efficacy. It has been pointed out that placement of properly configured (axial) halogen atom at C-2 exerts multiple desirable effects, reducing basicity, enhancing lipophilicity, and increasing stability of the glycosidic bond towards chemical or enzymatic hydrolysis [13,33,98].…”

“…It is noteworthy that both monosaccharide moieties in sabarubicin belong to the α-L-2,6-dideoxypyranose category. Prior to publication of these results, some novel ideas concerning structure-activity relationships of anthracyclines have been advanced by Priebe, who stressed the role of C-3 center basicity and demonstrated that exchange of daunosamine C-3 amino function for the hydroxyl group does not abolish anticancer activity [33,97,98]. Typical structural modifications of L-2,6-dideoxyhexoses, carried out with the intention of replacing daunosamine, include halogenation.…”

“…It turned out that the presence of the C-3 basic center (like the NH 2 group of Dau) is not necessary for anticancer activity. This is exemplified by synthetic annamycin, a new drug candidate in advanced clinical trials, which has 2,6-dideoxy-2-iodo-L-talo-pyranose in place of L-daunosamine [33][34][35]. Although in this case the binding energy with DNA is lower than for daunomycin, annamycin (being more lipophilic and having much lower affinity to Pgp efflux pump) offers some advantage in treatment of MDR leukemias, particularly when applied in liposomal formulation [36,37].…”

Modifying the Sugar Moieties of Daunorubicin Overcomes P-gp-Mediated Multidrug Resistance

“…In addition, C'-3-NH2 group has been reported to be critical for P-gp binding [14,29]. Therefore, we hypothesize that replacement of C'-3-NH2 group with an azido group or large triazole group may be able to change both the binding conformation and/or abolish the hydrogen bond between DNR and MsbA.…”