Structural studies of atom-specific anticancer drugs acting on DNA.

X L Yang, A H Wang

Department of Cell and Structural Biology, University of Illinois at Urbana-Champaign, Urbana 61801, USA.

Pharmacology & therapeutics 1999 Sep

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The interactions of many important anticancer drugs with DNA play important roles in their biological functions. In fact, DNA can be considered as a macromolecular receptor for those drugs. There are several classes of DNA-acting anticancer drugs. Some form noncovalent complexes with DNA by either intercalation (such as daunorubicin and doxorubicin) or groove-binding (such as distamycin A). Others, such as cisplatin, mitomycin C, and ecteinascidins, form covalent linkages with DNA. Finally, some (e.g., duocarmycin/CC-1065, bleomycin/pepleomycin, and enediyne antibiotics) cause DNA backbone cleavages. During the past decade, the detailed molecular interactions of several DNA-acting anticancer drugs with DNA have been studied with structural tools, including high resolution X-ray diffraction and NMR spectroscopy. These results have provided useful insights into DNA conformation and drug-DNA interactions. In particular, it was found that specific atomic sites on DNA are often the targets for drug covalent actions. Here we review the structural aspects of the interactions of several anticancer drugs acting on: (1) the N2 amino group of guanine in the minor groove, (2) the N3 atom of guanine and adenine in the minor groove, (3) the N7 atom of guanine and adenine in the major groove, and finally, (4) the C4', C5', and C1' atoms of the deoxyribose in the backbone of B-DNA double-helix. Understanding the underlying mechanism of the drug action at the cellular and molecular levels through those structural studies should be useful in the development of new anticancer drugs.