Khusnutdinova Elmira, Petrova Anastasiya, Zileeva Zulfia, Kuzmina Ulyana, Zainullina Liana, Vakhitova Yulia, Babkov Denis, Kazakova Oxana
Ufa Institute of Chemistry UFRC RAS, 71 pr. Oktyabrya, 450054 Ufa, Russia.
Institute of Biochemistry and Genetics UFRC RAS, 71 pr. Oktyabrya, 450054 Ufa, Russia.
Int J Mol Sci. 2021 Sep 10;22(18):9796. doi: 10.3390/ijms22189796.
A series of A-ring modified oleanolic and ursolic acid derivatives including C28 amides (3-oxo-C2-nicotinoylidene/furfurylidene, 3β-hydroxy-C2-nicotinoylidene, 3β-nicotinoyloxy-, 2-cyano-3,4-seco-4(23)-ene, indolo-, lactame and azepane) were synthesized and screened for their cytotoxic activity against the NCI-60 cancer cell line panel. The results of the first assay of thirty-two tested compounds showed that eleven derivatives exhibited cytotoxicity against cancer cells, and six of them were selected for complete dose-response studies. A systematic study of local SARs has been carried out by comparative analysis of potency distributions and similarity relationships among the synthesized compounds using network-like similarity graphs. Among the oleanane type triterpenoids, C2-[4-pyridinylidene]-oleanonic C28-morpholinyl amide exhibited sub-micromolar potencies against 15 different tumor cell lines and revealed particular selectivity for non-small cell lung cancer (HOP-92) with a GI value of 0.0347 μM. On the other hand, superior results were observed for C2-[3-pyridinylidene]-ursonic -methyl-piperazinyl amide , which exhibited a broad-spectrum inhibition activity with GI < 1 μM against 33 tumor cell lines and <2 μM against all 60 cell lines. This compound has been further evaluated for cell cycle analysis to decipher the mechanism of action. The data indicate that compound could exhibit both cytostatic and cytotoxic activity, depending on the cell line evaluated. The cytostatic activity appears to be determined by induction of the cell cycle arrest at the S (MCF-7, SH-SY5Y cells) or G/G phases (A549 cells), whereas cytotoxicity of the compound against normal cells is nonspecific and arises from apoptosis without significant alterations in cell cycle distribution (HEK293 cells). Our results suggest that the antiproliferative effect of compound is mediated through ROS-triggered apoptosis that involves mitochondrial membrane potential depolarization and caspase activation.
合成了一系列A环修饰的齐墩果酸和熊果酸衍生物，包括C28酰胺（3-氧代-C2-烟酰亚胺/糠叉亚胺、3β-羟基-C2-烟酰亚胺、3β-烟酰氧基、2-氰基-3,4-开环-4(23)-烯、吲哚、内酰胺和氮杂环庚烷），并针对NCI-60癌细胞系进行了细胞毒性活性筛选。对32种受试化合物的首次检测结果表明，11种衍生物对癌细胞具有细胞毒性，其中6种被选作完整的剂量反应研究。通过使用类网络相似性图对合成化合物之间的效价分布和相似性关系进行比较分析，对局部构效关系进行了系统研究。在齐墩果烷型三萜类化合物中，C2-[4-吡啶基亚基]-齐墩果烷型C28-吗啉基酰胺对15种不同肿瘤细胞系表现出亚微摩尔效价，对非小细胞肺癌（HOP-92）具有特殊选择性，GI值为0.0347μM。另一方面，C2-[3-吡啶基亚基]-熊果烷型-N-甲基-哌嗪基酰胺表现出更优异的结果，它对33种肿瘤细胞系表现出GI<1μM的广谱抑制活性，对所有60种细胞系表现出GI<2μM的抑制活性。该化合物已进一步进行细胞周期分析以阐明其作用机制。数据表明，根据所评估的细胞系不同，该化合物可能表现出细胞生长抑制和细胞毒性活性。细胞生长抑制活性似乎是由细胞周期阻滞在S期（MCF-7、SH-SY5Y细胞）或G1/G0期（A549细胞）所决定的，而该化合物对正常细胞的细胞毒性是非特异性的，是由凋亡引起的，细胞周期分布无明显改变（HEK293细胞）。我们的结果表明，该化合物的抗增殖作用是通过ROS触发的凋亡介导的，这涉及线粒体膜电位去极化和半胱天冬酶激活。
