Syntheses and Biological Activities of Disaccharide Daunorubicins

Zhang, Guisheng; Fang, Lanyan; Zhu, Lizhi; Aimiuwu, Josephine; Shen, Jie; Cheng, Hao; Muller, Mark T.; Lee, Gun Eui; Sun, Duxin; Wang, Peng George

doi:10.1021/jm050144u

Cited by 43 publications

(32 citation statements)

References 36 publications

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“…These analogs were tested to overcome P-gp binding by molecular modeling, cytotoxicity, and P-gp inhibition. Indeed, we have generated several lead compounds that maintain the anticancer activity and avert P-gp binding [23]. In addition, our results have also been confirmed by previous studies.…”

Section: Discussionsupporting

confidence: 86%

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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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Section: Discussionsupporting

confidence: 86%

“…It has been shown that modifying the sugar moiety in daunorubicin can change the anticancer efficacy of anthracyclines [21][22][23]. In addition, the 3'-amino group in the sugar may also play a role for P-gp recognition [24,25].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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“…Hence, there have been intensive attempts to develop analogs with an improved therapeutic index. In the last 50 y, most modifications have been focused on the sugar moiety, providing a successful drug, epirubicin, as well as several promising candidates under clinical trials (1,2). In contrast, only a few analogs have been generated by altering the anthracycline core, most of which were obtained by chemical synthesis.…”

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confidence: 99%

Hydroxyl regioisomerization of anthracycline catalyzed by a four-enzyme cascade

Zhang

Gong

Zhou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Ranking among the most effective anticancer drugs, anthracyclines represent an important family of aromatic polyketides generated by type II polyketide synthases (PKSs). After formation of polyketide cores, the post-PKS tailoring modifications endow the scaffold with various structural diversities and biological activities. Here we demonstrate an unprecedented four-enzyme-participated hydroxyl regioisomerization process involved in the biosynthesis of kosinostatin. First, KstA15 and KstA16 function together to catalyze a cryptic hydroxylation of the 4-hydroxyl-anthraquinone core, yielding a 1,4-dihydroxyl product, which undergoes a chemically challenging asymmetric reduction-dearomatization subsequently acted by KstA11; then, KstA10 catalyzes a region-specific reduction concomitant with dehydration to afford the 1-hydroxyl anthraquinone. Remarkably, the shunt product identifications of both hydroxylation and reduction-dehydration reactions, the crystal structure of KstA11 with bound substrate and cofactor, and isotope incorporation experiments reveal mechanistic insights into the redox dearomatization and rearomatization steps. These findings provide a distinguished tailoring paradigm for type II PKS engineering.biosynthesis | C-4 deoxyanthracycline | two-component hydroxylase | NmrA-like short-chain dehydrogenase | dehydroxylation

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“…Some 6-deoxy sugars form structural components of a variety of natural products, including antibiotics, 7,8) antifungals, 9) and anticancer agents. [10][11][12] These sugars generally participate in the molecular recognition of cellular targets by active compounds. 13) 6-Deoxy-L-galactose (L-fucose) is known as a major component of fucoidan from brown seaweed.…”

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Enzymatic production of three 6-deoxy-aldohexoses from l-rhamnose

Shompoosang

Yoshihara

Uechi

et al. 2014

Bioscience, Biotechnology, and Biochemistry

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6-Deoxy-l-glucose, 6-deoxy-l-altrose, and 6-deoxy-l-allose were produced from l-rhamnose with an immobilized enzyme that was partially purified (IE) and an immobilized Escherichia coli recombinant treated with toluene (TT). 6-Deoxy-l-psicose was produced from l-rhamnose by a combination of l-rhamnose isomerase (TT-PsLRhI) and d-tagatose 3-epimerase (TT-PcDTE). The purified 6-deoxy-l-psicose was isomerized to 6-deoxy-l-altrose and 6-deoxy-l-allose with l-arabinose isomerase (TT-EaLAI) and l-ribose isomerase (TT-AcLRI), respectively, and then was epimerized to l-rhamnulose with immobilized d-tagatose 3-epimerase (IE-PcDTE). Following purification, l-rhamnulose was converted to 6-deoxy-l-glucose with d-arabinose isomerase (TT-BpDAI). The equilibrium ratios of 6-deoxy-l-psicose:6-deoxy-l-altrose, 6-deoxy-l-psicose:6-deoxy-l-allose, and l-rhamnulose:6-deoxy-l-glucose were 60:40, 40:60, and 27:73, respectively. The production yields of 6-deoxy-l-glucose, 6-deoxy-l-altrose, and 6-deoxy-l-allose from l-rhamnose were 5.4, 14.6, and 25.1%, respectively. These results indicate that the aldose isomerases used in this study acted on 6-deoxy aldohexoses.

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Syntheses and Biological Activities of Disaccharide Daunorubicins

Cited by 43 publications

References 36 publications

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

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

Hydroxyl regioisomerization of anthracycline catalyzed by a four-enzyme cascade

Enzymatic production of three 6-deoxy-aldohexoses from l-rhamnose

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