Template-directed design of a DNA-DNA cross-linker based upon a bis-tomaymycin-duplex adduct

Jeh Jeng Wang, G. Craig Hill, Laurence Hurley

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

A template-directed approach to the design of a DNA-DNA interstrand cross-linker based upon the structure of a bis-tomaymycin-duplex adduct has been carried out. Tomaymycin is a member of the pyrrolo[1,4]benzodiazepines antitumor antibiotics. In a previous study (F. L. Boyd et al., Biochemistry 1990, 29, 2387-2403), we have shown that two tomaymycin molecules can be covalently bound to a 12-mer duplex molecule, where the drug molecules are on opposite strands six base-pairs apart, and the stereochemistry at the drug bonding site, and orientation in the minor groove, was defined by high-field NMR. This bis-tomaymycin 12-mer duplex adduct maintains the self-complementarity of the duplex and a B-type structure. In the present study we have shown using high-field NMR that this same 12-mer sequence can be truncated by two base pairs so that the two tomaymycin-modified guanines are now only four base-pairs apart, the two species of tomaymycin molecules are still bound with the same stereochemistry and orientation, and the 10-mer duplex adduct maintains its self-complementarity. In a second 10-mer duplex we have shown that changing the bonding sequence from 5′CGA to 5′AGC does not significantly affect the structure of the bis-tomaymycin-duplex adduct. However, when the sequence is rearranged so that the drugs point in a tail-to-tail orientation rather than in the previous head-to-head configuration, there are more than one species of tomaymycin bound to DNA, and, as a consequence, the bis-tomaymycin 10-mer duplex adduct loses its self-complementarity. Last, we have used the 10-mer duplex containing the 5′CGA sequence, in which the tomaymycin molecules are oriented head to head, to design an interstrand cross-linking species in which the two drug molecules are linked together with a flexible linker molecule.

Original languageEnglish (US)
Pages (from-to)2995-3002
Number of pages8
JournalJournal of Medicinal Chemistry
Volume35
Issue number16
StatePublished - 1992
Externally publishedYes

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DNA
Molecules
Base Pairing
Stereochemistry
Pharmaceutical Preparations
Nuclear magnetic resonance
tomaymycin
Biochemistry
Guanine
Anti-Bacterial Agents

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Template-directed design of a DNA-DNA cross-linker based upon a bis-tomaymycin-duplex adduct. / Wang, Jeh Jeng; Craig Hill, G.; Hurley, Laurence.

In: Journal of Medicinal Chemistry, Vol. 35, No. 16, 1992, p. 2995-3002.

Research output: Contribution to journalArticle

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