Structure by NMR of antitumor drugs aclacinomycin a and b complexed to d(CGTACG)

Danzhou Yang, Andrew H J Wang

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Abstract

Aclacinomycins A and B are anthracycline antibiotics with potent antitumor activity. Each consists of an alkavinone aglycon chromophore and a trisaccharide (rhodosamine-deoxyfucose-cinerulose A or B) tail attached at the C7 of ring A of the alkavinone. The structures of the 2:1 aclacinomycin-d(CGTACG) complexes have been studied in solution by 2D NMR spectroscopy using nuclear Overhauser effect data. SPEDREF refinement procedure (incorporating simulated annealing within the program X-PLOR) was used to obtain an ensemble of refined structures which reveal that the elongated alkavinone is intercalated between the CpG steps and the trisaccharide lies in the minor groove. In the complex, the two GC Watson-Crick base pairs (C1:G12 and G2:C11) that wrap around the aglycon have large buckles, consistent with those seen in the crystal structures of other anthracycline-DNA complexes. The intercalation geometry of aclcainomycin is a hybrid between those of daunorubicin and nogalamycin. Ring D of alkavinone is sandwiched by the C1 and C11 bases. The deoxyfucose ring of the trisaccharide is close to the DNA backbone at the A4 nucleotide, forcing the DNA helix to kink toward the major groove (with the opening in the minor groove). The kink between two adjacent A-T base pairs (T3-A10 and A4-T9) causes the adenine A4N6 to form two hydrogen bonds to T9O4 (interstrand) and T3O4 (intrastrand) simultaneously. There is a small unwinding of the helix resulting from the intercalated aclacinomycin. Several potential hydrogen bonds exist between the drug and the guanine bases in the minor groove of the helix. Multiple molecular species coexist in the solution of the 1:1 mixture of aclacinomycin and d(CGTACG) due to the slow rate of drug binding to DNA.

Original languageEnglish (US)
Pages (from-to)6595-6604
Number of pages10
JournalBiochemistry
Publication statusPublished - 1994
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry

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