125(P74) DNA切断活性分子の創製(ポスター発表の部)

概要

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We report the design, synthesis and evaluation of DNA cleaving activity of some hybrid molecules, 1a-c, 2a-c, 4a-c, 5a-c, and 6a-c, which contain the alkylating subunit of duocarmycins, CC-1065 and azinomycins linked by a pyrrole amide moiety of distamycin A, a minor groove DNA binding agents. Both enantiomers of these molecules were synthesized by using a lipase catalyzed asymmetric acetylation of prochiral diols or the Sharpless asymmetric epoxidation. DNA cleaving activities were evaluated by using supercoiled Col E1 plasmid DNA and the reactions with the synthesized hybrid molecules were carried out at 37℃ by alterations in concentration of drugs and reaction time. The cleaving activities were highly dependent upon the absolute structure of drugs and the length of the pyrrole amide moiety. It was also clarified by DNA cleavage analysis that compound 2b recognizes specifically the A-T rich regions and the alkylation occurrs preferentially at adenine bases. The reason of the difference of activity for the enantiomers 1b and 2b was speculated by MM2" calculated drug-DNA interaction model and the distance between adenine N-3 and the alkylated carbon proved to be crutial.
天然有機化合物討論会の論文
1996-09-02