Current Medicinal Chemistry - Volume 28, Issue 2, 2021

Cannabidiol (CBD) is a non-psychotropic phytocannabinoid which represents one of the constituents of the “phytocomplex” of Cannabis sativa. This natural compound is attracting growing interest since when CBD-based remedies and commercial products were marketed. This review aims to exhaustively address the extractive and analytical approaches that have been developed for the isolation and quantification of CBD. Recent updates on cutting-edge technologies were critically examined in terms of yield, sensitivity, flexibility and performances in general, and are reviewed alongside original representative results. As an add-on to currently available contributions in the literature, the evolution of the novel, efficient synthetic approaches for the preparation of CBD, a procedure which is appealing for the pharmaceutical industry, is also discussed. Moreover, with the increasing interest on the therapeutic potential of CBD and the limited understanding of the undergoing biochemical pathways, the reader will be updated about recent in silico studies on the molecular interactions of CBD towards several different targets attempting to fill this gap. Computational data retrieved from the literature have been integrated with novel in silico experiments, critically discussed to provide a comprehensive and updated overview on the undebatable potential of CBD and its therapeutic profile.

Pterostilbene, a phenolic compound derived from resveratrol, possesses greater bioavailability than its parent compound due to the presence of two methoxyl groups. In this review, the beneficial effects of pterostilbene on diabetes, liver steatosis and dyslipidemia are summarized. Pterostilbene is a useful bioactive compound in preventing type 1 diabetes, insulin resistance and type 2 diabetes in animal models. Concerning type 1 diabetes, the main mechanisms described to justify the positive effects of this phenolic compound are increased liver glycogen content and hepatic glucokinase and phosphofructokinase activities, the recovery of pancreatic islet architecture, cytoprotection and a decrease in serum and pancreatic pro-inflammatory cytokines. As for type 2 diabetes, increased liver glucokinase and glucose-6-phosphatase and decreased fructose-1,6-biphosphatase activities are reported. When insulin resistance is induced by diets, a greater activation of insulin signaling cascade has been reported, increased cardiotrophin-1 levels and liver glucokinase and glucose- 6-phosphatase activities, and a decreased fructose-1,6-biphosphatase activity. Data concerning pterostilbene and liver steatosis are scarce so far, but the reduction in oxidative stress induced by pterostilbene may be involved since oxidative stress is related to the progression of steatosis to steatohepatitis. Finally, pterostilbene effectively reduces total cholesterol, LDL-cholesterol and serum triglyceride levels, while increases HDL-cholesterol in animal models of dyslipidemia.

Background: The elucidation of the structure of cyclin-dependent kinase 2 (CDK2) made it possible to develop targeted scoring functions for virtual screening aimed to identify new inhibitors for this enzyme. CDK2 is a protein target for the development of drugs intended to modulate cellcycle progression and control. Such drugs have potential anticancer activities. Objective: Our goal here is to review recent applications of machine learning methods to predict ligand- binding affinity for protein targets. To assess the predictive performance of classical scoring functions and targeted scoring functions, we focused our analysis on CDK2 structures. Methods: We have experimental structural data for hundreds of binary complexes of CDK2 with different ligands, many of them with inhibition constant information. We investigate here computational methods to calculate the binding affinity of CDK2 through classical scoring functions and machine- learning models. Results: Analysis of the predictive performance of classical scoring functions available in docking programs such as Molegro Virtual Docker, AutoDock4, and Autodock Vina indicated that these methods failed to predict binding affinity with significant correlation with experimental data. Targeted scoring functions developed through supervised machine learning techniques showed a significant correlation with experimental data. Conclusion: Here, we described the application of supervised machine learning techniques to generate a scoring function to predict binding affinity. Machine learning models showed superior predictive performance when compared with classical scoring functions. Analysis of the computational models obtained through machine learning could capture essential structural features responsible for binding affinity against CDK2.

A large plethora of drugs and promising lead compounds contain halogens in their structures. The introduction of such moieties strongly modulates their physical-chemical features as well as pharmacokinetic and pharmacodynamic profile. The most important outcome was shown to be the ability of these halogens to favourably influence the drug-target interaction and energetic stability within the active site by the establishment of halogen bonds. This review attempted to demonstrate the key role exerted by these versatile moieties when correctly located in an organic scaffold to display Monoamine Oxidase (MAO) inhibition and selectivity towards the B isoform of this important enzyme. Human MAOs are well-recognized as therapeutic targets for mood disorders and neurodegenerative diseases and medicinal chemists were prompted to discover the structural requirements crucial to discriminate the slight differences between the active sits of the two isoforms (MAO-A and MAOB). The analysis of the structure-activity relationships of the most important scaffolds (hydrazothiazoles, coumarins, chromones, chalcones, pyrazolines) and the impact of halogen (F, Cl, Br and I) insertion on this biological activity and isozyme selectivity have been reported being a source of inspiration for the medicinal chemists.

The COVID-19 pandemic continues to wreak havoc worldwide due to the lack of risk assessment, rapid spreading ability, and propensity to precipitate severe disease in comorbid conditions. In an attempt to fulfill the demand for prophylactic and treatment measures to intercept the ongoing outbreak, the drug development process is facing several obstacles and renaissance in clinical trials, including vaccines, antivirals, immunomodulators, plasma therapy, and traditional medicines. This review outlines the overview of SARS-CoV-2 infection, significant recent findings, and ongoing clinical trials concerning current and future therapeutic interventions for the management of advancing pandemic of the century.

Lung cancer is a malignancy with a high morbidity and mortality rate, and affected patients have low survival and poor prognosis. The therapeutic approaches for the treatment of this cancer, including radiotherapy and chemotherapy, are not particularly effective partly due to late diagnosis. Therefore, the search for new diagnostic and prognostic tools is a critical issue. Novel biomarkers, such as exosomes, could be considered as potential diagnostic tools for malignancies, particularly lung cancer. Exosomes are nanovesicles, which are associated with different physiological and pathological conditions. It has been shown that these particles are released from many cells, such as cancer cells, immune cells and to some degree normal cells. Exosomes could alter the behavior of target cells through intercellular transfer of their cargo (e.g. DNA, mRNA, long non-coding RNAs, microRNAs and proteins). Thus, these vehicles may play pivotal roles in various physiological and pathological conditions. The current insights into lung cancer pathogenesis suggest that exosomes are key players in the pathogenesis of this cancer. Hence, these nanovesicles and their cargos could be used as new diagnostic, prognostic and therapeutic biomarkers in the treatment of lung cancer. Besides the diagnostic roles of exosomes, their use as drug delivery systems and as cancer vaccines is under investigation. The present review summarizes the current information on the diagnostic and pathogenic functions of exosomes in lung cancer.

Background: Artemisinin is a sesquiterpene lactone compound with a special peroxide bridge that is tightly linked to the cytotoxicity involved in fighting malaria and cancer. Artemisinin and its derivatives (ARTs) are considered to be potential anticancer drugs that promote cancer cell apoptosis, induce cell cycle arrest and autophagy, inhibit cancer cell invasion and migration. Additionally, ARTs significantly increase intracellular Reactive Oxygen Species (ROS) in cancer cells, which result in ferroptosis, a new form of cell death, depending on the ferritin concentration. Ferroptosis is regarded as a cancer suppressor and as well as considered a new mechanism for cancer therapy. Methods: The anticancer activities of ARTs and reference molecules were compared by literature search and analysis. The latest research progress on ferroptosis was described, with a special focus on the molecular mechanism of artemisinin-induced ferroptosis. Results: Artemisinin derivatives, artemisinin-derived dimers, hybrids and artemisinin-transferrin conjugates, could significantly improve anticancer activity, and their IC50 values are lower than those of reference molecules such as doxorubicin and paclitaxel. The biological activities of linkers in dimers and hybrids are important in the drug design processes. ARTs induce ferroptosis mainly by triggering intracellular ROS production, promoting the lysosomal degradation of ferritin and regulating the System Xc-/Gpx4 axis. Interestingly, ARTs also stimulate the feedback inhibition pathway. Conclusion: Artemisinin and its derivatives could be used in the future as cancer therapies with broader applications due to their induction of ferroptosis. Meanwhile, more attention should be paid to the development of novel artemisinin-related drugs based on the mechanism of artemisinininduced ferroptosis.

Nanomedicine is a good alternative to traditional methods of cancer treatment but does not solve all the limitations of oncology. Nanoparticles used in anticancer therapy can work as carriers of drugs, nucleic acids, imaging agents or they can sensitize cells to radiation. The present review focuses on the application of nanoparticles to treating cancer, as well as on its problems and limitations. Using nanoparticles as drug carriers, significant improvement in the efficiency of transport of compounds and their targeting directly to the tumour has been achieved; it also reduces the side effects of chemotherapeutic drugs on the body. However, nanoparticles do not significantly improve the effectiveness of the chemotherapeutic agent itself. Most nanodrugs can reduce the toxicity of chemotherapy, but do not significantly affect the effectiveness of treatment. Nanodrugs should be developed that can be effective as an anti-metastatic treatment, e.g. by enhancing the ability of nanoparticles to transport chemotherapeutic loads to sentinel lymph nodes using the immune system and developing chemotherapy in specific metastatic areas. Gene therapy, however, is the most modern method of treating cancer, the cause of cancer being tackled by altering genetic material. Other applications of nanoparticles for radiotherapy and diagnostics are discussed.

Cancer and inflammatory disorders are two important public health issues worldwide with significant socioeconomic impacts. Despite several efforts, the current therapeutic platforms are associated with severe limitations. Therefore, developing new therapeutic strategies for the treatment of these diseases is a top priority. Besides current therapies, the utilization of natural compounds has emerged as a new horizon for the treatment of cancer and inflammatory disorders as well. Such natural compounds could be used either alone or in combination with the standard cancer therapeutic modalities such as chemotherapy, radiotherapy, and immunotherapy. Resveratrol is a polyphenolic compound that is found in grapes as well as other foods. It has been found that this medicinal agent displays a wide pharmacological spectrum, including anti-cancer, anti-inflammatory, anti-microbial, and antioxidant activities. Recently, clinical and pre-clinical studies have highlighted the anti-cancer and anti-inflammatory effects of resveratrol. Increasing evidence revealed that resveratrol exerts its therapeutic effects by targeting various cellular and molecular mechanisms. Among cellular and molecular targets that are modulated by resveratrol, microRNAs (miRNAs) have appeared as key targets. MiRNAs are short non-coding RNAs that act as epigenetic regulators. These molecules are involved in many processes that are involved in the initiation and progression of cancer and inflammatory disorders. Herein, we summarized various miRNAs that are directly/indirectly influenced by resveratrol in cancer and inflammatory disorders.

In spite of therapeutic modalities such as surgical resection, chemotherapy, and radiotherapy, Glioblastoma Multiforme (GBM) remains an incurable fatal disease. This necessitates further therapeutic options that could enhance the efficacy of existing modalities. Nitric Oxide (NO), a short-lived small molecule, has been revealed to play a crucial role in the pathophysiology of GBM. Several studies have demonstrated that NO is involved in apoptosis, metastasis, cellular proliferation, angiogenesis, invasion, and many other processes implicated in GBM pathobiology. Herein, we elaborate on the role of NO as a therapeutic target in GBM and discuss some natural products affecting the NO signaling pathway.

Monoclonal antibodies carried in nanosystems have been extensively studied and reported as a promising tool for the treatment of various types of cancers. Monoclonal antibodies have great advantages for the treatment of cancer because their protein structure can bind to the target tissue; however, it has some challenges such as denaturation following heat exposure and extreme values of pH, temperature and solvents, the ability to undergo hydrolysis, oxidation and deamination and the formation of non-native aggregates, which compromise drug stability to a large extent. In addition to these characteristics, they suffer rapid elimination when in the blood, which results in a short half-life and the production of neutralizing antibodies, rendering the doses ineffective. These challenges are overcome with encapsulation in nanosystems (liposomes, polymer nanoparticles, cyclodextrins, solid lipid nanoparticles, nanostructured lipid carriers, dendrimers and micelles) due to the characteristics of improving solubility, permeability, and selectivity only with tumor tissue; with that, there is a decrease in side effects beyond controlled release, which is critical to improving the therapeutic efficacy of cancer treatment. The article was divided into different types of nanosystems, with a description of their definitions and applications in various types of cancers. Therefore, this review summarizes the use of monoclonal antibodies encapsulated in nanosystems and the description of clinical studies with biosimilars. Biosimilars are defined as products that are similar to monoclonal antibodies which are produced when the patent for the monoclonal antibodies expires.

Background: Prebiotics are substrates selectively utilized by host microorganisms to confer health benefits. The potential of prebiotics to decrease body weight in overweight/obese individuals was suggested by some clinical and animal studies. However, these studies were based on relatively small sample sizes and the precise effects of prebiotic products have not yet been evaluated. Therefore, the present meta-analysis of Randomized Controlled Trials (RCTs) was designed to comprehensively assess the effects of prebiotic products on overweight and obese individuals. Methods: PubMed, EMBASE and Cochrane Library were searched to identify RCT investigating the effects of prebiotic products on overweight and obese individuals. We calculated the pooled weighted mean difference (WMD) to assess the effects of prebiotic products on Body Mass Index (BMI), body weight, fat mass and inflammatory biomarkers. Results: Twelve RCTs with a total of 535 overweight and obese individuals were enrolled. Compared with placebo, prebiotic products decreased C reactive protein (WMD, -1.06 mg/L; 95%CI, -1.72 to - 0.40; p=0.002), tumour necrosis factor-α(WMD, -0.64 pg/mL; 95%CI, -1.11 to -0.18; p=0.006) and other inflammatory markers, such as interleukin-1β#140;lipopolysaccharide (p<0.05); whereas no reductions in BMI (WMD, -0.20 kg/m2; 95%CI, -0.58 to 0.19; p=0.32), body weight (WMD, -0.51 kg; 95%CI, -1.18 to 0.16; p=0.14) and fat mass (WMD, 0.11 kg; 95%CI, -0.04 to 0.25; p=0.15) were observed. Conclusion: In the present analysis, comprehensive evidence suggested that prebiotic products did not decrease adiposity parameters (BMI, body weight and body fat mass), but they could decrease the levels of systemic inflammatory biomarkers, implying adherence to prebiotic products might be a promising complementary approach to managing inflammatory states in overweight and obese individuals.