天然产物（NPs）由于其化学多样性和调节生物系统的能力，是高利润的药理学工具。在设计新型生物活性化合物的过程中，获取新的化学实体并保持天然化合物类型的生物相关性是一个基本目标。值得注意的是，NPs在理解Hedgehog（HH）信号传导及其在抗癌治疗中的药理调节方面发挥了关键作用。然而，目前开发的HH拮抗剂存在一些局限性，因此越来越多地关注第二代HH抑制剂的设计。通过巧妙地操纵NPs的核心骨架，我们成功地根据不同的设计策略得到了前所未有和有趣的结构。在这里，我们报告了一个基于蒲公英酸骨架与各种取代的哌嗪核团相结合的第一代和第二代蒽醌基杂交化合物的有理设计和合成。这些杂交化合物在结构上类似于已知的SMO拮抗剂的活性部分，SMO是HH信号通路的主要传递者。通过全面的功能和生物学研究，我们确定RH2_2和RH2_6基于蒲公英酸的杂交物作为通过SMO拮抗作用抑制HH的有价值候选物，从而抑制HH依赖性肿瘤生长。我们的发现也证实了基于NPs杂交设计策略在开发新型以NPs为基础的SMO拮抗剂中的成功应用。© 2023 Wiley-VCH GmbH.

Natural products (NPs) are highly profitable pharmacological tools due to their chemical diversity and ability to modulate biological systems. Accessing new chemical entities while retaining the biological relevance of natural chemotypes is a fundamental goal in the design of novel bioactive compounds. Notably, NPs have played a crucial role in understanding Hedgehog (HH) signalling and its pharmacological modulation in anticancer therapy. However, HH antagonists developed so far have shown several limitations, thus growing the interest in the design of second-generation HH inhibitors. Through smart manipulation of the NPs core-scaffold, unprecedented and intriguing architectures have been achieved following different design strategies. Here, we report the rational design and synthesis of a first and second generation of anthraquinone-based hybrids by combining the rhein scaffold with variously substituted piperazine nuclei that are structurally similar to the active portion of known SMO antagonists, the main transducer of the HH pathway. A thorough functional and biological investigation identified RH2_2 and RH2_6 rhein-based hybrids as valuable candidates for HH inhibition through SMO antagonism, with the consequent suppression of HH-dependent tumour growth. Our findings also corroborated the successful application of the NPs-based hybrid design strategy in the development of novel NP-based SMO antagonists.© 2023 Wiley-VCH GmbH.