Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
Bioorg Med Chem Lett. 2021 May 15;40:127952. doi: 10.1016/j.bmcl.2021.127952. Epub 2021 Mar 17.
The cytotoxicity properties of the β-carboline alkaloids have been broadly investigated. However, the potential application of β-carbolines was hindered due to the moderate activity in cancer. In the present study, thirty β-carboline-(phenylsulfonyl)furoxan hybrids (11a-j, 12a-j and 13a-j) were designed and synthesized through esterification and amidation reaction strategy, and their inhibitory activities against the human breast cancer cell lines MCF-7 and MDA-MB-231 were evaluated by CCK-8 assay. Biological evaluation presented that the most promising amide derivative 13h, substituted with p-methoxyphenyl group at position 1, generated high concentration of NO and evidently depressed the MCF-7 (IC = 0.89 μM) and MDA-MB-231 (IC = 0.62 μM) cells proliferation. Particularly, the wound healing and transwell assays demonstrated that 13h significantly inhibited the migration and invasion of MDA-MB-231cells. Furthermore, the preliminary mechanisms studies indicated that 13h induced G2/M phase arrest and apoptosis possibly causing by ROS accumulation and ROS-mediated DNA damage. Based on these considerations, 13h may be a promising antimetastatic agent for breast cancer, which is noteworthy for further exploration.
β-咔啉生物碱的细胞毒性特性已得到广泛研究。然而，由于在癌症方面的活性适中，β-咔啉的潜在应用受到了阻碍。在本研究中，通过酯化和酰胺化反应策略设计并合成了 30 种β-咔啉-(苯磺酰基)呋咱杂合（11a-j、12a-j 和 13a-j），并通过 CCK-8 测定法评估了它们对人乳腺癌细胞系 MCF-7 和 MDA-MB-231 的抑制活性。生物评价表明，最有前途的酰胺衍生物 13h，在 1 位取代对甲氧基苯基，产生高浓度的一氧化氮，并显著抑制 MCF-7（IC=0.89 μM）和 MDA-MB-231（IC=0.62 μM）细胞增殖。特别是，划痕愈合和 Transwell 测定表明 13h 显著抑制了 MDA-MB-231 细胞的迁移和侵袭。此外，初步的机制研究表明，13h 可能通过 ROS 积累和 ROS 介导的 DNA 损伤引起 G2/M 期阻滞和细胞凋亡。基于这些考虑，13h 可能是一种有前途的用于乳腺癌的抗转移药物，值得进一步探索。
