Configurational requirements of the sugar moiety for the pharmacological activity of anthracycline disaccharides

Arcamone, Federico; Animati, Fabio; Bigioni, Mario; Capranico, Giovanni; Caserini, Claudia; Cipollone, Amalia; Cesare, Michelandrea De; Ettorre, Alessandro; Guano, Fulvio; Manzini, Stefano; Monteagudo, Edith; Pratesi, Graziella; Salvatore, Carmela; Supino, Rosanna; Zunino, Franco

doi:10.1016/s0006-2952(99)00025-8

Cited by 32 publications

(22 citation statements)

References 9 publications

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“…Structure-activity studies in experimental solid tumors showed that replacing daunosamine with a disaccharide moiety dramatically reduced the cytotoxic potency of the drugs in the 4-methoxy series. In contrast, in the 4-demethoxy series, the C-4 axial configuration (but not the equatorial configuration) conferred a cytotoxic potency and antitumor activity severalfold higher than that of DNR or IDA and virtually comparable with that of DOX (Arcamone et al, 1999). The configuration also influenced the ability of disaccharide anthracyclines to stimulate topoisomerase II␣-mediated DNA cleavage.…”

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confidence: 93%

“…Only glycosides with the axial orientation proved to be active, but methoxy-substituted analogs were significantly less effective than demethoxy analogs. On balance, it became apparent that the axial orientation governed optimal interactions of disaccharide anthracyclines with the DNA-topoisomerase II complex only in the absence of the methoxy group (Arcamone et al, 1999). …”

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confidence: 99%

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Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

et al. 2004

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confidence: 93%

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confidence: 99%

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

et al. 2004

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“…Idarubicin differs from doxorubicin by lacking the methoxy group in the chromophore, and has an epimeric hydroxyl group in the sugar [204]. This compound is comparatively lipophilic, resulting in increased cellular uptake (the cellular concentrations exceed 100 times those achieved in plasma) [205] and strong serum protein binding [206]. The agent undergoes extensive extrahepatic metabolism to the 13-dihydro analog [207].…”

Section: Epirubicin Epirubicin (Ellence (19) a C4mentioning

confidence: 99%

“…15 for a schematic illustration of the proposed biosynthetic pathway leading to anthracyclines. Recent Developments and Things to Come Reviews of this topic are available in Refs [205,212,224].…”

Section: Valrubicin Valrubicinmentioning

confidence: 99%

Natural Products as Cytotoxic Agents

Cutler

2010

Burger's Medicinal Chemistry and Drug Discovery

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In the first decade of the twenty‐first century, the occurrence of cancers has increased not only in First World countries but also in those countries considered to have a lower standard of living, according to a world cancer report issued in 2008 for the IARC Nonserial Publication by Boyle and Levin. So widespread is cancer, in its various forms, that most adults have either had family members or had friends who have been afflicted by the disease. Projected figures for cancers indicate, in the aforementioned publication, that 12 million cancer cases were diagnosed in 2008 alone and that the number of cancer victims has doubled since 1978. Coupled to the psychological impact that a diagnosis has on an individual is the cost of treatment that must also be considered. Again, according to the National Cancer Institute (December 2008) these costs are estimated to be US$147 billion by 2020. An article, published in USA Today , claims that new cancer cases in 2008 were projected to be 40,480. And the cost for elderly Medicare patients will be US$21.1 billion for 5 years of treatment for the period 2004–2009. Sadly, one in eight patients with advanced stages of cancer will turn down the offer of recommended care because of costs. While cases may have been misdiagnosed in the twentieth century, the sophisticated techniques available today give a clearer graph of the incidence of the disease. With advanced diagnostics, there has been a concomitant advance in anticancer chemotherapy.

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“…Previous work [18,19] shows not only that a structure activity relationship exists between the sugar moiety and drug activity, but that the sugar plays a crucial role in the effectiveness of the drug. However, this relationship is neither clear, nor well understood.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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Anthracyclines are widely used in patients for anticancer activity. However, one of the limitations for their clinical use is P-gp-mediated drug resistance in cancer therapy.We hypothesize that modified anthracyclines will retain their anticancer activity, avert Pgp binding, and thus overcome P-gp-mediated drug resistance. Twenty-five daunorubicin analogues were synthesized with slight structure modifications in sugar moieties.Molecular docking, cytotoxicity, and P-gp inhibition assays in drug-resistant leukemia cells (K562/Dox) were used to identify several candidates that avert binding to multidrug-resistant protein (MsbA) and overcome drug resistance. Molecular docking showed that daunorubicin bound to the cavity between the intracellular domain (ICD) and nucleoside binding domain (NBD) of MsbA, which might be the "entry site" for the transport of its substrate. The molecular docking accurately predicted the substrates of multidrug-resistant protein. Several aspects are important for daunorubicin analogue binding to MsbA: (1) the substitution pattern and stereochemistry of the tetracyclic ring and sugar moiety; (2) the hydrogen bond donor or acceptor capability of the substituent at C`-3 and C`-4. Molecular docking, cytotoxicity, and P-gp inhibition assays identified ADNR, ADNR-1, and ADNR-3 for averting P-gp binding and overcoming drug resistance. The replacement of C`-3-NH2 with azido group in daunorubicin not only abolishes the hydrogen bond between the sugar moiety and MsbA but also completely changes the overall binding conformation, and thus averts the binding to MsbA.Cytotoxicity assays confirmed that these compounds showed high sensitivity against drug-resistant cancer cells (K562/Dox) with P-gp over-expression. P-gp inhibition assay indeed confirms that these appropriately modified compounds avert P-gp binding and thus overcome P-gp-mediated drug resistance. Robert F. BattistiPage 3 of 48 This proposal and subsequent experiments will seek to determine the effectiveness of new daunorubicin derivatives in averting multidrug resistance. Additionally, we will ascertain the mechanism of action of new anthracycline derivatives. MDR is one of the major threats to successful anti-neoplastic chemotherapy. MDR is often mediated by Pgp, which exports anthracyclines and other drugs from the cell. An anthracycline which can overcome P-gp related MDR would greatly improve chemotherapy success and enhance the overall and cancer-free survival rates of chemotherapy patients.

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Configurational requirements of the sugar moiety for the pharmacological activity of anthracycline disaccharides

Cited by 32 publications

References 9 publications

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

Natural Products as Cytotoxic Agents

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

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