New Natural, Semisynthetic and Synthetic Anthracycline Drugs

Brown, Jeffrey R.

doi:10.1007/978-1-349-06010-8_3

Cited by 11 publications

(4 citation statements)

References 138 publications

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“…The 11-unsubstituted anthracyclines (such as aclacinomycin and marcellomycin) by all indications bind to DNA in a fashion quite similar to daunomycin (83,85,100). The spectral and fluorometric changes are quite analogous, and are consistent with intercalation.…”

Section: Intercalation and Related Phenomenamentioning

confidence: 93%

“…With the biological evaluation of new anthracyclines, found to retain antitumor activity yet with diminished affinity for DNA, the situation is now much less certain (83), although it cannot be disputed that within the Adriamycin family an excellent correlation exists between antibiotic efficacy and DNA affinity. There are however anthracyclines that are active; and inhibit DNA and RNA synthesis near equally (Adriamycin), or RNA preferentially (aclacinomycin), or poorly inhibit either (menogarol).…”

Section: Intercalation and Related Phenomenamentioning

confidence: 99%

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A chemical perspective on the anthracycline antitumor antibiotics.

Abdella¹,

Fisher²

1985

Environ Health Perspect

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The anthracycline antitumor antibiotics occupy a central position in the chemotherapeutic control of cancer. They remain, however, antibiotics of the last resort and thus exhibit toxicity both to the neoplasm and to the host organism. As part of the continuing effort to dissociate the molecular processes responsible for these two separate toxicities, attention has been drawn to the intrinsic redox capacity of their tetrahydronapthacenedione aglycone moiety, and to the possible expression of this redox activity against those biomolecules for which anthracyclines have a particular affinity (polynucleotides and membranes). This review is a synopsis of the present trends and thoughts concerning this relationship, written from the point of view of the intrinsic chemical competence of the anthracyclines and their metabolites. While our ignorance is profound-the precise molecular locus of the antitumor expression of the anthracyclines remains unknown-there is now evidence that the relationship of the anthracyclines to the DNA (possibly requiring enzymatic cooperation) and to the membranes, with neither event requiring redox chemistry, may comprise the core of the antitumor effects. The adventitious expression of the redox activity under either aerobic conditions (in which circumstances molecular oxygen is reduced) or anaerobic conditions (in which circumstances potentially reactive aglycone tautomers are obtained) is therefore thought to contribute more strongly to the host toxicity. Yet little remains proven, and the understanding of the intrinsic chemical competence can do little more than lightly define the boundaries within which are found these and numerous other working hypotheses.

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Section: Intercalation and Related Phenomenamentioning

confidence: 93%

Section: Intercalation and Related Phenomenamentioning

confidence: 99%

A chemical perspective on the anthracycline antitumor antibiotics.

Abdella¹,

Fisher²

1985

Environ Health Perspect

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“…Although indirect evidence from studies of structure-activity relationships suggests that DNA is the main target of the cytotoxic action of these drugs (2)(3)(4)(5)(6), the mechanism of antitumor activity still remains controversial (7). In a recent study of structure-activity relations (8), we reported that methylation of the hydroxyl groups at positions 6 or 11 of the B ring of the daunorubicin chromophore ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Biochemical and biological activity of the anthracycline analog, 4-demethyl-6-0-methyl-doxorubicin

Zunino

Barbieri²,

Bellini³

et al. 1986

Invest New Drugs

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The chromophore-modified derivative of doxorubicin, 4-demethyl-6-O-methyl-doxorubicin, has been tested for antitumor activity in a range of experimental murine tumor systems. In contrast to the inactive 6-O-methyl derivative of daunorubicin, 4-demethyl-6-O-methyl-doxorubicin provided antitumor effects comparable to that of the parent compound. In addition, detailed DNA-interaction studies showed that the doxorubicin derivative retains the ability to bind DNA by the intercalation mechanism. However, the binding affinity was appreciably reduced following structural modification in the anthraquinone chromophore. On the basis of the proposed models of intercalation, these results could be rationalized in terms of steric influence of the bulky methoxy group. The results of this study are in agreement with the correlation already observed between DNA binding and relative antitumor activity of anthracyclines.

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“…Since their discovery, a number of studies have suggested that the cytotoxic action of anthracyclines is related to their ability to react with cellular DNA [1]. Though there is no simple relationship between DNAbinding affinity and antitumor activity, structural specificity of these drugs was clearly noted, and it also appeared that an intercalative DNA binding is necessary for drug cytotoxicity [2]. The binding of anthracyclines to DNA has been extensively studied by a variety of biochemical and biophysical methods [3].…”

mentioning

confidence: 99%

Degradation of the morpholino ring in the crystal structure of cyanomorpholinodoxorubicin complexed with d(CGATCG)

Ettorre

Cirilli²,

Ughetto³

1998

European Journal of Biochemistry

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The cyanomorpholino analogue of antitumor anthracycline doxorubicin possesses an intense potency and differs from the parent compound in cross-resistance and other biological properties. The induction by cyanomorpholinodoxorubicin of both DNA cross-links and strand scission suggests an altered mode of action relative to doxorubicin with a different DNA-interacting capacity. We have co-crystallized 3′-(3-cyano-4-morpholinyl)-3′-desaminodoxorubicin (CMD) with the DNA hexamer d(CGATCG) and have determined the crystal structure at 0.16-nm resolution. The complex crystallizes in the space group P4 1 2 1 2 and is similar to the previously reported anthracycline/DNA structures, with the drug intercalated at the CpG step, forming hydrogen bonds with the guanine residue. The structure reveals that the morpholino moiety has undergone a major rearrangement with loss of the cyano group and opening of the morpholino ring. The compound actually bound to DNA in the complex resembles N-(2-hydroxyethyl)doxorubicin, which was previously identified as a hydrolysis product of CMD. No DNA alkylation has been observed. However, the structure shows that the active site of the morpholino ring, after dissociation of the cyano group, lies in the minor groove in proximity of the A/T base pair. This may indicate that a C/G base pair next to the intercalation site, with NH 2 group in the minor groove, is required for DNA alkylation.Keywords : anthracycline; drug/DNA complex ; anticancer drugs design ; X-ray structure ; DNA intercalation.Anthracycline antibiotics, of which daunomycin (daunorubicin) and adriamycin (doxorubicin) are the best known members, have been widely used as antitumor drugs for over two decades, and adriamycin has been one of the most successful chemotherapeutic agents in clinical use. Since their discovery, a number of studies have suggested that the cytotoxic action of anthracyclines is related to their ability to react with cellular DNA [1]. Though there is no simple relationship between DNAbinding affinity and antitumor activity, structural specificity of these drugs was clearly noted, and it also appeared that an intercalative DNA binding is necessary for drug cytotoxicity [2]. The binding of anthracyclines to DNA has been extensively studied by a variety of biochemical and biophysical methods [3]. Crystallographic data from several three-dimensional structures of DNA-anthracycline complexes have well characterized the molecular interaction between drug and DNA and have established specific sequences as preferred sites of drug intercalation [4Ϫ8].Despite intensive investigation, the mode of action of these drugs is still to be totally understood. Currently, the widely accepted view is that the mechanism of anthracycline cytotoxicity Correspondence to G. Ughetto, Istituto di Strutturistica Chimica 'Giordano Giacomello', C.N.R., Area della Ricerca di Roma, C.P. 10, I-00016 Monterotondo Stazione, Italy Fax: ϩ39 690 672630. E-mail: alex@isc.mlib.cnr.it Abbreviation. CMD, 3′-(3-cyano-4-morpholinyl)-3′-desaminodoxorubicin...

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New Natural, Semisynthetic and Synthetic Anthracycline Drugs

Cited by 11 publications

References 138 publications

A chemical perspective on the anthracycline antitumor antibiotics.

A chemical perspective on the anthracycline antitumor antibiotics.

Biochemical and biological activity of the anthracycline analog, 4-demethyl-6-0-methyl-doxorubicin

Degradation of the morpholino ring in the crystal structure of cyanomorpholinodoxorubicin complexed with d(CGATCG)

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