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DOI | 10.1038/s41467-018-03384-9 |
Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1 | |
Suen, Linda M.1; Tekle-Smith, Makeda A.1; Williamson, Kevin S.1; Infantine, Joshua R.1; Reznik, Samuel K.1; Tanis, Paul S.1; Casselman, Tyler D.1; Sackett, Dan L.2; Leighton, James L.1 | |
2018-11-09 | |
发表期刊 | NATURE COMMUNICATIONS |
ISSN | 2041-1723 |
出版年 | 2018 |
卷号 | 9 |
文章类型 | Article |
语种 | 英语 |
国家 | USA |
英文摘要 | Spongistatin 1 is among the most potent anti-proliferative agents ever discovered rendering it an attractive candidate for development as a payload for antibody-drug conjugates and other targeted delivery approaches. Unfortunately, it is unavailable from natural sources and its size and complex stereostructure render chemical synthesis highly time- and resource-intensive. As a result, the design and synthesis of more acid-stable and linker functional group-equipped analogs that retain the low picomolar potency of the parent natural product requires more efficient and step-economical synthetic access. Using uniquely enabling direct complex fragment coupling crotyl- and alkallylsilylation reactions, we report a 22-step synthesis of a rationally designed D-ring modified analog of spongistatin 1 that is characterized by GI(50) values in the low picomolar range, and a proof-of-concept result that the C (15) acetate may be replaced with linker functional group-bearing esters with only minimal reductions in potency. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000449627800005 |
WOS关键词 | STEREOCONTROLLED TOTAL-SYNTHESIS ; COMPLEX NATURAL-PRODUCTS ; ALTOHYRTIN A/SPONGISTATIN-1 ; ENANTIOSELECTIVE SYNTHESIS ; CANCER-THERAPY ; BIOLOGICAL EVALUATION ; SPIROACETAL SEGMENT ; PART 2 ; FRAGMENT ; EFFICIENT |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/203704 |
专题 | 资源环境科学 |
作者单位 | 1.Columbia Univ, Dept Chem, New York, NY 10027 USA; 2.Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA |
推荐引用方式 GB/T 7714 | Suen, Linda M.,Tekle-Smith, Makeda A.,Williamson, Kevin S.,et al. Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1[J]. NATURE COMMUNICATIONS,2018,9. |
APA | Suen, Linda M..,Tekle-Smith, Makeda A..,Williamson, Kevin S..,Infantine, Joshua R..,Reznik, Samuel K..,...&Leighton, James L..(2018).Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1.NATURE COMMUNICATIONS,9. |
MLA | Suen, Linda M.,et al."Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1".NATURE COMMUNICATIONS 9(2018). |
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