本文描述了一种高效合成新颖的雌二醇基A环融合噁唑衍生物的方法，这些衍生物可以被看作是含有共同苯结构基团的苯噁唑类固醇结构融合产物。目标化合物是通过杂环形成或官能团互转（FGI）策略从类固醇2-氨基酚前体制备而成。根据基于2D投影的t-分布随机邻域嵌入（t-SNE），新颖分子被证明代表了类固醇药物中的新化学空间。它们根据理论模拟和实验数据进行了关键的理化参数表征。实验测试了化合物在四种人类癌细胞系和非癌细胞上的细胞增殖抑制活性。进一步研究了IC50和疏水性配体效能（LLE）值、癌细胞选择性和诱导凋亡特性。药理学测试和LLE指标表明，一些衍生物，特别是2-(4-乙基哌嗪-1-基)噁唑衍生物，表现出较强的抗癌活性，并且与结构上最接近且经过深入研究的抗癌药物2-甲氧基雌二醇相似，具有相对较低的混配性风险。© 2023 Wiley-VCH GmbH.

The efficient synthesis of novel estradiol-based A-ring-fused oxazole derivatives, which can be considered as benzoxazole-steroid domain-integrated hybrids containing a common benzene structural motif, is described. The target compounds were prepared from steroidal 2-aminophenol precursors by heterocycle formation or functional group interconversion (FGI) strategies. According to 2D projection-based t-distributed stochastic neighbor embedding (t-SNE), the novel molecules were proved to represent a new chemical space among steroid drugs. They were characterized based on critical physicochemical parameters using in silico and experimental data. The performance of the compounds to inhibit cell proliferation was tested on four human cancer cell lines and non-cancerous cells. Further examinations were performed to reveal IC50 and lipophilic ligand efficiency (LLE) values, cancer cell selectivity, and apoptosis-triggering features. Pharmacological tests and LLE metric revealed that some derivatives, especially the 2-(4-ethylpiperazin-1-yl)oxazole derivative exhibit strong anticancer activity and trigger the apoptosis of cancer cells with relatively low promiscuity risk similarly to the structurally most closely-related and intensively studied anticancer agent, 2-methoxy-estradiol.© 2023 Wiley-VCH GmbH.