In this study, a series of 2-Aryl-1H-benzo[d]imidazole derivatives were developed to target intra- and extracellular microtubule networks. Compounds O-7 and O-10 showed impressive anti-proliferative activity across various tested cell lines, demonstrating selectivity indexes of 151.7 and 61.9, respectively. O-7 achieved an IC₅₀ value of 0.236 ± 0.096 μM, while O-10 showed an IC₅₀ value of 0.622 ± 0.13 μM against A549 cell lines. The induction of early-stage apoptosis in a dose-dependent manner further underscored the potential of O-7 and O-10 as effective anti-proliferative agents. O-7 and O-10 exhibited substantial inhibition of wound closure, with wound closure percentages decreasing from 23% at 0 μM to 0.43% and 2.62% at 20 μM, respectively. Colony formation reduction rates were impressive, with O-7 at 74.2% and O-10 at 81.2%. These results indicate that the O-7 and O-10 can impede cancer cell migration and have a high potential to curtail colony formation. The mode of action investigations for O-7 and O-10 revealed that O-7 could inhibit in vitro tubulin polymerization and disrupt the intracellular microtubule cytoskeleton. This disruption led to cell cycle arrest in the G₂/M phase, indicating that O-7 exerts its anticancer activity through microtubule destabilization. However, O-10 shows a different mode of action than O-7 and requires further investigation. Overall, our study showcases the potential of the synthesized benzimidazole derivatives as novel and selective anticancer agents, motivating further exploration of their pharmacological properties and therapeutic applications.

2024-01-01·JMA Journal

Characteristics of Fresh Lumbar Spondylolysis Occurring below the Age of 9 Years

Article

作者: Ishikawa, Tetsuya ; Himi, Ryo ; Sugiyama, Takaya ; Watanabe, Kazuma

IntroductionThis study aimed to compare two groups (9 years or younger [U-9] and 10 years or older [O-10]) of patients with fresh lumbar spondylolysis and elucidate their characteristics.MethodsThis study enrolled 51 elementary school students diagnosed with fresh lumbar spondylolysis through magnetic resonance imaging between March 2015 and March 2022. Study 1 included 10 and 46 patients in the early- and late-grade groups, respectively. Patient characteristics at disease onset (sex, presence or absence of spina bifida occulta [SBO] in the affected vertebra, vertebral level, unilaterality or bilaterality of lesions, presence of a contralateral terminal stage, and disease stage) were compared between the two groups. Meanwhile, Study 2 included 34 patients with confirmed successful or failed bone union. The bone union rates in both groups were compared, and the factors affecting bone union in the entire study cohort were examined.ResultsIn Study 1, the proportions of SBO, bilateral, and advanced stage cases were significantly higher in the U-9 group than in the O-10 group. In Study 2, the bone union rate was significantly lower in the U-9 group than in the O-10 group.ConclusionsThe proportions of SBO, bilateral, and advanced stage cases were significantly higher in the U-9 group than in the O-10 group. The bone union rate was significantly lower in the U-9 group than in the O-10 group.

2023-06-01·Bioorganic & medicinal chemistry letters

Discovery of imidazo[1,2-b]pyridazine macrocyclic derivatives as novel ALK inhibitors capable of combating multiple resistant mutants.

Article

作者: Yang, Yulei ; Xu, Hongjiang ; Chen, Yinbo ; Xie, Zhendong ; Yu, Xihua ; Xu, Yunsheng ; Zhu, Xueyan ; Zhao, Weiwei ; Zhang, Peng ; Xiao, Xiaofei

Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) often loses effectiveness against non-small cell lung malignancies (NSCLCs) with ALK gene rearrangements (ALK⁺).19 Novel imidazo[1,2-b]pyridazine macrocyclic derivatives, e.g., I, were designed, synthesized, and tested for their biol. activities in an effort to develop ALK inhibitors that would overcome second-generation ALK-TKIs, particularly G1202R mutation and lorlatinib-resistant L1196M/G1202R double mutations.Of all target substances, compound I had most effective enzymic inhibitory activity, with IC₅₀ values for ALK^WT, ALK^G1202R, and ALK^{L1196M/G1202R} of 2.6, 6.4, and 23 nM, resp.Compound I, on other hand, reduced growth of ALK-pos. Karpas299, BaF3-EML4-ALK^G1202R, and BaF3-EML4-ALK^{L1196M/G1202R} cells with IC₅₀ values of 38, 52, and 64 nM, resp.This was equally effective to reference drug Repotrectinib (IC₅₀ = 40, 164, and 208 nM).The kinase selectivity profile, liver microsome stability test and in vivo pharmacokinetic properties in SD rats of compound I were further evaluated.Compound I was regarded as an effective ALK inhibitor for treatment of mutations overall.

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