Natural products have historically represented a major source of therapeutics and small-molecule probes for interrogating biological systems. Here, we describe the design and implementation of P450-mediated chemoenzymatic diversity-oriented synthesis (CeDOS), a strategy in which selective, regiodivergent P450-catalyzed oxyfunctionalizations are leveraged as key steps for enabling the skeletal rearrangement and diversification of a parent compound. Using this strategy and plant-derived parthenolide as the parent molecule, a structurally diverse library of over 50 unprecedented natural-product-like scaffolds was generated via divergent chemoenzymatic routes. Importantly, several members of this CeDOS library were found to exhibit notable cytotoxicity against human cancer cells as well as diversified anticancer activity profiles. This work demonstrates the power of CeDOS as a strategy for directing the construction and discovery of novel bioactive molecules, and it offers a blueprint for the broader application of this approach toward the creation and exploration of natural-product-like chemical libraries.

中文翻译：

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由晚期 P450 催化的氧官能化实现的骨骼多样化的生物活性天然产物样化合物库


天然产物历来是用于研究生物系统的治疗剂和小分子探针的主要来源。在这里，我们描述了 P450 介导的化学酶多样性导向合成 （CeDOS） 的设计和实施，这是一种策略，其中选择性的、区域分歧的 P450 催化的氧官能化作为实现骨架重排和母体化合物多样化的关键步骤。使用这种策略和植物来源的小白菊内酯作为母体分子，通过不同的化学酶途径产生了一个结构多样化的文库，其中包含 50 多个前所未有的天然产物样支架。重要的是，发现该 CeDOS 文库的几个成员对人类癌细胞表现出显着的细胞毒性以及多样化的抗癌活性特征。这项工作证明了 CeDOS 作为指导新型生物活性分子构建和发现的策略的力量，并为这种方法在创建和探索类天然产物化学库方面的更广泛应用提供了蓝图。