Kornev Anton A, Shmakov Stanislav V, Ponyaev Alexander I, Stepakov Alexander V, Boitsov Vitali M
Laboratory of Nanobiotechnologies, Saint-Petersburg National Research Academic University of the Russian Academy of Sciences, Saint Petersburg 194021, Russia.
Saint-Petersburg State Institute of Technology, Saint Petersburg 190013, Russia.
Pharmaceuticals (Basel). 2024 Nov 25;17(12):1582. doi: 10.3390/ph17121582.
: A series of spiro-fused heterocyclic compounds containing cyclopropa[a]pyrrolizidine-2,3'-oxindole and 3-spiro[3-azabicyclo[3.1.0]-hexane]oxindole frameworks were synthesized and studied for their in vitro antiproliferative activity against human erythroleukemia (K562), cervical carcinoma (HeLa), acute T cell leukemia (Jurkat), melanoma (Sk-mel-2) and breast cancer (MCF-7) as well as mouse colon carcinoma (CT26) cell lines. : Cell proliferation was evaluated in vitro by MTS assay. Confocal microscopy was used to study actin cytoskeleton structure and cell motility. Cell cycle analysis was evaluated by flow cytometry. : It was found that compounds , , and showed antiproliferative activity against the Jurkat, K-562, HeLa and Sk-mel-2 cell lines with IC ranging from 2 to 10 μM (72 h). Evaluation of the impact on cell cycle progression showed that the tested compounds achieved significant cell-cycle perturbation with a higher accumulation of cells in the SubG1 and G0/G1 phases of the cell cycle, in comparison to the negative control. I Incubation with tested compounds led to the disappearance of stress fibers (granular actin was distributed diffusely in the cytoplasm in up to 38% of treated HeLa cells) and changes in the number of filopodia-like deformations (reduced from 93% in control cells to 64% after treatment). The impact on the Sk-mel-2 cell actin cytoskeleton structure was even greater: granular actin was distributed diffusely in the cytoplasm in up to 90% of treated cells while the number of filopodia-like deformations was reduced by up to 23%. A scratch test performed on the human melanoma cell line showed that these cells did not fill the scratched strip and lose their ability to move under treatment. : The obtained results support the antitumor effect of the tested spiro-compounds and encourage the extension of this study in order to improve their anticancer activity as well as reduce their toxicological risks.
合成了一系列含有环丙[a]吡咯里西啶-2,3'-氧化吲哚和3-螺[3-氮杂双环[3.1.0]己烷]氧化吲哚骨架的螺稠杂环化合物，并研究了它们对人红白血病（K562）、宫颈癌（HeLa）、急性T细胞白血病（Jurkat）、黑色素瘤（Sk-mel-2）和乳腺癌（MCF-7）以及小鼠结肠癌（CT26）细胞系的体外抗增殖活性。通过MTS法在体外评估细胞增殖。共聚焦显微镜用于研究肌动蛋白细胞骨架结构和细胞运动性。通过流式细胞术评估细胞周期分析。结果发现，化合物 、 、 和 对Jurkat、K-562、HeLa和Sk-mel-2细胞系具有抗增殖活性，IC50范围为2至10 μM（72小时）。对细胞周期进程影响的评估表明，与阴性对照相比，测试化合物导致细胞周期明显紊乱，细胞在细胞周期的SubG1和G0/G1期积累增加。用测试化合物孵育导致应力纤维消失（在高达38%的经处理的HeLa细胞中，颗粒状肌动蛋白在细胞质中呈弥漫性分布）以及丝状伪足样变形数量的变化（从对照细胞中的93%减少到处理后的64%）。对Sk-mel-2细胞肌动蛋白细胞骨架结构的影响甚至更大：在高达90%的经处理细胞中，颗粒状肌动蛋白在细胞质中呈弥漫性分布，而丝状伪足样变形数量减少多达23%。对人黑色素瘤细胞系进行的划痕试验表明，这些细胞在处理后没有填满划痕条并失去移动能力。获得的结果支持测试的螺环化合物的抗肿瘤作用，并鼓励扩展该研究以提高其抗癌活性并降低其毒理学风险。
