新型一氧化氮供体型二硝戊烯-香豆素杂合体作为有效的抗肝内胆管癌试剂。
Novel Nitric Oxide Donor Dinitroazetidine-Coumarin Hybrids as Potent Anti-Intrahepatic Cholangiocarcinoma Agents.
机构信息
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
出版信息
Molecules. 2022 Jun 22;27(13):4021. doi: 10.3390/molecules27134021.
Intrahepatic cholangiocarcinoma (iCC) is a serious liver cancer threatening human health. However, there are a few chemotherapeutic drugs for the treatment of iCC in the clinic. It is extremely urgent to develop new drugs for iCC. In this study, twenty dinitroazetidine and coumarin hybrids were synthesized and evaluated anti-iCC bioactivity as a new type of nitric oxide (NO) donors. Among them, compounds and showed a higher antiproliferative activity against RBE cell lines (human intrahepatic cholangiocarcinoma cell lines) and low cytotoxicity in nontumor cells (HOSEpiC and T29). The preliminary study of pharmacology mechanism indicated that compounds and could release effective concentration of NO in RBE cell lines, which leaded to inhibit the proliferation of RBE cell lines. The research results revealed that compound inhibited the proliferation of RBE cell lines by inducing apoptosis and arresting cell cycle at G/M phase. Additionally, compound had acceptable metabolic stability. Therefore, compound was merited to further explore for developing a desirable NO donor lead with anti-iCC activity.
肝内胆管癌（iCC）是一种严重威胁人类健康的肝癌。然而，临床上用于治疗 iCC 的化疗药物寥寥无几。因此，开发治疗 iCC 的新药迫在眉睫。在这项研究中，合成了二十个二硝基亚唑烷和香豆素的杂合体，并将其作为新型一氧化氮（NO）供体评估抗 iCC 生物活性。其中，化合物 和 对 RBE 细胞系（人肝内胆管癌细胞系）表现出更高的增殖抑制活性，而对非肿瘤细胞（HOSEpiC 和 T29）的细胞毒性较低。药理学机制的初步研究表明，化合物 和 能够在 RBE 细胞系中释放有效浓度的 NO，从而抑制 RBE 细胞系的增殖。研究结果表明，化合物 通过诱导细胞凋亡和将细胞周期阻滞在 G/M 期来抑制 RBE 细胞系的增殖。此外，化合物 具有可接受的代谢稳定性。因此，化合物 值得进一步探索，以开发具有抗 iCC 活性的理想 NO 供体先导化合物。
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