Current Medicinal Chemistry - Volume 28, Issue 4, 2021

Background: Monoclonal antibodies (mAbs) against tumor-associated antigens have been shown to target tumors with specificity and selectivity; therefore, it was hypothesized that cancer could be treated with mAbs without side effects. In the early 1980s, clinical studies demonstrated that tumors could be visualized using radiolabeled mAbs. However, with the introduction of positron emission tomography (PET) with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG), antibody-based imaging became less important because of its limited diagnostic accuracy. During the last two decades, a revival of imaging with radiolabeled mAbs has taken place, specifically PET with longer half-life isotopes. Development of immune checkpoints as targets for immunotherapy has opened opportunities for the development of a wide variety of antibodies, such as anti-CTLA-4, anti-PD-L1, and anti-PD1. Thus, imaging with these antibodies radiolabeled with ⁸⁹Zr or another long–half-life PET isotope, known as immuno-PET, has become mainstream. Objective: This study aimed to review the rapid development of immuno-PET for the detection of cancer and assessment of therapeutic response combining surgery, radiation, chemotherapy, and/or immunotherapy. This review includes reports on the radiolabeling, imaging and clinical utility of ⁸⁹Zr-, ⁶⁴Cu-and ¹²⁴I-labeled mAbs. Results: More than 120 research and review articles on immuno-PET were reviewed. Conclusion: Many mAbs have been developed and used for the treatment of cancer; however, a limited number of antibodies have been radiolabeled for immuno-PET. While much progress has been made with the therapeutic applications of mAbs, immuno-PET for diagnosis and treatment assessment needs more research. Improved chelating agents and extensive imaging studies are needed to refine immuno-PET for the diagnosis of cancers and assessment of response to therapy.

Despite significant research progress on the pathogenesis, molecular biology, diagnosis, treatment, and prevention of cancer, its morbidity and mortality are still high around the world. The emerging resistance of cancer cells to anticancer drugs remains still a significant problem in oncology today. Furthermore, an important challenge is the inability of anticancer drugs to selectively target tumor cells thus sparing healthy cells. One of the new potential options for efficient and safe therapy can be provided by opioid growth factor (OGF), chemically termed Met-enkephalin. It is an endogenous pentapeptide (Tyr-Gly-Gly-Phe-Met) with antitumor, analgesic, and immune-boosting properties. Clinical trials have demonstrated that OGF therapy alone, as well as in combination with standard chemotherapies, is a safe, non-toxic anticancer agent that reduces tumor size. In this paper, we review the structure-activity relationship of OGF and its analogues. We highlight also OGF derivatives with analgesic, immunomodulatory activity and the ability to penetrate the blood-brain barrier and may be used as safe agents enhancing chemotherapy efficacy and improving quality of life in cancer patients. The reviewed papers indicate that Met-enkephalin and its analogues are interesting candidates for the development of novel, non-toxic, and endowed with an analgesic activity anticancer drugs. More preclinical and clinical studies are needed to explore these opportunities.

Melanoma is the most life-threatening and aggressive class of skin malignancies. The incidence of melanoma has steadily increased. Metastatic melanoma is greatly resistant to standard antimelanoma treatments such as chemotherapy, and the 5-year survival rate of cases with melanoma who have a metastatic form of the disease is less than 10%. The contributing role of apoptosis, angiogenesis and autophagy in the pathophysiology of melanoma has been previously demonstrated. Thus, it is extremely urgent to search for complementary therapeutic approaches that could enhance the quality of life of subjects and reduce treatment resistance and adverse effects. Resveratrol, known as a polyphenol component present in grapes and some plants, has anti-cancer properties due to its function as an apoptosis inducer in tumor cells, and anti-angiogenic agent to prevent metastasis. However, more clinical trials should be conducted to prove resveratrol efficacy. Herein, for the first time, we summarize the current knowledge of anti-cancerous activities of resveratrol in melanoma.

Heterocyclic compounds hold a huge and recognized place in the field of medicinal chemistry thanks to their multiple biological activities. Their synthetic pathways allow their easy and rapid access due to different bond-forming methodologies and provide a huge amount of multi-functionalized compounds for drug delivery. The syntheses of heterocyclic compounds are today well known for the majority, described and reviewed in an extensive literature. In this review, we choose to gather and classify available information concerning the biological activities of quinoxaline-based compounds annulated at bond a containing one and more nitrogen atoms in the fused azole ring.

Neurotransmitter γ-aminobutyric acid (GABA) plays a principal role in the regulation of mammalian central nervous system functions. GABA evoked neurotransmission is terminated by a rapid uptake via dependent plasma membrane GABA transporters (GATs) located in the cell membrane. Potent inhibitors of these GATs are of fundamental importance for elucidation of the physiological function of these targets. Over recent years, a wide range of new GAT1-selective and less common non-GAT1-selective inhibitors have been successfully developed. This review highlights development and recent significant achievements in the field of GABA reuptake inhibitors. Special attention is paid to their pharmacological roles, structure and subtype selectivity relationships.

Nanocarriers, as drug delivery frameworks, have been intended to enhance the pharmacological and restorative properties of traditional medications. The consolidation of medical atoms as nanocarriers can function as the drug that is required against corruption, as well as offer the desired potential outcomes in regards to targeting and controlled discharge. In the present overview article, applications of magnetic nanoparticles (MNPs) in medication conveyance are outlined. The MNPs have increased the excitement due to their biocompatibility - low poisonous quality, and their capacity to be handled in a magnetic field, which enables their applications as drug-bearing vehicles. The simplicity of surface modification of these particles can provide opportunities for targeting the moieties that are linked to the particle surface. We trust that the intriguing particles will gain further attention alongside achievements in the current ones in the near future.

Background: Obesity is known to be a multifactorial disease. In its pathogenesis, different factors such as chronic inflammation, oxidative stress, insulin resistance, genetic factors, environmental effects, vegetative disturbance, and unbalanced nutrition play a significant role. Methodology: This study describes the association of obesity and insulin resistance with chronic inflammation, genetic, and epigenetic factors. Previous literature has been reviewed to explain the relation of obesity with those factors involved in chronic low-grade inflammation and insulin. Results: Obesity is associated with a decrease in ghrelin secretion, elevated plasma leptin levels, oxidative stress, increased macrophage phagocytic activity, and the induction of proinflammatory synthesis of cytokines and interferon-gamma. Obesity is linked to decreased levels of cytochrome P450 (CYP) enzymes and impaired detoxification processes. Deficiency of vitamins and minerals can also play a significant role in the development of oxidative stress and chronic inflammation in obesity. There is evidence of associations between a genetic predisposition to obesity in children with elevated levels of certain miRNAs. Conclusion: The purpose of the present review is an analysis of the multiple factors associated with obesity.

Intestinal hyperpermeability is a complex metabolic process mediated by different pathways in close relation to the gut microbiota. Previous studies suggested that the gut microbiota is involved in different metabolic regulations, and its imbalance is associated with several metabolic diseases, including obesity. It is well known that intestinal hyperpermeability is associated with dysbiosis, and the combination of these two conditions can lead to an increase in the level of low-grade inflammation in obese patients due to an increase in pro-inflammatory cytokine levels. Inflammatory bowel syndrome often accompanies this condition causing an alteration of the intestinal mucosa and thus reinforcing the dysbiosis and gut hyperpermeability. The onset of metabolic disorders depends on violations of the integrity of the intestinal barrier as a result of increased intestinal permeability. Chronic inflammation due to endotoxemia is responsible for the development of obesity. Metabolic disorders are associated with dysregulation of the microbiota-gut-brain axis and with an altered composition of gut flora. In this review, we will discuss the mechanisms that illustrate the relationship between hyperpermeability, the composition of the gut microbiota, and obesity.

Background: A systematic review and meta-analysis of clinical trials were undertaken to evaluate the effect of diacerein intake on cardiometabolic profiles in patients with type 2 diabetes mellitus (T2DM). Methods: Electronic databases such as PubMed, EMBASE, Scopus, Web of Science, Google Scholar, and Cochrane Central Register of Controlled Trials were searched from inception to 31 July 2019. Statistical heterogeneity was evaluated using Cochran’s Q test and I-square (I²) statistic. Data were pooled using random-effects models and weighted mean difference (WMD). Results: From 1,733 citations, seven clinical trials were eligible for inclusion and meta-analysis. A significant reduction in hemoglobin A1c (HbA1c) (WMD -0.73; 95%CI -1.25 to -0.21; P= 0.006; I2= 72.2%) and body mass index (BMI) (WMD -0.55; 95%CI -1.03 to -0.07; P= 0.026; I²= 9.5%) was identified. However, no significant effect of diacerein intake was identified on fasting blood sugar (FBS) (WMD -9.00; 95%CI -22.57 to 4.57; P= 0.194; I2= 60.5%), homeostatic model assessment for insulin resistance (HOMA-IR) (WMD 0.39; 95%CI -0.95 to 1.73; P= 0.569; I²= 2.2%), body weight (WMD - 0.54; 95%CI -1.10 to 0.02; P= 0.059), triglycerides (WMD -0.56; 95%CI -24.16 to 23.03; P= 0.963; I²= 0.0%), total-cholesterol (WMD -0.21; 95%CI -12.19 to 11.78; P= 0.973; I²= 0.0%), HDL-cholesterol (WMD -0.96; 95%CI -2.85 to 0.93; P= 0.321; I²= 0.0%), and LDL-cholesterol levels (WMD -0.09; 95%CI -8.43 to 8.25; P= 0.983; I²= 37.8%). Conclusion: Diacerein intake may reduce HbA1c and BMI; however, no evidence of the effect was observed for FBS, HOMA-IR, body weight, triglycerides, total cholesterol, HDL-cholesterol or LDLcholesterol.