CommentaryRole of the sugar moiety in the pharmacological activity of anthracyclines: development of a novel series of disaccharide analogs
Introduction
Anthracycline antibiotics represent a major class of antitumor agents, with a wide spectrum of activity in human cancer [1]. In spite of intense efforts in analog synthesis, the most effective agent of this class remains doxorubicin. Like other DNA-intercalating agents effective as antitumor compounds, anthracyclines exert their cytotoxic activity by interfering with the function of DNA topoisomerase II, an essential nuclear enzyme that regulates DNA topology during multiple DNA processes (replication, transcription, recombination) [2]. The inhibitory properties of anthracyclines are not simply related to the DNA–drug intercalation. The recognition that DNA topoisomerase II is the primary target of anthracyclines provides a more rational basis for the design of effective analogs. The topoisomerase II inhibitors form a DNA–drug–enzyme complex (ternary complex) by stabilizing an intermediate of the enzyme reaction (the so-called cleavable complex) in which DNA strands are broken and the enzyme subunits are covalently linked to the broken DNA strands. DNA binding and intercalation are necessary but not sufficient conditions for optimal activity of anthracyclines [3]. Indeed, the external (non-intercalating) moieties of the anthracyclines (Fig. 1 ) appear crucial for poisoning topoisomerase activity and therapeutic efficacy [4], [5]. For example, in spite of a DNA-binding affinity comparable to that of doxorubicin, 9-deoxy-doxorubicin is characterized by a substantially reduced ability to stimulate topoisomerase-mediated DNA cleavage and a markedly reduced cytotoxic potency [6], [7]. Thus, although DNA intercalation may have a relevant role in the mechanism of drug interaction in the ternary complex, external interactions involving the sugar moiety and cyclohexene ring A appear to be more critical than the strength of the DNA–drug interaction. In particular, the sugar moiety is recognized to be critical for the activity of anthracyclines as topoisomerase poisons. The recent development of a novel series of anthracycline disaccharides provides further insights into the role of the sugar moiety [8], [9]. A doxorubicin analog of this series exhibits an improved profile of antitumor activity as compared with doxorubicin and could represent the progenitor of a new generation of promising anthracyclines [10], [11].
Section snippets
Role of the sugar moiety
Original studies on structure–activity relationship have shown an important role for the structure and stereochemistry of the aminosugar (daunosamine) on the pharmacological activity of anthracyclines related to doxorubicin [12], [13], [14], [15]. These studies implicated the basic amino group at C-3′ as a determinant of the stabilization of drug intercalation into DNA [16]. This interpretation was based on the evidence that the blocking of the amino function, as in the amide derivatives,
Rationale for the development of disaccharide analogs
The interest in modifying the sugar moiety is spawned by evidence that minor groove binders are characterized by sequence-recognizing properties [20], [22]. In an attempt to enhance the recognition potential of the sugar in the minor groove, the 4′-position appears suitable for introduction of a bulky substituent (e.g. additional sugar residues). Several anthracycline glycosides containing a disaccharide or trisaccharide chain have been described [23], [24]. A structural feature common to
Influence of orientation of the second sugar on biological activity of disaccharide analogs
Detailed structure–activity studies performed with disaccharide analogs have documented striking configurational requirements of the sugar moiety for their biological activity [8], [9]. Among daunorubicin analogs (Fig. 2 , compounds 1 and 2), the introduction of a second sugar residue dramatically reduces the cytotoxic potency. This effect could be ascribed, at least in part, to a reduction of intracellular drug accumulation as a consequence of increased hydrophilicity. In contrast, when the
Conclusions
The most relevant pharmacological feature of the idarubicin disaccharides is the ability of the analog with the optimal (axial) orientation of the second sugar to significantly inhibit the growth of human solid tumor xenografts [8]. The antitumor efficacy of the disaccharide analog is comparable to that of doxorubicin. The activity of a daunorubicin-related analog against solid tumors is a somewhat unexpected feature in anthracyclines lacking the 14-hydroxy group. Indeed, the structurally
Acknowledgements
This work was partially supported by the Associazione Italiana per la Ricerca sul Cancro, Milan, and by the Ministero della Sanita’, Roma, Italy.
References (37)
- et al.
Configurational requirements of the sugar moiety for the pharmacological activity of anthracycline disaccharides
Biochem Pharmacol
(1999) - et al.
Changes of activity of daunorubicin, adriamycin and stereoisomers following the introduction of removal of hydroxyl groups in the amino sugar moiety
Chem Biol Interact
(1977) - et al.
The interaction of adriamycin and its β anomer with DNA
Biochim Biophys Acta
(1977) - et al.
Interaction of daunomycin and its derivatives with DNA
Biochim Biophys Acta
(1972) - et al.
A protein-mediated mechanism for the DNA sequence-specific action of topoisomerase II poisons
Trends Pharmacol Sci
(1997) - et al.
New developments in antitumor anthracyclines
Pharmacol Ther
(1997) Molecular pharmacology of anthracycline antitumor antibiotics
- et al.
Conformational analysis of 4-demethoxy-7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-l-lyxo-hexopyranosyl)-α-l-lyxo-hexopyranosyl] adriamycinone, the first doxorubicin disaccharide analogue to be reported
Carbohydr Res
(1997) The anthracyclineswill we ever find a better doxorubicin?
Semin Oncol
(1992)- et al.
DNA topoisomerasesessential enzymes and lethal targets
Annu Rev Pharmacol Toxicol
(1994)
DNA topoisomerase II as the primary target of anti-tumor anthracyclines
Anticancer Drug Des
Biochemical and pharmacological activity of novel 8-fluoroanthracyclinesinfluence of stereochemistry and conformation
Mol Pharmacol
Influence of structural modifications at the 3′ and 4′ positions of doxorubicin on the drug ability to trap topoisomerase II and to overcome multidrug resistance
Mol Pharmacol
Role of DNA breakage in cytotoxicity of doxorubicin, 9-deoxydoxorubicin, and 4-demethyl-6-deoxydoxorubicin in murine leukemia P388 cells
Cancer Res
Change of the sequence specificity of daunorubicin-stimulated topoisomerase II DNA cleavage by epimerization of the amino group of the sugar moiety
Cancer Res
Topoisomerase poisoning activity of novel disaccharide anthracyclines
Mol Pharmacol
Doxorubicin disaccharide analogueapoptosis-related improvement of efficacy in vivo
J Natl Cancer Inst
Improved efficacy and enlarged spectrum of activity of a novel anthracycline disaccharide analogue of doxorubicin against human tumor xenografts
Clin Cancer Res
Cited by (70)
Topoisomerase II inhibitors design: Early studies and new perspectives
2023, Bioorganic ChemistryRecent developments in the identification and biosynthesis of antitumor drugs derived from microorganisms
2022, Engineering MicrobiologyPathway engineering of anthracyclines: Blazing trails in natural product glycodiversification
2020, Journal of Organic ChemistryRegioselective glycosylation of novobiocin alters activity
2017, Carbohydrate ResearchCitation Excerpt :Glycosylation modifies antimicrobial agent pharmacokinetic parameters such as solubility, membrane transport, pharmacodynamics, mechanism and potency [8]. The sugar residues can increase or decrease potency [9,10] either by being directly involved in the binding process [11,12] or by being essential for antimicrobial activity [13]. Novobiocin is a member of the aminocoumarin family and acts as a bacterial DNA synthesis inhibitor by binding to the B subunit of the DNA gyrase [14].
Structural modifications in the sugar moiety as a key to improving the anticancer effectiveness of doxorubicin
2017, Life SciencesCitation Excerpt :Experimental data show that anthracyclines stabilise a DNA–TOP II complex, hindering DNA strand relegation and enhancing DNA breaks level [30]. From the model of DNA–drug complex, the carbohydrate moiety appears in the DNA minor groove [31,32]. As the 3-NH2 group of daunosamine is important for non-covalent [33] and covalent interactions [34,35] with DNA, these modifications might change the properties of the compound.
Systematic comparison of the functional physico-chemical characteristics and biocidal activity of microbial derived biosurfactants on blood-derived and breast cancer cells
2016, Journal of Colloid and Interface ScienceCitation Excerpt :Dose-response curves showed that DOX had an IC50 of 11.12, 8.35 and 4.60 μg/ml on MCF-7 cells after 24-72 h. THP-1 showed greater sensitivity to DOX compared to the four BSs with IC50 values of 15.68, 6.48 and 2.95 μg/ml after 24, 48 and 72 h respectively. Structure-activity relationships have shown an important role for the structure and stereochemistry of the aminosugar (daunosamine) on the pharmacological activity of anthracyclines related to DOX based on the evidence that blocking the amino function resulted in a substantial loss of cytotoxic activity and reduced DNA-binding affinity [2,44]. Another important parameter to determine in cytotoxicity studies against cancer cell lines is the selectivity index (SI) which is the toxicity against cancerous cells of the compound of interest relative to normal cells [3], in this case BSs and DOX against THP-1 relative to HEK 293 and against MCF-7 relative to HEK 293.