A 鈥淢ethyl Extension鈥?Strategy for Polyketide Natural Product Linker Site Validation and Its Application to Dictyostatin

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• 作者：Stephen Ho ; Dan L. Sackett ; James L. Leighton
• 刊名：Journal of the American Chemical Society
• 出版年：2015
• 出版时间：November 11, 2015
• 年：2015
• 卷：137
• 期：44
• 页码：14047-14050
• 全文大小：387K
• ISSN：1520-5126

文摘

An approach to the validation of linker strategies for polyketide natural products with few or no obvious handles for linker attachment, and its application to dictyostatin, are described. Analogues in which the C(6)- and C(12)-methyl groups were replaced by 4-azidobutyl groups were prepared and shown to retain the low nanomolar potency of dictyostatin. Further, conjugation of the C(6) analogue with a cyclooctyne resulted in only minor attenuations in potency. Together, these results shed light on the binding of dictyostatin to 尾-tubulin, establish a validated linker strategy for dictyostatin, and set the stage for the synthesis and study of dictyostatin conjugates.