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Aim: This study focused on designing and synthesizing novel derivatives of 3,5,8-trisubstituted coumarin. Results: The synthesized compounds, particularly compound 5 , exhibited significant cytotoxic effects on MCF-7 cells, surpassing staurosporine, and reduced toxicity toward MCF-10A cells, highlighting potential pharmacological advantages. Further, compound 5 altered the cell cycle and significantly increased apoptosis in MCF-7 cells, involving both early (41.7-fold) and late stages (33-fold), while moderately affecting necrotic signaling. The antitumor activity was linked to a notable reduction (4.78-fold) in topoisomerase IIβ expression. Molecular modeling indicated compound 5 's strong affinity for EGFR, human EGF2 and topoisomerase II proteins. Conclusion: These findings highlight compound 5 as a multifaceted antitumor agent for breast cancer.

Two novel steroidal saponins, trilliumosides K (1) and L (2), were isolated from the rhizomes of Trillium govanianum led by bioactivity-guided phytochemical investigation along with seven known compounds: govanoside D (3), protodioscin (4), borassoside E (5), 20-hydroxyecdysone (6), 5,20-hydroxyecdysone (7), govanic acid (8), and diosgenin (9). The structure of novel compounds 1-2 was established using analysis of spectroscopic data including 1D and 2D nuclear magnetic resonance (NMR) and high resolution mass spectrometry (HR-ESI-MS) data. All isolated compounds were evaluated for in vitro cytotoxic activity against a panel of human cancer cell lines. Compound 1 showed significant cytotoxic activity against the A-549 (Lung) and SW-620 (Colon) cancer cell lines with IC50 values of 1.83 and 1.85 μΜ, respectively whereas the IC50 value of Compound 2 against the A-549 cell line was found to be 1.79 μΜ. Among the previously known compounds 3, 5, and 9, the cytotoxic IC50 values were found to be in the range of 5-10 μΜ. Comprehensive anti-cancer investigation revealed that Compound 2 inhibited in vitro migration and colony-forming capability in the A-549 cell line. Additionally, the mechanistic analysis of Compound 2 on the A-549 cell line indicated distinctive alterations in nuclear morphology, increased reactive oxygen species (ROS) production, and decreased levels of mitochondrial membrane potential (MMP). By upregulating the pro-apoptotic protein BAX and downregulating the anti-apoptotic protein BCL-2, the aforementioned actions eventually cause apoptosis, a crucial hallmark in cancer research, which activates Caspase-3. To the best of our knowledge, this study reports the first mechanistic anticancer evaluation of the compounds isolated from the rhizomes of T. govanianum with remarkable cytotoxic activity in the desired micromolar range. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer in women, responsible for over half a million deaths in 2020. Almost 75% of FDA-approved drugs are mainly nitrogen- and sulfur-containing heterocyclic compounds, implying the importance of such compounds in drug discovery. Among heterocycles, thiazole-based heterocyclic compounds have demonstrated a broad range of pharmacological activities. In the present study, a novel set of 1,3-thiazole derivatives was designed and synthesized based on the coupling of acetophenone derivatives, and phenacyl bromide was substituted as a key reaction step. The activity of synthesized compounds was screened against the proliferation of two breast cancer cell lines (MCF-7 and MDA-MB-231). Almost all compounds exhibited a considerable antiproliferative activity toward the breast cancer cells as compared to staurosporine, with no significant cytotoxicity toward the epithelial cells. Among the synthesized compounds, compound 4 exhibited the most potent antiproliferative activity, with an IC50 of 5.73 and 12.15 µM toward MCF-7 and MDA-MB-231 cells, respectively, compared to staurosporine (IC50 = 6.77 and 7.03 µM, respectively). Exploring the mechanistic insights responsible for the antiproliferative activity of compound 4 revealed that compound 4 possesses a significant inhibitory activity toward the vascular endothelial growth factor receptor-2 (VEGFR-2) with (IC50 = 0.093 µM) compared to Sorafenib (IC50 = 0.059 µM). Further, compound 4 showed the ability to induce programmed cell death by triggering apoptosis and necrosis in MCF-7 cells and to induce cell cycle arrest on MCF-7 cells at the G1 stage while decreasing the cellular population in the G2/M phase. Finally, detailed in silico molecular docking studies affirmed that this class of compounds possesses a considerable binding affinity toward VEGFR2 proteins. Overall, these results indicate that compound 4 could be a promising lead compound for developing potent anti-breast cancer compounds. [ABSTRACT FROM AUTHOR]

The equilibrium between the pro-apoptotic ceramide and pro-vital sphingosine-1-phosphate is considered to be decisive for cell death or survival. The different ceramidases thus play key roles in cell fate and might offer attractive targets for pharmacological intervention. Although until recently only moderately active inhibitors have been described, first in vivo experiments suggest activity against cancer cell survival and multi-drug resistance. Here, we provide a brief overview on the different ceramidases, and we will review the known inhibitors and current strategies for further inhibitor development. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Testicular torsion (TT) is the most common urological emergency in children and young adults that can lead to infertility in many cases. The ischemia-reperfusion (IR) injury due to TT has been implicated in the pathogenesis of testicular damage. The main pathological mechanisms of contralateral injury after ipsilateral TT are not fully understood. In the presented study, we investigated the molecular and microscopic basis of ipsilateral and contralateral testicular injury following ipsilateral testicular torsion detorsion (T/D) and explored the possible protective role of vitamin D3. The biochemical analysis indicated that IR injury following T/D significantly decreased the activity of testicular glutathione peroxidase (GPx) enzyme, level of serum testosterone, serum inhibin B, and expression of testicular miRNA145, while increased the activity of testicular myeloperoxidase (MPO) enzyme, level of testicular malondialdehyde (MDA), level of serum antisperm-antibody (AsAb), and expression of ADAM-17. The histological and semen analysis revealed that torsion of the testis caused damages on different tissues in testis. Interestingly, administration of vitamin D3 prior to the IR injury reversed the deterioration effect of IR injury on the testicular tissues as indicated by biochemical and histological analysis which revealed normal appearance of the seminiferous tubules with an apparent decrease in collagen fiber deposition in both ipsilateral and contralateral testes. Our results revealed that the protective effect of vitamin D3 treatment could be attributed to target miRNA145 and ADAM17 protein. To further investigate these findings, we performed a detailed molecular modelling study in order to explore the binding affinity of vitamin D3 toward ADAM17 protein. Our results revealed that vitamin D3 has the ability to bind to the active site of ADAM17 protein via a set of hydrophobic and hydrophilic interactions with high docking score. In conclusion, this study highlights the protective pharmacological application of vitamin D3 to ameliorate the damages of testicular T/D on the testicular tissues via targeting miRNA145 and ADAM17 protein. [ABSTRACT FROM AUTHOR]