Current Medicinal Chemistry - Volume 28, Issue 7, 2021

Metabolic changes driven by the hostile tumor microenvironment surrounding cancer cells and the effect of these changes on tumorigenesis and metastatic potential have been known for a long time. The usual point of interest is glucose and changes in its utilization by cancer cells, mainly in the form of the Warburg effect. However, amino acids, both intra- and extracellular, also represent an important aspect of tumour microenvironment, which can have a significant effect on cancer cell metabolism and overall development of the tumor. Namely, alterations in the metabolism of amino acids glutamine, sarcosine, aspartate, methionine and cysteine have been previously connected to the tumor progression and aggressivity of cancer. The aim of this review is to pinpoint current gaps in our knowledge of the role of amino acids as a part of the tumor microenvironment and to show the effect of various amino acids on cancer cell metabolism and metastatic potential. This review shows limitations and exceptions from the traditionally accepted model of Warburg effect in some cancer tissues, with the emphasis on prostate cancer, because the traditional definition of Warburg effect as a metabolic switch to aerobic glycolysis does not always apply. Prostatic tissue both in a healthy and transformed state significantly differs in many metabolic aspects, including the metabolisms of glucose and amino acids, from the metabolism of other tissues. Findings from different tissues are, therefore, not always interchangeable and have to be taken into account during experimentation modifying the environment of tumor tissue by amino acid supplementation or depletion, which could potentially serve as a new therapeutic approach.

Background: Human HDACs represent a group of enzymes able to modify histone and non-histone proteins, which interact with DNA to generate chromatin. The correlation between irregular covalent modification of histones and tumor development has been proved over the last decades. Therefore, HDAC inhibitors are considered as potential drugs in cancer treatment. Romidepsin (FK228), Belinostat (PXD-101), Vorinostat (SAHA), Panobinostat (LBH-589) and Chidamide were approved by FDA as novel antitumor agents. Objective: The aim of this review article is to highlight the structure-activity relationships of several FK228 analogues as HDAC inhibitors. In addition, the synergistic effects of a dual HDAC/PI3K inhibition by some derivatives have been investigated. Materials and Methods: PubMed, MEDLINE, CAPLUS, SciFinder Scholar database were considered by selecting articles which fulfilled the objectives of this review, dating from 2015 till present time. Results: HDAC inhibitors have a significant role in cancer pathogenesis and evolution. Class I HDAC isoforms are expressed in many tumor types, therefore, potent and selective Class I HDAC inhibitors are of great interest as candidate therapeutic agents with limited side effects. By structurebased optimization, several FK228 analogues [15 (FK-A5), 22, 23 and 26 (FK-A11)] were identified, provided with significant activity against Class I HDAC enzymes and dose dependent antitumor activity. Compound 26 was recognized as an interesting HDAC/PI3K dual inhibitor (IC₅₀ against p110α of 6.7 μM while for HDAC1 inhibitory activity IC₅₀ was 0.64 nM). Conclusion: Romidepsin analogues HDAC inhibitors have been confirmed as useful anticancer agents. In addition, dual HDAC/PI3K inhibition showed by some of them exhibited synergistic effects in inducing apoptosis in human cancer cells. Further studies on FK228 analogues may positively contribute to the availability of potent agents in tumor treatment.

PROTAC (Proteolysis Targeting Chimera) degraders based on protein knockdown technology are now suggested as a novel option for the treatment of various diseases. Over the last couple of years, the application of PROTAC technology has spread in a wide range of disorders, and plenty of PROTAC molecules with high potency have been reported. Mostly developing for anticancer therapy, these molecules showed high selectivities to target proteins, the ability to significantly induce degradation of oncoproteins, good in vitro and in vivo results. In this review, we summarized the recent development of PROTAC technology in the anticancer therapy field, including molecular design, types of targeted proteins, in vitro and in vivo results. Additionally, we also discuss the prospects and challenges for the application of candidates based on PROTAC strategy in clinical trials.

Background: Oxidative stress is a hallmark of many diseases. A growing body of evidence suggests that hyperglycemia-induced oxidative stress plays an important role in pancreatic β-cells dysfunction and apoptosis, as well as in the development and progression of diabetic complications. Considering the vulnerability of pancreatic β-cells to oxidative damage, the induction of endogenous antioxidant enzymes or exogenous antioxidant administration has been proposed to protect pancreatic β-cells from damage. Objectives: The present review aims to provide evidence of the effect of oxidative stress and antioxidant therapies on pancreatic β-cell function, based on in vitro and in vivo studies. Methods: The MEDLINE and EMBASE databases were searched to retrieve available data. Results: Due to poor endogenous antioxidant mechanisms, pancreatic β-cells are extremely sensitive to Reactive Oxygen Species (ROS). Many natural extracts have been tested in vitro in pancreatic β-cell lines in terms of their antioxidant and diabetes mellitus ameliorating effects, and the majority of them have shown a dose-dependent protective role. On the other hand, there is relatively limited evidence regarding the in vitro antioxidant effects of antidiabetic drugs on pancreatic β -cells. Concerning in vivo studies, several natural extracts have shown beneficial effects in the setting of diabetes by decreasing blood glucose and lipid levels, increasing insulin sensitivity, and by up-regulating intrinsic antioxidant enzyme activity. However, there is limited evidence obtained from in vivo studies regarding antidiabetic drugs. Conclusion: Antioxidants hold promise for developing strategies aimed at the prevention or treatment of diabetes mellitus associated with pancreatic β-cells dysfunction, as supported by in vitro and in vivo studies. However, more in vitro studies are required for drugs.

Mitochondria-associated Endoplasmic Reticulum (ER) Membranes (MAMs) are the cellular structures that connect the ER and mitochondria and mediate communication between these two organelles. MAMs have been demonstrated to be involved in calcium signaling, lipid transfer, mitochondrial dynamic change, mitophagy, and the ER stress response. In addition, MAMs are critical for metabolic regulation, and their dysfunction has been reported to be associated with metabolic syndrome, including the downregulation of insulin signaling and the accelerated progression of hyperlipidemia, obesity, and hypertension. This review covers the roles of MAMs in regulating insulin sensitivity and the molecular mechanism underlying MAM-regulated cellular metabolism and reveals the potential of MAMs as a therapeutic target in treating metabolic syndrome.

Cardiovascular Disease (CVD) is the most important and the number one cause of mortality in both developing and industrialized nations. The co-morbidities associated with CVD are observed from infancy to old age. Apolipoprotein B100 (Apo B) is the primary apolipoprotein and structural protein of all major atherogenic particles derived from the liver including Very-Low- Density Lipoproteins (VLDL), Intermediate-density Lipoprotein (IDL), and Low-density Lipoprotein (LDL) particles. It has been suggested that measurement of the Apo B concentration is a superior and more reliable index for the prediction of CVD risk than is the measurement of LDL-C. Nutraceuticals and medicinal plants have attracted significant attention as it pertains to the treatment of non-communicable diseases, particularly CVD, diabetes mellitus, hypertension, and Nonalcoholic Fatty Liver Disease (NAFLD). The effect of nutraceuticals and herbal products on CVD, as well as some of its risk factors such as dyslipidemia, have been investigated previously. However, to the best of our knowledge, the effect of these natural products, including herbal supplements and functional foods (e.g. fruits and vegetables as either dry materials, or their extracts) on Apo B has not yet been investigated. Therefore, the primary objective of this paper was to review the effect of bioactive natural compounds on plasma Apo B concentrations. It is concluded that, in general, medicinal plants and nutraceuticals can be used as complementary medicine to reduce plasma Apo B levels in a safe, accessible, and inexpensive manner in an attempt to prevent and treat CVD.

Background: Siderophores are small-molecule iron-chelators produced by microorganisms and plants growing mostly under low iron conditions. Siderophores allow iron capture and transport through cell membranes into the cytoplasm, where iron is released for use in biological processes. These bacterial iron uptake systems can be used for antibiotic conjugation or as targets for killing pathogenic bacteria. Siderophores have been explored recently because of their potential applications in environmental and therapeutic research. They are present in Streptomyces, Grampositive bacteria that are an important source for discovering new siderophores. Objective: This review summarizes siderophore molecules produced by the genus Streptomyces emphasizing their potential as biotechnological producers and also illustrating genomic tools for discovering siderophores useful for treating bacterial infections. Methods: The literature search was performed using PUBMED and MEDLINE databases with keywords siderophore, secondary metabolites, Trojan horse strategy, sideromycin and Streptomyces. The literature research focused on bibliographic databases including all siderophores identified in the genus Streptomyces. In addition, reference genomes of Streptomyces from GenBank were used to identify siderophore biosynthetic gene clusters by using the antiSMASH platform. Results: This review has highlighted some of the many siderophore molecules produced by Streptomyces, illustrating the diversity of their chemical structures and a wide spectrum of bioactivities against pathogenic bacteria. Furthermore, the possibility of using siderophores conjugated with antibiotics could be an alternative to overcome bacterial resistance to drugs and could improve their therapeutic efficacy. Conclusion: This review confirms the importance of Streptomyces as a rich source of siderophores, and underlines their potential as antibacterial agents.

Background: Neurotoxic chemical warfare agents can be classified as some of the most dangerous chemicals for humanity. The most effective of those agents are the Organophosphates (OPs) capable of restricting the enzyme Acetylcholinesterase (AChE), which in turn, controls the nerve impulse transmission. When AChE is inhibited by OPs, its reactivation can be usually performed through cationic oximes. However, until today, it has not been developed one universal defense agent, with complete effective reactivation activity for AChE inhibited by any of the many types of existing neurotoxic OPs. For this reason, before treating people intoxicated by an OP, it is necessary to determine the neurotoxic compound that was used for contamination, in order to select the most effective oxime. Unfortunately, this task usually requires a relatively long time, raising the possibility of death. Cationic oximes also display a limited capacity of permeating the Blood-Brain Barrier (BBB). This fact compromises their capacity to reactivating AChE inside the nervous system. Methods: We performed a comprehensive search on the data about OPs available on the scientific literature today in order to cover all the main drawbacks still faced in the research for the development of effective antidotes against those compounds. Results: Therefore, this review about neurotoxic OPs and the reactivation of AChE, provides insights for the new agents’ development. The most expected defense agent is a molecule without toxicity and effective to reactivate AChE inhibited by all neurotoxic OPs. Conclusion: To develop these new agents, the application of diverse scientific areas of research, especially theoretical procedures as computational science (computer simulation, docking and dynamics), organic synthesis, spectroscopic methodologies, biology, biochemical and biophysical information, medicinal chemistry, pharmacology and toxicology, is necessary.

Beyond being epiphenomenon of shared epidemiological factors, the integration of Osteoporosis (OP) with Cardiovascular Disease (CVD) - termed “calcification paradox” - reflects a continuum of aberrant cardiometabolic status. The present review provides background knowledge on “calcification paradox”, focusing on the endocrine aspect of vasculature orchestrated by the osteoblastic molecular fingerprint of vascular cells, acquired via imbalance among established modulators of mineralization. Osteoprotegerin (OPG), the well-established osteoprotective cytokine, has recently been shown to exert a vessel-modifying role. Prompted by this notion, the present review interrogates OPG as the potential missing link between OP and CVD. However, so far, the confirmation of this hypothesis is hindered by the equivocal role of OPG in CVD, being both proatherosclerotic and antiatherosclerotic. Further research is needed to illuminate whether OPG could be a biomarker of the “calcification paradox”. Moreover, the present review brings into prominence the dual role of statins - cardioprotective and osteoprotective - as a potential illustration of the integration of CVD with OP. Considering that the statins-induced modulation of OPG is central to the statins-driven osteoprotective signalling, statins could be suggested as an illustration of the role of OPG in the bone/vessels crosstalk, if further studies consolidate the contribution of OPG to the cardioprotective role of statins. Another outstanding issue that merits further evaluation is the inconsistency of the osteoprotective role of statins. Further understanding of the varying bone-modifying role of statins, likely attributed to the unique profile of different classes of statins defined by distinct physicochemical characteristics, may yield tangible benefits for treating simultaneously OP and CVD.