Curcumin and cinnamaldehyde are natural products whose antineoplastic activity has been well explored in biological evaluations. However, their poor chemical stability under physiological conditions has been an obstacle to their use as therapeutic agents. Herein, we designed and synthesized two series of curcumin-cinnamaldehyde hybrids by removing reactive functionalities, including β-diketone and aldoxyl moieties. All compounds were evaluated by the MTT assay to determine their antiproliferative activity against women’s cancer cells. Compound 5a (3′-hydroxychalcone) demonstrated potent antiproliferative activity against all cancer cell lines tested, with IC₅₀ values ranging from 2.7 to 36.5 µM. Compound 5a was more active and selective than curcumin and cinnamaldehyde (parent compounds) against the CaSki, SiHa, C33, and A431 cell lines, displaying a higher selectivity index (SI = 8.5) than curcumin (SI = 0.8) toward the non-tumorigenic HaCaT cell line. Clonogenic experiments indicated that compound 5a inhibited A431 colony formation in a concentration-dependent manner. In addition, 5a was more stable than its parent compounds in pH 7.4 at 37 °C. In silico investigations suggested that 5a has good drug-likeness properties. In conclusion, our results indicate the use of curcumin and cinnamaldehyde as parent compounds for the design of hybrids with attractive antiproliferative activity and chemical stability.

姜黄素和肉桂醛是天然产物，其抗肿瘤活性已在生物学评价中得到充分探索。然而，它们在生理条件下的化学稳定性差一直是它们用作治疗剂的障碍。在此，我们通过去除反应性官能团，包括 β-二酮和醛氧基部分，设计并合成了两个系列的姜黄素-肉桂醛杂化物。所有化合物均通过 MTT 分析进行评估，以确定它们对女性癌细胞的抗增殖活性。化合物 5a（3'-羟基查尔酮）对所有测试的癌细胞系均表现出有效的抗增殖活性，IC ₅₀值范围从 2.7 到 36.5 µM。化合物 5a 比姜黄素和肉桂醛（母体化合物）对 CaSki、SiHa、C33 和 A431 细胞系更具活性和选择性，对非致瘤细胞系显示出比姜黄素（SI = 0.8）更高的选择性指数（SI = 8.5） HaCaT 细胞系。克隆形成实验表明，化合物 5a 以浓度依赖性方式抑制 A431 集落形成。此外，5a 在 pH 7.4 和 37 °C 下比其母体化合物更稳定。计算机研究表明，5a 具有良好的药物相似性。总之，我们的结果表明使用姜黄素和肉桂醛作为母体化合物来设计具有有吸引力的抗增殖活性和化学稳定性的杂种。