State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China.
College of Pharmacy and Health Sciences, St. John's University, Queens, New York, 11439, United States.
Eur J Med Chem. 2022 Mar 5;231:114155. doi: 10.1016/j.ejmech.2022.114155. Epub 2022 Jan 29.
The natural product oridonin has the potential to be a broad-spectrum antineoplastic agent. To develop oridonin analogues with high potency, a series of novel oridonin analogues were designed and synthesized by removing the multiple hydroxyl groups of parent compound. The representative analogues 14, 19, and 26 exhibited potent anticancer effects against K562, MDA-MB-231, SMMC-7721, and MCF-7 cells. Further structural modification on their 14-OH generated more potent derivatives 16n, 21d, and 28d respectively, in which the IC value of compound 16n was 50-fold more potent than parent oridonin in K562 cells. Furthermore, compound 16n significantly induced the cell cycle arrest of K562 cells at the G2 phase and increased the fraction of apoptotic cells. Importantly, compounds 16n, 21d, and 28d exhibited good antitumor activities in H22 allograft mice in vivo. These results suggest that compounds 16n, 21d, and 28d deserve further development as promising candidates for the treatment of cancers.
天然产物冬凌草甲素具有成为广谱抗肿瘤药物的潜力。为了开发高活性的冬凌草类似物，通过去除母体化合物的多个羟基基团，设计并合成了一系列新型冬凌草类似物。代表性类似物 14、19 和 26 对 K562、MDA-MB-231、SMMC-7721 和 MCF-7 细胞表现出强大的抗癌作用。进一步对其 14-OH 进行结构修饰，生成了更有效的衍生物 16n、21d 和 28d，其中化合物 16n 在 K562 细胞中的 IC 值比母体冬凌草甲素高 50 倍。此外，化合物 16n 可显著诱导 K562 细胞周期停滞在 G2 期，并增加凋亡细胞的比例。重要的是，化合物 16n、21d 和 28d 在体内 H22 同种异体移植小鼠中表现出良好的抗肿瘤活性。这些结果表明，化合物 16n、21d 和 28d 值得进一步开发，作为治疗癌症的有前途的候选药物。
Anticancer Agents Med Chem. 2019
J Enzyme Inhib Med Chem. 2018-12
Bioorg Med Chem. 2022-10-15
J Enzyme Inhib Med Chem. 2024-12
Zotero 插件