Current Medicinal Chemistry - Volume 28, Issue 18, 2021

Aberrant activation of monomeric G-protein signaling pathways drives some of the most aggressive cancers. Suppressing these hyperactivities has been the focus of efforts to obtain targeted therapies. Polyisoprenylated methylated protein methyl esterase (PMPMEase) is overexpressed in various cancers. Its inhibition induces the death of cancer cells that harbor the constitutively active K-Ras proteins. Furthermore, the viability of cancer cells driven by factors upstream of K-Ras, such as overexpressed growth factors and their receptors or the mutationally-activated receptors, is also susceptible to PMPMEase inhibition. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) were thus designed to target cancers with hyperactive signaling pathways involving the G-proteins. The PCAIs were, however, poor inhibitors of PMPMEase, with Ki values ranging from 3.7 to 20 μM. On the other hand, they inhibited cell viability, proliferation, colony formation, induced apoptosis in cells with mutant K-Ras and inhibited cell migration and invasion with EC50 values of 1 to 3 μM. HUVEC tube formation was inhibited at submicromolar concentrations through their disruption of actin filament organization. At the molecular level, the PCAIs at 2 to 5 μM depleted monomeric G-proteins such as K-Ras, RhoA, Cdc42 and Rac1. The PCAIs also deplete vinculin and fascin that are involved in actin organization and function while disrupting vinculin punctates in the process. These demonstrate a polyisoprenylation-dependent mechanism that explains the observed PCAIs’ inhibition of the proliferative, invasive and angiogenic processes that promote both tumor growth and metastasis.

The usage of dendrimers or cascade molecules in the biomedical area has recently attracted much attention worldwide. Furthermore, dendrimers are interesting in clinical and pre-clinical applications due to their unique characteristics. Cancer is one of the most widespread challenges and important diseases, which has the highest mortality rate. In this review, the recent advances and developments (from 2009 up to 2019) in the field of electrochemical and electroluminescence immunosensors for detection of the cancer markers are presented. Moreover, this review covers the basic fabrication principles and types of electrochemical and electrochemiluminescence dendrimer-based immunosensors. In this review, we have categorized the current dendrimer based-electrochemical/ electroluminescence immunosensors into five groups: dendrimer/ magnetic particles, dendrimer/ferrocene, dendrimer/metal nanoparticles, thiol-containing dendrimer, and dendrimer/quantum dots based-immunosensors.

Over the past decades, several advances in cancer cell biology have led to relevant details about a phenomenon called the ‘Warburg effect’. Currently, it has been accepted that the Warburg effect is not compatible with all cancer cells, and thus the process of aerobic glycolysis is now challenged by the knowledge of a large number of cells presenting mitochondrial function. The energy metabolism of cancer cells is focused on the bioenergetic and biosynthetic pathways in order to meet the requirements of rapid proliferation. Changes in the metabolism of carbohydrates, amino acids and lipids have already been reported for cancer cells and this might play an important role in cancer progression. To the best of our knowledge, these changes are mainly attributed to genetic reprogramming which leads to the transformation of a healthy into a cancerous cell. Indeed, several enzymes that are highly relevant for cellular energy are targets of oncogenes (e.g. PI3K, HIF1, and Myc) and tumor suppressor proteins (e.g. p53). As a consequence of extensive studies on cancer cell metabolism, some new therapeutic strategies have appeared that aim to interrupt the aberrant metabolism, in addition to influencing genetic reprogramming in cancer cells. In this review, we present an overview of cancer cell metabolism (carbohydrate, amino acid, and lipid), and also describe oncogenes and tumor suppressors that directly affect the metabolism. We also discuss some of the potential therapeutic candidates which have been designed to target and disrupt the main driving forces associated with cancer cell metabolism and proliferation.

Alzheimer’s disease (AD) is one of the most prevalent age-related neurodegenerative disease that affects the cognition, behavior, and daily activities of individuals. Studies indicate that this disease is characterized by several pathological mechanisms, including the accumulation of amyloid-beta peptide, hyperphosphorylation of tau protein, impairment of cholinergic neurotransmission, and increase in inflammatory responses within the central nervous system. Chronic neuroinflammation associated with AD is closely related to disturbances in metabolic processes, including insulin release and glucose metabolism. As AD is also called type III diabetes, diverse compounds having antidiabetic effects have been investigated as potential drugs for its symptomatic and disease-modifying treatment. In addition to insulin and oral antidiabetic drugs, scientific attention has been paid to cyclic-3′,5′-adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE) inhibitors that can modulate the concentration of glucose and related hormones and exert beneficial effects on memory, mood, and emotional processing. In this review, we present the most recent reports focusing on the involvement of cAMP-specific PDE4, PDE7, and PDE8 in glycemic and inflammatory response controls as well as the potential utility of the PDE inhibitors in the treatment of AD. Besides the results of in vitro and in vivo studies, the review also presents recent reports from clinical trials.

The COVID-19 pandemic has had global catastrophic effects on financial markets, jobs and peoples’ lives. Future prevention/therapy of COVID-19 will rely heavily on vaccine development and attempts to repurpose drugs previously used for other microbial diseases. Little attention, however, has been paid to possible difficulties and delays in producing these drugs. Sometimes, unfortunately, these endeavours have been politicized and if these two approaches founder in any way or resistance subsequently occurs, then the world will be left once again to the mercy of these devastating viral pandemics. This review, therefore, briefly outlines the challenges in the development of vaccines and repurposed antiviral drugs, which will hopefully lead to new treatments for COVID-19. It also concludes, however, that the armoury against COVID-19 urgently needs to be enlarging due to the potential severity and likely future reoccurrence of new emergent viruses. Therefore, serious consideration is given to alternative ways of preventing and controlling these pathogens that have received scant attention from the media in the present pandemic. The development of innovative, broad-spectrum, antiviral drugs from natural products is therefore particularly advocated with the challenges involved by new regulatory and scientific initiatives.

Respiratory viruses, including influenza virus, respiratory syncytial virus, coronavirus, etc., have seriously threatened the human health. For example, the outbreak of severe acute respiratory syndrome coronavirus, SARS, affected a large number of countries around the world. Marine organisms, which could produce secondary metabolites with novel structures and abundant biological activities, are an important source for seeking effective drugs against respiratory viruses. This report reviews marine natural products with activities against respiratory viruses, the emphasis of which was put on structures and antiviral activities of these natural products. This review has described 167 marinederived secondary metabolites with activities against respiratory viruses published from 1981 to 2019. Altogether 102 references are cited in this review article.

Background: Diabetes, a metabolic disease, occurs due to a decreased or no effect of insulin on the blood glucose level. The current oral medications stimulate insulin release, increase glucose absorption and its utilization, and decrease hepatic glucose output. Two major incretin hormones like Glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide - 1 (GLP-1) stimulate insulin release after a meal, but their action is inhibited by enzyme dipeptidyl peptidase- IV. Objective: The activity of endogenous GLP-1 and GIP prolongs and extends with DPP IV inhibitors, which are responsible for the stimulation of insulin secretion and regulation of blood glucose level. DPP IV inhibitors have shown effectiveness and endurability with a neutral effect on weight as well as less chances of hypoglycemia in the management of type 2 diabetes. These journeys started from Sitagliptin (marketed in 2006) to Evogliptin (marketed in 2015, Korea). Conclusion: Treatment of type 2 diabetes includes lifestyle changes, oral medications, and insulin. Newer and superior therapies are needed more than currently prescribed drugs. Various heterocyclic derivatives have been tried, but due to masking of DASH proteins, CYP enzymes, and hERG channel, they showed side effects. Based on these, the study has been focused on the development of safe, influential, selective, and long-lasting inhibitors of DPP IV.

COX-2, a key enzyme that catalyzed the rate-limiting steps in the conversion of arachidonic acid to prostaglandins, played a pivotal role in the inflammatory process. Different from other family members, COX-2 was barely detectable in normal physiological conditions and highly inducible during the acute inflammatory response of human bodies to injuries or infections. Therefore, the therapeutic utilization of selective COX-2 inhibitors has already been considered as an effective approach for the treatment of inflammation with diminished side effects. Currently, both traditional and newer NSAIDs are the commonly prescribed medications that treat inflammatory diseases by targeting COX-2. However, due to the cardiovascular side-effects of the NSAIDs, finding reasonable alternatives for these frequently prescribed medicines are a hot spot in medicinal chemistry research. Naturallyoccurring compounds have been reported to inhibit COX-2, thereby possessing beneficial effects against inflammation and certain cell injury. The review mainly concentrated on recently identified natural products and derivatives as COX-2 inhibitors, the characteristics of their structural core scaffolds, their anti-inflammatory effects, molecular mechanisms for enzymatic inhibition, and related structure-activity relationships. According to the structural features, the natural COX-2 inhibitors were mainly divided into the following categories: natural phenols, flavonoids, stilbenes, terpenoids, quinones, and alkaloids. Apart from the anti-inflammatory activities, a few dietary COX-2 inhibitors from nature origin also exhibited chemopreventive effects by targeting COX-2-mediated carcinogenesis. The utilization of these natural remedies in future cancer prevention was also discussed. In all, the survey on the characterized COX-2 inhibitors from natural sources paves the way for the further development of more potent and selective COX-2 inhibitors in the future.

Kidney disease is a serious health problem that burdens our healthcare system. It is crucial to find the accurate pathogenesis of various types of kidney disease to provide guidance for precise therapies for patients suffering from these diseases. However, the exact molecular mechanisms underlying these diseases have not been fully understood. Disturbance of calcium homeostasis in renal cells plays a fundamental role in the development of various types of kidney disease, such as primary glomerular disease, diabetic nephropathy, acute kidney injury and polycystic kidney disease, through promoting cell proliferation, stimulating extracellular matrix accumulation, aggravating podocyte injury, disrupting cellular energetics as well as dysregulating cell survival and death dynamics. As a result, preventing the disturbance of calcium homeostasis in specific renal cells (such as tubular cells, podocytes and mesangial cells) is becoming one of the most promising therapeutic strategies in the treatment of kidney disease. The endoplasmic reticulum and mitochondria are two vital organelles in this process. Calcium ions cycle between the endoplasmic reticulum and mitochondria at the conjugation of these two organelles known as the mitochondria-associated endoplasmic reticulum membrane, maintaining calcium homeostasis. The pharmacologic modulation of cellular calcium homeostasis can be viewed as a novel therapeutic method for renal diseases. Here, we will introduce calcium homeostasis under physiological conditions and the disturbance of calcium homeostasis in kidney diseases. We will focus on the calcium homeostasis regulation in renal cells (including tubular cells, podocytes and mesangial cells), especially in the mitochondria- associated endoplasmic reticulum membranes of these renal cells.

Atherosclerosis is a chronic arterial wall illness that forms atherosclerotic plaques within the arteries. Plaque formation and endothelial dysfunction are atherosclerosis' characteristics. It is believed that the occurrence and development of atherosclerosis mainly include endothelial cell damage, lipoprotein deposition, inflammation and fibrous cap formation, but its molecular mechanism has not been elucidated. Therefore, protecting the vascular endothelium from damage is one of the key factors against atherosclerosis. The factors and processes involved in vascular endothelial injury are complex. Finding out the key factors and mechanisms of atherosclerosis caused by vascular endothelial injury is an important target for reversing and preventing atherosclerosis. Changes in cell adhesion are the early characteristics of EndMT, and cell adhesion is related to vascular endothelial injury and atherosclerosis. Recent researches have exhibited that endothelial-mesenchymal transition (EndMT) can urge atherosclerosis' progress, and it is expected that inhibition of EndMT will be an object for anti-atherosclerosis. We speculate whether inhibition of EndMT can become an effective target for reversing atherosclerosis by improving cell adhesion changes and vascular endothelial injury. Studies have shown that H2S has a strong cardiovascular protective effect. As H2S has anti- inflammatory, anti-oxidant, inhibiting foam cell formation, regulating ion channels and enhancing cell adhesion and endothelial functions, the current research on H2S in cardiovascular aspects is increasing, but anti-atherosclerosis's molecular mechanism and the function of H2S in EndMT have not been explicit. In order to explore the mechanism of H2S against atherosclerosis, to find an effective target to reverse atherosclerosis, we sum up the progress of EndMT promoting atherosclerosis, and Hydrogen sulfide's potential anti- EndMT effect is discussed in this review.