Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 24, Issue 15, 2024

Background: Globally, colorectal cancer (CRC) is categorized as the third type of cancer associated with mortalities. Chemotherapeutic drugs such as cisplatin can be used to treat cancer-affected patients. However, several adverse effects are associated with its application. This motivated the researchers to search for alternatives that are more efficient and have fewer undesirable effects. Kolaviron is a bioflavonoid that has been reported to have antioxidant and anti-inflammatory properties. Aim: This study aimed to compare the anticancer effects of kolaviron and cisplatin on Caco-2 cells. The IC50 of kolaviron and cisplatin were calculated, and redox status, apoptotic-related proteins and the cell cycle were also examined. Methods: Caco-2 cells were treated with kolaviron ( 133;“, and ½ of IC50 dose) and cisplatin (IC50 dose) for 24 h and 48 h. Cell viability was assessed using the MTT protocol. Redox status and apoptotic-related proteins, in addition to the cell cycle, were examined. Results: The MTT assay showed the IC50 of kolaviron is 9.49 μg/mL, and that of cisplatin is 2.71 μg/ml against Caco-2 cells. Further, both doses of kolaviron significantly increased the leakage of lactate dehydrogenase (LDH), the production of reactive oxygen species (ROS), and lipoperoxidation (LPO), besides decreasing the antioxidant potency of tumor cells as revealed by the diminished reduced glutathione (GSH). At the molecular level, a significant increase in the levels of p53, cytochrome c, Bax, and caspase 3 was recorded, coupled with a decrease in the level of Bcl2, after treating the Caco-2 cells with kolaviron and cisplatin. Furthermore, kolaviron demonstrated asserted more effects on apoptosis and increased cell percentage in the subG1 phase. In addition, a notable decrease in the expression of proliferating cell nuclear antigen (PCNA) and cyclin D1 is associated with an increase in the expression of tumor protein P53 (TP53) in kolaviron-treated Caco-2 cells cancerous cells. Conclusion: Conclusively, these data suggest that kolaviron has a potential antitumor capacity against colorectal cancer via multiple pathways, including enhancement of ROS production, redox status, p53 pathway, and apoptosis. Therefore, this study authenticated the capability of kolaviron as a valuable chemotherapeutic agent.

Aims: Validating the docking procedure and maintaining the structural water molecules at HDAC8 catalytic site. Background: Molecular docking simulations play a significant role in Computer-Aided Drug Design, contributing to the development of new molecules. To ensure the reliability of these simulations, a validation process called "self-docking or re-docking" is employed, focusing on the binding mode of a ligand co-crystallized with the protein of interest. Objective: In this study, several molecular docking studies were conducted using five X-ray structures of HDAC8-ligand complexes from the PDB. Methods: Ligands initially complexed with HDAC8 were removed and re-docked onto the free protein, revealing a poor reproduction of the expected binding mode. In response to this, we observed that most HDAC8-ligand complexes contained one to two water molecules in the catalytic site, which were crucial for maintaining the cocrystallized ligand. Results: These water molecules enhance the binding mode of the co-crystallized ligand by stabilizing the proteinligand complex through hydrogen bond interactions between ligand and water molecules. Notably, these interactions are lost if water molecules are removed, as is often done in classical docking methodologies. Considering this, molecular docking simulations were repeated, both with and without one or two conserved water molecules near Zn⁺² in the catalytic cavity. Simulations indicated that replicating the native binding pose of co-crystallized ligands on free HDAC8 without these water molecules was challenging, showing greater coordinate displacements (RMSD) compared to those including conserved water molecules from crystals. Conclusion: The study highlighted the importance of conserved water molecules within the active site, as their presence significantly influenced the successful reproduction of the ligands' native binding modes. The results suggest an optimal molecular docking procedure for validating methods suitable for filtering new HDAC8 inhibitors for future experimental assays.

Background: Drug resistance has been a problem in cancer chemotherapy, which often causes shortterm effectiveness. Further, the literature indicates that telomere G-quadruplex could be a promising anti-cancer target. Objective: We synthesized and characterized two new pyrimidine derivatives as ligands for G-quadruplex DNA. Methods: The interaction of novel non-cationic and cationic pyrimidine derivatives (3a, b) with G-quadruplex DNA (1k8p and 3qsc) was explored by circular dichroism (CD) and ultraviolet-visible spectroscopy and polyacrylamide gel electrophoresis (PAGE) methods. The antiproliferative activity of desired compounds was evaluated by the MTT assay. Apoptosis induction was assessed by Propidium iodide (P.I.) staining and flow cytometry. Computational molecular modeling (CMM) and molecular dynamics simulation (MD) were studied on the complexes of 1k8p and 3qsc with the compounds. The van der Waals, electrostatic, polar solvation, solventaccessible surface area (SASA), and binding energies were calculated and analyzed. Results: The experimental results confirmed that both compounds 3a and 3b interacted with 1k8p and 3qsc and exerted cytotoxic and proapoptotic effects on cancer cells. The number of hydrogen bonds and the RMSD values increased in the presence of the ligands, indicating stronger binding and suggesting increased structural dynamics. The electrostatic contribution to binding energy was higher for the cationic pyrimidine 3b, indicating more negative binding energies. Conclusion: Both experimental and MD results confirmed that 3b was more prone to form a complex with DNA G-quadruplex (1k8p and 3qsc), inhibit cell growth, and induce apoptosis, compared to the non-cationic pyrimidine 3a.

Background: Non-Small Cell Lung Cancer (NSCLC) ranks as a leading cause of cancer-related mortality, necessitating the urgent search for cost-effective and efficient anti-NSCLC drugs. Our preliminary research has demonstrated that arsenic trioxide (ATO) significantly inhibits NSCLC angiogenesis, exerting anti-tumor effects. In conjunction with existing literature reports, the Nrf2-IL-33 pathway is emerging as a novel mechanism in NSCLC angiogenesis. Objective: This study aimed to elucidate whether ATO can inhibit NSCLC angiogenesis through the Nrf2-IL-33 pathway. Methods: Immunohistochemistry was employed to assess the expression of Nrf2, IL-33, and CD31 in tumor tissues from patients with NSCLC. DETA-NONOate was used as a nitric oxide (NO) donor to mimic high levels of NO in the tumor microenvironment. Western blot, quantitative real-time PCR, and enzyme-linked immunosorbent assay were utilized to evaluate the expression of Nrf2 and IL-33 in the NCI-H1299 cell line. Subcutaneous xenograft models were established in nude mice by implanting NCI-H1299 cells to assess the anti-tumor efficacy of ATO. Results: High expression levels of Nrf2 and IL-33 were observed in tumor samples from patients with NSCLC, and Nrf2 expression positively correlated with microvascular density in NSCLC. In vitro, NO (released from 1mM DETA-NONOate) promoted activation of the Nrf2-IL-33 signaling pathway in NCI-H1299 cells, which was reversed by ATO. Additionally, both Nrf2 deficiency and ATO treatment significantly attenuated NOinduced IL-33 expression. In vivo, both ATO and the Nrf2 inhibitor ML385 demonstrated significant inhibitory effects on angiogenesis tumor growth. Conclusion: Nrf2-IL-33 signaling is usually activated in NSCLC and positively correlates with tumor angiogenesis. ATO effectively disrupts the activation of the Nrf2-IL-33 pathway in NSCLC and thus inhibits angiogenesis, suggesting its potential as an anti-angiogenic agent for use in the treatment of NSCLC.

Background: Chronic myelogenous leukemia (CML) is an uncommon type of cancer of the bone marrow associated with high mortality. Although several effective therapies have been developed to reduce symptoms in patients with CML, many of these methods are associated with side effects. Coreopsis tinctoria Nutt. (C. tinctoria) is a natural medicinal material that possesses antioxidant and anticancer activities. Yet, its effect in treating leukemia has still not been fully explored. Objective: To optimize the C. tinctoria flower extraction process and investigate whether these extracts can impair CML cell survival. Methods: The extraction process of C. tinctoria was optimized by the Box-Behnken design response surface method. K562 cells were treated with different volumes (0, 10, 25, 50, and 100 μL) of C. tinctoria flower extracts. The effect of C. tinctoria extract on cell morphology and cell apoptosis was assessed by light microscopy, laser confocal microscopy, and flow cytometry. Results: We established the following optimized C. tinctoria flower extraction conditions: temperature of 84.4°C, extraction period of 10 mins, solid-liquid ratio of 1:65, and times 4. These conditions were applied for C. tinctoria flower extraction. Pre-incubation of extracts prepared under the aforementioned optimal conditions with K562 cells induced cell cytotoxicity and cell apoptosis. Conclusion: C. tinctoria flower extracts exert obvious anti-leukemia effects in vitro and may be a potential drug candidate for leukemia treatment.

Background: The Fibroblast Growth Factor Receptor-1 (FGFR-1) is a tyrosine kinase and a validated target for the treatment of different cancer types. Objective: Design and synthesis of novel thiazole-based analogues of anticancer agents. Methods: Series of 2-aryl-5-methylthiazole analogues linked to structurally variable basic heads were synthesized as novel anticancer agents. Developed compounds were tested for their cytotoxic activities against several cancer cell lines. Results: Many analogues exhibited strong antiproliferative activities against breast cancer cell lines, with higher potency towards the highly metastatic form (MDA-MB-231). Pharmacophoric profiling using an in-house pharmacophore database identified FGFR-1 as a molecular target of active analogues. Synthesized compounds were bioassayed for their FGFR-1 inhibitory activities and many hits exhibited IC50 values in the low micromolar to nanomolar range. Conclusion: The 2-aryl-5-methylthiazole linked to a basic head is a novel chemical scaffold of ATP-competitive inhibitor of FGFR-1 with potential therapeutic activities against different types of cancer.