Chemically engineered extracts as an alternative source of bioactive natural product-like compounds
Chemically engineered extracts as an alternative source of bioactive natural product-like compounds
复制标题
DOI：
10.1073/pnas.0608438104
复制
发表时间：
2007-01-09
影响因子：
11.1
通讯作者：
Furlan, Ricardo L. E.
中科院分区：
文献类型：
--
作者：
Lopez, Silvia N.;Ramallo, I. Ayelen;Furlan, Ricardo L. E.
获得具有感兴趣的生物分子特性的分子库是药物发现过程中的限制性步骤。由于长期的分子进化过程，天然产物被认为是文库开发的结构空间中生物学验证的起点。我们在这里介绍一种策略，以产生天然产物的图书馆。化合物的半合成混合物是通过天然产物提取物的多样化来产生的，所述天然产物提取物通过将天然产物中的常见化学官能团化学转化为在自然界中很少发现的化学官能团。所得混合物显示出对白色念珠菌的抗真菌活性，而起始提取物没有显示出这种活性。生物导向分馏导致一个以前未描述的活性半合成吡唑的分离。该结果说明了如何通过天然产物混合物的设计化学多样化来产生生物活性，并代表了从天然产物文库产生天然产物样文库的替代策略的原理证明。
The access to libraries of molecules with interesting biomolecular properties is a limiting step in the drug discovery process. By virtue of a long molecular evolution process, natural products are recognized as biologically validated starting points in structural space for library development. We introduce here a strategy to generate natural product-like libraries. A semisynthetic mixture of compounds was produced by diversification of a natural product extract through the chemical transformation of common chemical functionalities in natural products into chemical functionalities rarely found in nature. The resulting mixture showed antifungal activity against Candida albicans, whereas the starting extract did not show such activity. Bioguided fractionation led to the isolation of a previously undescribed active semisynthetic pyrazole. The result illustrates how biological activity can be generated by designed chemical diversification of a natural product mixture, and represents the proof of principle of an alternative strategy for producing natural product-like libraries from natural products libraries.