Yu Jia, Li Shengyou, Zeng Xueyi, Song Junrong, Hu Shengcao, Cheng Sha, Chen Chao, Luo Heng, Pan Weidong
State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, China.
The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, China.
Bioorg Chem. 2021 Dec;117:105383. doi: 10.1016/j.bioorg.2021.105383. Epub 2021 Sep 22.
In this study, we present the design and synthesis of novel fully synthetic L-shaped ortho-quinone analogs with tanshinone IIA as the lead compoud, which is a molecule with numerous pharmacological benefits and potential to treat life-threatening diseases, such as cancer and viral infections. 24 L-shaped ortho-quinone analogs were designed and synthesized via click chemistry and introduced 1,2,3-triazole at the C-2 terminal of the furan ring. The cytotoxicity of these analogs toward different cancer cell lines was investigated in vitro. The new TD compounds showed potent inhibitory activities toward prostate cancer (PC3), leukemia (K562), breast cancer (MDA-231), lung cancer (A549), and cervical cancer (Hela) cell lines. Among them, TD1, TD11, and TD17 showed excellent broad-spectrum cytotoxic effects on five cancer cell lines by inducing apoptosis and arresting the cell cycle phase. Besides, TD1, TD11, and TD17 could target-bind with NQO1 protein in the prostate cancer cells PC3 leukemia cells K562. The results showed that removing the methyl group at C-3 and introducing 1,2,3-triazoles at the C-2 terminal of the furan ring were effective strategies for improving the broad-spectrum anticancer activity of L-shaped ortho-quinone analogs.
在本研究中，我们展示了以丹参酮IIA为先导化合物设计并合成新型全合成L型邻醌类似物的过程，丹参酮IIA是一种具有多种药理益处且有潜力治疗危及生命疾病（如癌症和病毒感染）的分子。我们通过点击化学设计并合成了24种L型邻醌类似物，并在呋喃环的C-2末端引入了1,2,3-三唑。体外研究了这些类似物对不同癌细胞系的细胞毒性。新的TD化合物对前列腺癌（PC3）、白血病（K562）、乳腺癌（MDA-231）、肺癌（A549）和宫颈癌（Hela）细胞系显示出强效抑制活性。其中，TD1、TD11和TD17通过诱导凋亡和阻滞细胞周期阶段，对五种癌细胞系表现出优异的广谱细胞毒性作用。此外，TD1、TD11和TD17可与前列腺癌细胞PC3、白血病细胞K562中的NQO1蛋白靶向结合。结果表明，去除C-3位的甲基并在呋喃环的C-2末端引入1,2,3-三唑是提高L型邻醌类似物广谱抗癌活性的有效策略。
