Reversed and Sandwiched Analogs of Duocarmycin SA: Establishment of the Origin of the Sequence-Selective Alkylation of DNA and New Insights into the Source of Catalysis

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• 作者：Dale L. Boger ; Bernd Bollinger ; Donald L. Hertzog ; Douglas S. Johnson ; Hui Cai ; Philippe Mé ; sini ; Robert M. Garbaccio ; Qing Jin ; and Paul A. Kitos
• 刊名：Journal of the American Chemical Society
• 出版年：1997
• 出版时间：May 28, 1997
• 年：1997
• 卷：119
• 期：21
• 页码：4987 - 4998
• 全文大小：530K
• 年卷期：v.119,no.21(May 28, 1997)
• ISSN：1520-5126

文摘

The synthesis and examination of two unique classes of duocarmycinSA analogs are described which werefer to as reversed and sandwiched analogs. Their examinationestablished both the origin of the DNA alkylationselectivity and that both enantiomers of this class of natural productsare subject to the same polynucleotide recognitionfeatures. The most beautiful demonstration of this is the completeswitch in the enantiomeric alkylation selectivityof the reversed analogs which is only consistent with the noncovalentbinding model and incompatible with alkylationsite models of the origin of the DNA alkylation selectivity. Inaddition, dramatic alterations in the rates of DNAalkylation were observed among the agents and correlate with thepresence or absence of an extended, rigid N²amide substituent. This has led to the proposal of a previouslyunrecognized source of catalysis for the DNA alkylationreaction which was introduced in the preceding paper of this issue(J. Am. Chem. Soc. 1997, 119,4977-4986).