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鉴定螺环[3-氮杂双环[3.1.0]己烷]氧吲哚类化合物作为潜在的抗肿瘤药物:初步体外评价其在 3T3 和 3T3-SV40 成纤维细胞中的抗增殖作用和肌动蛋白细胞骨架转化。

Identification of Spiro-Fused [3-azabicyclo[3.1.0]hexane]oxindoles as Potential Antitumor Agents: Initial In Vitro Evaluation of Anti-Proliferative Effect and Actin Cytoskeleton Transformation in 3T3 and 3T3-SV40 Fibroblast.

机构信息

Saint-Petersburg Clinical Scientific and Practical Center for Specialized Types of Medical Care (Oncological), 197758 Saint Petersburg, Russia.

Institute of Cytology, Russian Academy of Sciences, 194064 Saint Petersburg, Russia.

出版信息

Int J Mol Sci. 2021 Jul 31;22(15):8264. doi: 10.3390/ijms22158264.

Abstract

Novel heterocyclic compounds containing 3-spiro[3-azabicyclo[3.1.0]hexane]oxindole framework (, and ) have been studied as potential antitumor agents. The in silico ADMET (adsorption, distribution, metabolism, excretion and toxicity) analysis was performed on - compounds with promising antiproliferative activity, previously synthetized and screened against human erythroleukemic cell line K562 tumor cell line. Cytotoxicity of - against murine fibroblast 3T3 and SV-40 transformed murine fibroblast 3T3-SV40 cell lines were evaluated. The and compounds were cytotoxic against 3T3-SV40 cells in comparison with those of 3T3. In agreement with the DNA cytometry studies, the tested compounds have achieved significant cell-cycle perturbation with higher accumulation of cells in G0/G1 phase. Using confocal microscopy, we found that with and treatment of 3T3 cells, actin filaments disappeared, and granular actin was distributed diffusely in the cytoplasm in 82-97% of cells. The number of 3T3-SV40 cells with stress fibers increased to 7-30% against 2% in control. We discovered that transformed 3T3-SV40 cells after treatment with compounds and significantly reduced the number of cells with filopodium-like membrane protrusions (from 86 % in control cells to 6-18% after treatment), which indirectly suggests a decrease in cell motility. We can conclude that the studied compounds and have a cytostatic effect, which can lead to a decrease in the number of filopodium-like membrane protrusions.

摘要

新型含 3-螺[3-氮杂双环[3.1.0]己烷]色满骨架的杂环化合物(, 和 )已被研究作为潜在的抗肿瘤药物。对具有有前景的增殖抑制活性的 - 化合物进行了计算机辅助的 ADMET(吸收、分布、代谢、排泄和毒性)分析,这些化合物先前已经被合成并针对人红白血病细胞系 K562 肿瘤细胞系进行了筛选。评估了 - 对小鼠成纤维细胞 3T3 和 SV-40 转化的小鼠成纤维细胞 3T3-SV40 细胞系的细胞毒性。与 3T3 相比, 和 化合物对 3T3-SV40 细胞具有细胞毒性。与 DNA 细胞周期分析研究一致,测试的化合物实现了显著的细胞周期扰乱,使更多的细胞在 G0/G1 期积累。通过共聚焦显微镜观察,我们发现用 和 处理 3T3 细胞时,肌动蛋白丝消失,颗粒状肌动蛋白在细胞质中弥散分布,在 82-97%的细胞中。与对照中的 2%相比,具有应激纤维的 3T3-SV40 细胞的数量增加到 7-30%。我们发现用化合物 和 处理后,转化的 3T3-SV40 细胞中具有类似丝状伪足的细胞膜突起的细胞数量显著减少(从对照细胞中的 86%减少到处理后的 6-18%),这间接表明细胞迁移能力降低。我们可以得出结论,研究的化合物 和 具有细胞停滞作用,可导致类似丝状伪足的细胞膜突起数量减少。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e43c/8347490/57ef30912f8b/ijms-22-08264-g001.jpg

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