Systematic Exploration of the Structural Features of Yatakemycin Impacting DNA Alkylation and Biological Activity

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• 作者：Mark S. Tichenor ; Karen S. MacMillan ; John D. Trzupek ; Thomas J. Rayl ; Inkyu Hwang ; Dale L. Boger
• 刊名：Journal of the American Chemical Society
• 出版年：2007
• 出版时间：September 5, 2007
• 年：2007
• 卷：129
• 期：35
• 页码：10858 - 10869
• 全文大小：823K
• 年卷期：v.129,no.35(September 5, 2007)
• ISSN：1520-5126

文摘

A systematic examination of the impact of the yatakemycin left and right subunits and theirsubstituents is detailed along with a study of its unique three subunit arrangement (sandwiched vs extendedand reversed analogues). The examination of the ca. 50 analogues prepared illustrate that within theyatakemycin three subunit structure, the subunit substituents are relatively unimportant and that it is theunique sandwiched arrangement that substantially increases the rate and optimizes the efficiency of itsDNA alkylation reaction. This potentiates the cytotoxic activity of yatakemycin and its analogues overcominglimitations typically observed with more traditional compounds in the series (CC-1065, duocarmycins).Moreover, a study of the placement of the alkylation subunit within the three subunit arrangement(sandwiched vs extended and reversed analogues) indicates that it not only has a profound impact on therate and efficiency of DNA alkylation but also controls and establishes the DNA alkylation selectivity aswell, where both enantiomers of such sandwiched agents alkylate the same adenine sites exhibiting thesame DNA alkylation selectivity independent of their absolute configuration.