X-ray crystallographic and NMR structural studies of anthracycline anticancer drugs. Implication in drug design

研究成果: 雜誌貢獻文章同行評審

4 引文 斯高帕斯(Scopus)

摘要

Crystal structure analysis of several complexes between important anthracycline drugs and DNA oligonucleotides affords us valuable information for understanding the role of various functional groups of the drug molecules. Moreover, the excellent agreement between the crystal and solution structures shown in the analyses of the Ng-CGTACG complex showed that a quantitative treatment of NOE data is an effective alternate way of producing a reliable three-dimensional structure of drug-DNA complexes. Aclacinomycins A and B, complexed to DNA by the same procedure, provided us with a structure that is not yet available from X-ray crystallography. Similar analyses of other drugs, such as arugomycin,57 will be useful in our understanding of the function of anthracycline antibiotics in general. The structural results also offer some clues for the design of new and unique classes of potential drugs. For example, our preliminary data on the nature of the drug-DNA cross-link suggest that such a complex has several potential beneficial properties as an anticancer drug:o1.The conjugate can be prepared readily and efficiently with very high loading of the drug [to a maximum of one DOX per three base pairs for poly(dG-dC)].2.The conjugate may be long-lived in the blood stream, serving as a slow-releasing drug reservoir.3.The cytotoxic agent is hidden in the DNA lattice, avoiding the attack by enzyme that causes the formation of the free radical species of DOX. This may reduce the cardiotoxicity side effect.4.If the conjugate can be picked up by the cancer cells directly, it may be effective against resistant cells.5.The conjugate should be resistant to nuclease, since the DNA conformation is severely distorted by the intercalated drug.6.A sequence-specific DNA-DOX adduct may be prepared, as long as some guanine nucleotides are present. We believe that continuing structural studies on many drugs bound to their receptors will be extremely fruitful in guiding the design of new drugs.

原文英語
頁(從 - 到)59-100
頁數42
期刊Advances in DNA Sequence-Specific Agents
2
發行號C
DOIs
出版狀態已發佈 - 1996
對外發佈

ASJC Scopus subject areas

  • 分子生物學

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