Current medicinal chemistry最新文献

Background: Calix[n]arenes have attracted great attention due to their biocompatibility and superior stability. When the necessary functional groups are attached to these compounds, they may have the potential to target tumor tissues. Benzimidazoles were among the anticancer drugs discovered in recent years.

Aim: The aim of this study was to design and synthesise a series of calix[4]arenes-benzimidazole. For comparison purposes, a benzimidazole derivative was synthesized by attaching it to the diester. Present the anticancer effects of these compounds by performing cell proliferation, apoptosis and cell imaging studies in cancer cell lines.

Methods: Some of the obtained compounds were synthesized by methods in literature studies, and the rest were synthesized by modifying previous methods. As a result, a total of 3 new fluorescent calix[4]arene-benzimidazole derivatives were synthesized. MTT was used for cell proliferation, and Annexin V was used for apoptosis studies. For Confocal imaging studies, cells were treated with DAPI and MitoTracker dyes.

Results: Four designed calix[4]arene-benzimidazole were successfully synthesized and structurally confirmed by NMR, and IR spectroscopy. Anticancer study of four synthesized substances was performed. Bio-imaging studies were performed using Confocal Microscopy for these three successfully synthesized fluorescent compounds.

Conclusion: CB5-a and CB5-b were found to be the most effective against HT-29 cells and CB5-c against HELA cells in the MTT test. Apoptosis analyses also proved that these compounds inhibited the proliferation of cancer cells. As a comparison substance, the synthesized CB5-R proven to be less cytotoxic than the fluorescent compounds by the MTT method, and we can say that the cationic compound bound to the calix[4]arene is more effective than the molecule bound to the diester.

Lipids play a variety of roles in living systems. They are a source of extremely high energy and a part of almost all signaling and biological processes. Despite the liver being the hub of lipid metabolism, lipid metabolism occurs across the human body. Any perturbation in the lipid metabolism or lipid storage systems can lead to diseases or disorders that can hamper the normal functioning of the human body. Lipids have been explored for their role in cancers. The intake of saturated fatty acids has been found to increase the metastasis and growth of cancerous cells. The role of lipids has also been studied in brain diseases. In Tay-Sachs disease, the inability to metabolize GM2 ganglioside alters normal nerve cell functioning. Similarly, lipids also play critical roles in Parkinson's and Alzheimer's disease. Moreover, atherosclerosis is a leading cause of cardiovascular diseases and brain stroke. Dyslipidemia or excess fatty acids is a leading cause of non-alcoholic fatty liver disease, insulin resistance, and diabetes mellitus. Dyslipidemia also leads to jaundice, which, in turn, can seriously damage the kidneys. This review focuses on the various human diseases occurring because of lipid metabolism.

The present review was undertaken to clarify the potential role of the lysyl oxidase (Lox) family of enzymes in delaying graft dysfunction. Delayed graft failure is a well-known event that occurs post-transplantation period. Ischemia and trauma to the graft tissue before or during the operation procedures are likely to be the most important etiological causes of this complication. The lox proteins family including Lox and Lox-- like proteins (LoxL1-4) are copper-dependent enzymes that catalyze the cross-linking of collagens to stabilize extracellular matrix (ECM). Hypoxia-induced factor 1-α (HIF-1α) and transforming growth factor β (TGF-β) are two upstream regulators of the Lox proteins family whose expression increased following hypoxia and tissue injury. Lox proteins' overactivation upregulates several intracellular transduction pathways to promote oxidative stress (OS), ECM proteins accumulation, and epithelial to mesenchymal transition (EMT) contribute to vascular stiffness and tissue fibrogenesis, which increase the risk of graft failure post solid organ transplantation (SOT). Preclinical studies have shown that Lox protein inhibitors have the potential to prevent organ fibrosis. Regarding the molecular effects of Lox proteins in causing tissue fibrosis, these molecules can be further investigated as a drug target in reducing the possibility of organ fibrosis after allograft transplantation.

Background: Infertility was often considered a female issue, but male infertility emerged significantly after the Covid-19 pandemic. Hence, assessments are crucial for planning policies on health care and family planning and reasons thereof post vaccinations.

Material and methods: The present study was a case-control, dual-centers, prospective study with normal sperm parameters. Semen samples collected by masturbation for idiopathic reasons were conducted at King Abdulaziz University with 133 samples, followed by molecular modeling via interaction between IZUMO1, Alpha2A adrenergic receptor, and Fibroblast growth factor receptor 2 protein with IgA antibody produced post vaccination/infection.

Results & discussion: The infertile males under 30 (21%), 31-40 (50%), 41-50 (24%) and over 50 (5%), with altered sperm motility grades are A (8.45%), B (11.1%), C (15.8%), and D (59.8%) were reported. Liquefaction times range from 36 to 30 minutes by age, with abnormal sperm percentages between 43.85% and 46.33%. Protein molecular interaction between IZUMO1, Alpha2A adrenergic receptor, and Fibroblast growth factor receptor 2 protein with IgA antibody shows cumulative length of 25.354 Å, 39.049 Å, and 41.999 Å, respectively, with significant interaction between atoms chain, amino acid, marked variation in bond length.

Conclusion: Male infertility peaks at 31-40 years, with lowering in men aged 41-50 years, IgA antibody reduced sperm motility, causing immunogenic infertility exacerbated post-Covid-19 vaccination or infection. Interaction of IgA and various receptors produced stable interactive molecules of IgA and proteins on sperm, affecting motility, aliquefication, and abnormal sperm percentage disturbing the normal dynamics of sperm cells opening a new dimension of infertility among males.

Mercury is a pervasive global pollutant, with primary anthropogenic sources including mining, industrial processes, and mercury-containing products such as dental amalgams. These sources release mercury into the environment, where it accumulates in ecosystems and enters the food chain, notably through bioamplification in marine life, posing a risk to human health. Dental amalgams, widely used for over a century, serve as a significant endogenous source of inorganic mercury. Studies have demonstrated that mercury vapor can be released from amalgams at room temperature due to material corrosion, potentially leading to chronic exposure. Pregnant women and children are particularly susceptible to mercury's toxic effects, with research linking prenatal mercury exposure to developmental delays, neurocognitive deficits, and conditions such as autism spectrum disorder. Moreover, the long-term accumulation of mercury in the body raises concerns about delayed health impacts in individuals exposed during childhood. Recent findings suggest even low levels of mercury exposure may contribute to kidney damage mediated by oxidative stress, highlighting the importance of monitoring mercury levels in vulnerable populations. Prenatal mercury transfer and postnatal exposure through breastfeeding further amplify the risks. This review critically assesses the health implications of mercury exposure from dental amalgams, focusing on its impact on pregnancy and childhood development. It underscores the need for updated regulatory measures to mitigate mercury-related risks and calls for further research to clarify the extent of mercury's long-term effects on human health.

The investigation of naturally derived anticancer drugs has gained prominence in cancer therapy research. Within a broad context, this review seeks to elucidate the molecular foundations and diverse mechanisms underlying these compounds to understand their pivotal role in advancing effective interventions. Additionally by employing a systematic approach, this study examined the interplay between cellular components, signaling pathways, and genetic factors, providing valuable insights into the regulatory networks governing the efficacy of these drugs. Categorization based on sources (plants, animals, marine organisms, and microbes) revealed unique bioactive constituents and therapeutic potential. Mechanistic investigations have revealed the ability of these compounds to induce apoptosis, inhibit angiogenesis, modulate metabolic processes, stimulate the immune system, and arrest the cell cycle. This overview encompasses both approved drugs and those undergoing clinical trials, highlighting their heightened efficacy and reduced toxicity compared to their synthetic counterparts. However, challenges persist in terms of standardization, quality control, and large-scale production. In conclusion, this review examined the potential of naturally derived anticancer drugs to contribute to advancements in cancer treatment and enhance patient outcomes. In addition to their effectiveness, natural anticancer drugs are generally less toxic and have fewer harmful side effects than conventional chemotherapies. This emphasizes the need for continued research, collaborative efforts, and addressing the regulatory and intellectual property challenges associated with natural products. This review provides a balanced perspective on the mechanisms, advantages, and prospects.

Introduction: Arjunolic acid, a well-known natural product with various medicinal properties, was isolated from the heartwood of Terminalia arjuna. Various amides of arjunolic acid were synthesized using different aryl and cyclic amines, characterized, and evaluated for their anti-cancer activities at the National Cancer Institute (NCI).

Method: All the derivatives were active against all the cell lines of NCI compared to the parent molecule arjunolic acid. Eight compounds were selected for dose-dependent activity based on the preliminary results. IC50 of selected eight compounds was evaluated. Based on IC50 values against various cell lines, compound 2l was further investigated to understand the mechanism of action against HCT-116 and CT-26 colon cancer cell lines.

Result: Mechanistic studies of compound 2l in these two cell lines demonstrated that compound 2l arrested the colon cancer cells at the G/G1 phase. Compound 2l-treated cells were also found to have an increased percentage of ROS compared to untreated cells. It induced apoptosis in both these cell lines.

Conclusion: Compound 2l was found to inhibit cancer growth in the mice model and was very effective against all the cancer cell lines. Therefore, it could be used for further development to treat colon cancer.

Background: Super-enhancer-associated long noncoding RNAs (SE-lncRNAs) play crucial roles in CRC pathogenesis.

Objective: RP11-803D5.4 and AC005592.2 were identified as SE-lncRNAs of interest via microarray analysis, and our study aimed to evaluate their clinical value in CRC diagnosis and prognosis assessment.

Methods: Fluorescence quantitative real-time PCR (qRT-PCR) was used to measure the expression of RP11-803D5.4 and AC005592.2 in the tissues and serum of CRC patients. Receiver operating characteristic (ROC) curves were generated to determine the predictive value of the two SE-lncRNAs. Functional assays were applied to assess the ability of RP11-803D5.4 to promote the proliferation, migration, and invasion of CRC cells.

Results: The two SE-lncRNAs were significantly upregulated in CRC tissue and serum samples vs. corresponding controls. ROC curve analysis indicated that RP11-803D5.4 (AUC=0.842) and AC005592.2 (AUC=0.811) had a high diagnostic performance for CRC. The combination of RP11-803D5.4, AC005592.2, and CEA had an AUC of 0.946 and distinguished CRC patients and healthy controls better than SE-lncRNA alone. The serum levels of RP11-803D5.4 and AC005592.2 were strongly correlated with their tissue expression levels. The expression levels of the two SE-lncRNAs were significantly lower in postoperative samples than in preoperative samples. Furthermore, similar to the findings of previous studies on AC005592.2, high RP11-803D5.4 expression promoted the proliferation, invasion, and migration of CRC cells.

Conclusion: The findings suggested that RP11-803D5.4 and AC005592.2 are upregulated in CRCact and are crucial promoters of CRC progression. They also suggested that they might serve as noninvasive biomarkers for diagnosing CRC.

With the escalation of viral infections in recent decades, including the COVID- 19 pandemic, viral infectious diseases have increasingly become a global concern, attracting significant attention. Among many viral epidemics, the dengue virus, an RNA virus from the Flaviviridae family, has been reported by the WHO as one of the most prevalent mosquito-borne diseases, infecting roughly 400 million people yearly and spreading across all continents worldwide. In the last two decades, researchers from academia and industry have diligently studied many aspects of the virus, including its structure, life cycle, potential therapeutic agents, and vaccines. Dengvaxia® and Qdenga®, approved vaccines for DENV-4, have been a milestone in dengue prevention and treatment. However, these vaccines have some noticeable drawbacks, including Dengvaxia® being a monovalent vaccine against DENV-4 with a risk of severe dengue infection following the first use, Qdenga® being mainly effective for all 4 serotypes only in the cases of previously infected patients while being effective against only DENV-1 and DENV-2 in dengue-naïve patients. Additionally, no drug against dengue has been approved. Thus, numerous screening campaigns have been conducted on both natural and synthesized substances to search for anti-dengue agents, especially those targeting the virus's key protease (NS2B/NS3), to mitigate the dengue fever epidemic. As hit screening is only the first step in the drug discovery and development cycle, subsequent in-depth analyses (using a wide range of approaches from computational simulations to protein-ligand co-crystallization) have been conducted to provide more insights into the characteristics of optimal DENV NS2B/NS3 protease inhibitors. This review discusses recent discoveries in the search for novel inhibitors and highlights the importance of understanding the structural relationship between hits and the NS2B/NS3 protease for effective lead optimization.