The Fifth Affiliated Hospital & School of Pharmaceutical Sciences, Key Laboratory of Molecular Target & Clinical Pharmacology, Guangzhou Medical University, Guangzhou 511436, China; The State Key Laboratory of Respiratory Disease & NMPA Key Laboratory for Clinical Research and Evaluation of Drug for Thoracic Diseases, Guangzhou Medical University, Guangzhou 511436, China.
The Fifth Affiliated Hospital & School of Pharmaceutical Sciences, Key Laboratory of Molecular Target & Clinical Pharmacology, Guangzhou Medical University, Guangzhou 511436, China.
Bioorg Med Chem Lett. 2021 Sep 1;47:128230. doi: 10.1016/j.bmcl.2021.128230. Epub 2021 Jun 27.
A series of novel ligustrazine-chalcone hybrids were synthesized and evaluated for their in vitro and in vivo antitumor activities. The results showed that most of these compounds exhibited significant in vitro cytotoxicity against MDA-MB-231, MCF-7, A549 and HepG2 cell lines with IC values as low as sub-micromole. Among them, compounds 6c and 6f possessed better comprehensive characteristics for the antiproliferation effects on both MDA-MB-231 (IC: 6c, 1.60 ± 0.21 μM; 6f, 1.67 ± 1.25 μM) and MCF-7 (IC: 6c, 1.41 ± 0.23 μM; 6f, 1.54 ± 0.30 μM). They also exhibited the potent colony-formation inhibitory abilities on above two cell lines in both concentration and time dependent manners, as well as the significantly suppression capabilities against the migration of such cell lines in a concentration dependent manner by wound-healing assay. Of note, compound 6c could significantly induce the apoptosis of MDA-MB-231 cells in a concentration dependent manner and inhibited the transformation of the growth cycle of MDA-MB-231 cells and blocked the cell growth cycle in G0/G1 phase. Moreover, the in vivo antiproliferation assay of compound 6c on TNBC model indicated such compound had a remarkable potency against tumor growth with a widely safety window. Further immunohistochemistry analysis illustrated that compound 6c was provided with a potent capacity to significantly reduce the Ki-67 positive rate in a dose dependent manner. All the results suggested that these hybrids presented both in vitro and in vivo proliferation inhibition potency against breast cancer and further development with good therapeutic potential should be of great interest.
一系列新型川芎嗪-查尔酮杂合体被合成并评估其体外和体内抗肿瘤活性。结果表明，大多数化合物对 MDA-MB-231、MCF-7、A549 和 HepG2 细胞系表现出显著的体外细胞毒性，IC 值低至亚微摩尔。其中，化合物 6c 和 6f 在抑制 MDA-MB-231（IC：6c，1.60±0.21μM；6f，1.67±1.25μM）和 MCF-7（IC：6c，1.41±0.23μM；6f，1.54±0.30μM）增殖方面具有更好的综合特性。它们还表现出对两种细胞系的集落形成抑制作用，具有浓度和时间依赖性，以及通过划痕愈合试验以浓度依赖性方式显著抑制细胞迁移的能力。值得注意的是，化合物 6c 能够以浓度依赖的方式显著诱导 MDA-MB-231 细胞凋亡，并抑制 MDA-MB-231 细胞生长周期的转化，阻止细胞生长周期进入 G0/G1 期。此外，化合物 6c 在 TNBC 模型中的体内抗肿瘤活性研究表明，该化合物对肿瘤生长具有显著的抑制作用，且具有广泛的安全窗口。进一步的免疫组化分析表明，化合物 6c 具有显著的剂量依赖性降低 Ki-67 阳性率的能力。所有结果表明，这些杂合体对乳腺癌具有体外和体内增殖抑制作用，具有很好的治疗潜力，值得进一步研究。
