What Did We Accomplish in Fighting Radical Species in Human Health?

Excerpt Note: In lieu of an abstract, this is an excerpt from the first page. Maintaining the physiological level of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the body is highly important in the fight against radical species in the context of human health. An excess of ROS and RNS, also called the bad radical species, plays a critical role in many diseases, including cancer and neurodegeneration. Therefore, the development of new approaches based on small molecules mitigating the above physiological level of ROS/RNS is crucial. For example, identifying new therapeutic strategies capable of modifying the course of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease, autism, and migraine, is currently one of the major goals of researchers in this field. Strong evidence suggests that natural and non-natural antioxidant compounds are alternative therapeutics that can be used to mitigate oxidative stress in various models [1,2]. Natural antioxidant plant-based compounds, such as curcumin (e.g., Curcuma longa) and resveratrol (e.g., cranberry—Vaccinium macrocarpon), are highly abundant and accessible with low toxicity and side effects. On the other hand, non-natural antioxidants are a class of compounds created from a well-defined synthetic route that are highly efficacious but less accessible and may have considerable toxicity (e.g., ferrostatin-1, a lipophilic antioxidant inhibitor of ferroptosis cell death) [3,4]. Therefore, further investigations of additional resources of natural antioxidants are needed to reduce oxidative stress in the body safely. In this Special Issue entitled “Fighting Radical Species in Human Health: Mitigating Radical Species with Natural and Synthetic Compounds”, we discuss a broad range of multidisciplinary investigative contributions, spanning from neuroscience, cancer, chemical biology, and plant biology to nutraceuticals with antioxidative properties. In an elegant review of this issue, Remigante et al. [5] provided an insightful discussion on the mechanism of action of band 3 protein (B3p) in erythrocyte, a simple in vitro model to study the impact of antioxidants on cellular homeostasis. B3p protein is responsible for exchanging Cl− and HCO3− anions through erythrocyte membranes and for acid balance, ion distribution, and gas exchange, thus accounting for homeostasis of both erythrocytes and entire organisms. The review also highlights the benefit of natural antioxidants, such as curcumin, magnesium, and melatonin, in blocking B3p anion exchange capability under in vitro oxidative conditions, suggesting that antioxidant supplements may be useful in improving endogenous antioxidants and increase the body defense machinery. Morán-Santibañez et al. [6] reported in an original paper the potential antioxidant properties of Creosote bush (Larrea tridentata, LT) leaves (collected from the Chihuahuan desert in the region of El Paso del Norte (TX, USA) [7]. LT leaf extracts were tested for their potential efficacy to mitigate cellular oxidative stress on human neuroblastoma SH-SY5Y cells as an in vitro model of PD. Overall, the LT extract exhibited a protective effect on SH-SY5Y cells undergoing oxidative stress in vitro, functioning as a natural anti-apoptotic extract. On the other hand, a review by De Lazzari et al. [8] discussed the clinical relevance of the use of Drosophila melanogaster (fruit flies) as an animal model to evaluate the therapeutic potential of natural and synthetic antioxidants therapy in PD. Protein aggregation is primarily characterized by the degenerative human ALS disease. ALS is a common degenerative disease of the central nervous system concerning a progressive loss of upper and lower motor neurons. As the wobbler mouse and ALS show striking similarities in view of phenotypical attributes, the wobbler mouse is rated as an animal model for the disease. In an original paper, Zwilling et al. [9] reported that nicotinamide adenine dinucleotide (NAD+) acts as a neuroprotector which facilitates the reduction in oxidative stress. NAD+ is primarily known as an essential co-enzyme in energy metabolism, gene expression, and DNA repair. The authors investigated the effect of NAD+ enhancement on motor neuronal development in an in vitro model of the wobbler mouse. They also reported that the small molecule caffein, a known antioxidant compound, increased the level of nicotinic acid mononucleotide transferase 2 (Nmnat2) specifically in neuronal cells. The authors concluded that caffeine as well as NAD+ were both shown to have a positive impact on the in vitro development of motor neurons of wobbler mice. This study represents a significant advance toward uncovering potential pharmacological treatments of both wobbler and ALS disease. Polyphenolic natural products are known to exhibit significant anti-oxidative and anti-inflammatory properties. Altered immune alteration and oxidative stress have also been found in patients with autism spectrum disorders (ASD), and these alterations could add to the pathophysiology associated with ASD. The review conducted by Malaguarnera et al. [10] focused on the benefit of resveratrol in ASD. The stilbene resveratrol is a polyphenolic small molecule with substantial anti-oxidative and anti-inflammatory properties recently tested in animal models of several neurological diseases. Headache disorders including migraine are still underdiagnosed and lack efficacious treatments. Therefore, the development of a new classes of treatments is desirable. Goschorska et al. [11] elucidated the use of antioxidants such as vitamin C, curcumin, coenzyme Q10, and ginkgolide B in the treatment of migraine. The present review provided a summary of the studies on nutraceuticals with antioxidative properties. The results presented therein seem to indicate the possible use of nutraceuticals with antioxidative properties as an alternative to conventionally used medication in migraine treatment. Natural-based compounds bearing antioxidants and anti-inflammatory properties are highly useful in mitigating oxidative stress. Oxidative stress and inflammation are reported to be among the major contributors to cancer. Considering the key role of oxidative stress during acute pancreatitis (AP), Cordaro et al. [12] tested the effect of one of the main sources of polyphenols in the diet worldwide, cashew nuts (Anacardium occidentale L. originated from Ivory Coast, Africa), on pancreatic and lung injury induced by cerulein injection in vivo. In this study, cashew nuts showed many benefits in several cellular pathways. For example, the levels of nucleotide-binding domain leucine-rich repeat containing family pyrin domain containing receptor 3 (NLRP3), the apoptosis-associated speck like protein containing a caspase recruitment domain (ASC), and caspase-1 were significantly increased after cerulein induction, and cashew nuts considerably diminished this increase in both the pancreas and lung. Additionally, the activation of the nuclear factor E2-related factor 2 (Nrf2) pathway was boosted, which suggests its antioxidant properties. In another original manuscript, Fusco et al. [13] reported the use of hydroxytyrosol, a known phenolic small molecule obtained from olive oil, in a pancreatitis-associated gut injury in vivo model. Specifically, the pharmacological effect of hydroxytyrosol treatment prior to cerulein (a pancreatic and intestinal injury inducer) administration on a CD1 female mice was efficacious in decreasing amylase and lipase (the serum hallmarks of pancreatitis). In addition, the lipid peroxidation and oxidative stress levels (e.g., superoxide dismutase and glutathione peroxidase) decreased, suggesting that hydroxytyrosol may be an important therapeutic tool against pancreatitis-induced injuries in the pancreas and gut. Park et al. [14] examined in an original manuscript the mechanism of action of the known dietary antioxidant β-carotene in gastric epithelial cells infected with Helicobacter pylori. The pretreatment of cells with β-carotene prior to helicobacter pylori infection significantly attenuates the overall oxidative stress (e.g., nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and nuclear factor kappa-light-chain-enhancer of activated B (NF-kB)), suggesting that dietary supplementation with β-carotene-rich foods may prevent or delay the development of gastric diseases, including gastric cancer, associated with Helicobacter pylori infection. Finally, identifying novel natural compounds and nutraceuticals bearing antioxidant properties will significantly enhance our understanding of their roles against the bad radical species in biological systems. Eventually, this may lead to the design of novel mono- or combined therapeutic strategies offering more effective treatments that will positively impact clinical outcomes and human health

Role of Indole Scaffolds as Pharmacophores in the Development of Anti-Lung Cancer Agents

Lung cancer is the leading cause of death in men and women worldwide, affecting millions of people. Between the two types of lung cancers, non-small cell lung cancer (NSCLC) is more common than small cell lung cancer (SCLC). Besides surgery and radiotherapy, chemotherapy is the most important method of treatment for lung cancer. Indole scaffold is considered one of the most privileged scaffolds in heterocyclic chemistry. Indole may serve as an effective probe for the development of new drug candidates against challenging diseases, including lung cancer. In this review, we will focus on discussing the existing indole based pharmacophores in the clinical and pre-clinical stages of development against lung cancer, along with the synthesis of some of the selected anti-lung cancer drugs. Moreover, the basic mechanism of action underlying indole based anti-lung cancer treatment, such as protein kinase inhibition, histone deacetylase inhibition, DNA topoisomerase inhibition, and tubulin inhibition will also be discussed

Étude comparative entre deux voies de synthèse de macrolactames conçus pour s'empiler sous forme de nanotubes

Avant d'entrer dans le vif du sujet de ce travail de maîtrise, il serait utile de débuter par la généalogie des nanotechnologies, et par un aperçu de l'utilité des nanotubes à base d'acides aminés naturels. De tels nanotubes ont été impliqués dans différentes applications scientifiques, ce qui explique l'intérêt général envers ce genre de nanotube. Cependant, ceux auxquels nous faisons référence ici ont été synthétisés à partir d'acides aminés non-naturels par deux différentes voies de synthèse: une voie de macrocyclisation directe et une voie de cyclooligomérisation. Notre partie expérimentale porte sur la préparation des précurseurs de ces deux voies de synthèse. En effet, nous avons préparé des monomères conjugués ou non-conjugués à partir de produits commerciaux, l'acide ß- trans -hydromuconique et le 3-amino-1-propanol. Ces précurseurs réagissent soit par cyclooligomérisation, dans le cas du monomère, soit par macrocyclisation directe, dans le cas du précurseur di-, tri- et tétramère linéaire. Nous avons également étudié les avantages et les inconvénients des deux méthodes qui sont très influencées par la conjugaison des systèmes. La discussion portera aussi sur la nature des structures tubulaires obtenues à la lumière de résultats de modélisation moléculaire, de cristallographie, de spectroscopie RMN, LC/MS et d'observation au microscope optique et électronique

Development of Thiophene Compounds as Potent Chemotherapies for the Treatment of Cutaneous Leishmaniasis Caused by Leishmania major

Leishmania major (L. major) is a protozoan parasite that causes cutaneous leishmaniasis. About 12 million people are currently infected with an annual incidence of 1.3 million cases. The purpose of this study was to synthesize a small library of novel thiophene derivatives, and evaluate its parasitic activity, and potential mechanism of action (MOA). We developed a structure–activity relationship (SAR) study of the thiophene molecule 5A. Overall, eight thiophene derivatives of 5A were synthesized and purified by silica gel column chromatography. Of these eight analogs, the molecule 5D showed the highest in vitro activity against Leishmania major promastigotes (EC50 0.09 ± 0.02 µM), with an inhibition of the proliferation of intracellular amastigotes higher than 75% at only 0.63 µM and an excellent selective index. Moreover, the effect of 5D on L. major promastigotes was associated with generation of reactive oxygen species (ROS), and in silico docking studies suggested that 5D may play a role in inhibiting trypanothione reductase. In summary, the combined SAR study and the in vitro evaluation of 5A derivatives allowed the identification of the novel molecule 5D, which exhibited potent in vitro anti-leishmanial activity resulting in ROS production leading to cell death with no significant cytotoxicity towards mammalian cells

Assessing the Antioxidant Properties of Larrea tridentata Extract as a Potential Molecular Therapy against Oxidative Stress

Oxidative stress has been linked to neurodegenerative diseases such as Huntington’s, Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis diseases. Larrea tridentata (LT) also known as Creosote Bush is an evergreen shrub found in the Chihuahuan desert which has been used medicinally by Native American tribes in southwestern North America and the Amerindians of South America. However, studies of the antioxidant capacity of the crude extract of LT towards the discovery of novel molecular therapies bearing antioxidants and drug-like properties are lacking. In this study, we assessed the antioxidant properties of Larrea tridentata, collected specifically from the Chihuahuan desert in the region of El Paso del Norte, TX, USA. LT phytochemicals were obtained from three different extracts (ethanol; ethanol: water (60:40) and water). Then the extracts were evaluated in eight different assays (DPPH, ABTS, superoxide; FRAP activity, nitric oxide, phenolic content, UV visible absorption and cytotoxicity in non-cancerous HS27 cells). The three extracts were not affecting the HS27 cells at concentrations up to 120 µg/mL. Among the three extracts, we found that the mixture of ethanol: water (60:40) LT extract has the most efficient antioxidant properties (IC50 (DPPH at 30 min) = 111.7 ± 3.8 μg/mL; IC50 (ABTS) = 8.49 ± 2.28 μg/mL; IC50 (superoxide) = 0.43 ± 0.17 μg/mL; IC50 (NO) = 230.4 ± 130.4 μg/mL; and the highest phenolic content was estimated to 212.46 ± 7.05 mg GAE/L). In addition, there was a strong correlation between phenolic content and the free-radical scavenging activity assays. HPLC-MS study identified nine compounds from the LT-ethanol: water extract including Justicidin B and Beta peltain have been previously reported as secondary metabolites of Larrea tridentata

Larrea tridentata Extract Mitigates Oxidative Stress-Induced Cytotoxicity in Human Neuroblastoma SH-SY5Y Cells

Creosote bush (Larrea tridentata; LT) leaves extracts were tested for their potential efficacy to mitigate cellular oxidative stress on human SH-SY5Y cells. Here, the differential nuclear staining assay, a bioimager system, and flow cytometric protocols, concurrently with several specific chemicals, were used to measure the percentage of cell viability and several facets implicated in the cytoprotective mechanism of LT extracts. Initially, three LT extracts, prepared with different solvents, ethanol, ethanol:water (e/w), and water, were tested for their capacity to rescue the viability of cells undergoing aggressive H2O2-induced oxidative stress. Results indicate that the LT extract prepared with a mixture of ethanol:water (LT-e/w; 60:40% v/v) displayed the most effective cytoprotection rescue activity. Interestingly, by investigating the LT-e/w mechanism of action, it was found that LT-e/w extract decreases the levels of H2O2-provoked reactive oxidative species (ROS) accumulation, mitochondrial depolarization, phosphatidylserine externalization, caspase-3/7 activation, and poly (ADP-ribose) polymerase (PARP) cleavage significantly, which are hallmarks of apoptosis. Thus, out of the three LT extracts tested, our findings highlight that the LT-e/w extract was the most effective protective reagent on SH-SY5Y cells undergoing oxidative stress in vitro, functioning as a natural anti-apoptotic extract. These findings warrant further LT-e/w extract examination in a holistic context

Virucidal and Synergistic Activity of Polyphenol-Rich Extracts of Seaweeds against Measles Virus

Although preventable by vaccination, Measles still causes thousands of deaths among young children worldwide. The discovery of new antivirals is a good approach to control new outbreaks that cause such death. In this study, we tested the antiviral activity against Measles virus (MeV) of Polyphenol-rich extracts (PPs) coming from five seaweeds collected and cultivated in Mexico. An MTT assay was performed to determine cytotoxicity effect, and antiviral activity was measured by syncytia reduction assay and confirmed by qPCR. PPs from Ecklonia arborea (formerly Eisenia arborea, Phaeophyceae) and Solieria filiformis (Rhodophyta) showed the highest Selectivity Index (SI), \u3e3750 and \u3e576.9 respectively. Both PPs extracts were selected to the subsequent experiments owing to their high efficacy and low cytotoxicity compared with ribavirin (SI of 11.57). The combinational effect of PPs with sulphated polysaccharides (SPs) and ribavirin were calculated by using Compusyn software. Synergistic activity was observed by combining both PPs with low concentrations of Solieria filiformis SPs (0.01 µg/mL). The antiviral activity of the best combinations was confirmed by qPCR. Virucidal assay, time of addition, and viral penetration evaluations suggested that PPs act mainly by inactivating the viral particle. To our knowledge, this is the first report of the virucidal effect of Polyphenol-rich extracts of seaweeds

Gold-catalyzed carbon-carbon, carbon-oxygen and carbon-nitrogen bond formations : efficient synthesis of isoflavanones, aza-isoflavanones, [plus or minus symbol]-pterocarpans and isoflavones

Recent years have witnessed a tremendous growth in the number of gold-catalyzed highly selective chemical transformations. The aim of this study was to develop new gold catalytic methods to mediate carbon-carbon, carbon-oxygen and carbon-nitrogen bond forming reactions.Chapter 2 describes new annulations catalyzed by gold(I) of simple o-hydroxyaldehydes with alkynes. This annulation efficiently generates isoflavanone-type structures, which have many possible applications in the synthesis of isoflavanone natural products. This chapter details the development and the optimization of the reaction conditions. The annulation was applied to various aldehydes and arylalkynes with good efficiency. Furthermore, it incorporated all atoms of both starting materials into the product and thus has a theoretical atom economy of 100%.Chapter 3 extends the scope of the annulations developed in Chapter 2. Indeed, 2,3-dihydro-1-tosylquinolin-3(1H)-one derivatives, aza-isoflavanones, have been efficiently synthesized via a gold-catalyzed annulation of 2-tosylaminobenzaldehyde and alkynes. The annulation was applied to various arylalkynes with good efficiency. This annulation can be used for the synthesis of a range of potentially bioactive molecules.Chapter 4 describes applications in the total synthesis of the annulation developed in chapter 2. (+/-)-Pterocarpan and analogues have been efficiently synthesized via the annulation of salicylaldehydes and o-methoxymethoxylphenylacetylene followed by a one-pot reduction and acidic cyclization of the ketones. In addition, isoflavone derivatives have been synthesized rapidly via the annulation of salicylaldehyde and arylacetylenes followed by IBX/DMSO oxidation of the isoflavanones.As part of our ongoing studies on metal-catalyzed atom economical reactions, the gold/silver-catalyzed addition of arenes to mono-substituted allene, generate exclusive terminal addition products are described in Chapter 5.Finally, Appendix A explores the use of commercially available polymer-supported triphenylphosphine as a catalyst for the efficient gamma-addition of methyl 2-butynoate with various pronucleophiles. In addition, optimization studies shows no need of a co-catalyst for the reaction in the presence of a mixture of water:toluene (5:1). The polymer-supported triphenylphosphine is recoverable and can be reused efficiently. This gamma-addition is highly atom-economical and the reaction time was reduced under microwave irradiation

Étude comparative entre deux voies de synthèse de macrolactames conçus pour s'empiler sous forme de nanotubes

Avant d'entrer dans le vif du sujet de ce travail de maîtrise, il serait utile de débuter par la généalogie des nanotechnologies, et par un aperçu de l'utilité des nanotubes à base d'acides aminés naturels. De tels nanotubes ont été impliqués dans différentes applications scientifiques, ce qui explique l'intérêt général envers ce genre de nanotube. Cependant, ceux auxquels nous faisons référence ici ont été synthétisés à partir d'acides aminés non-naturels par deux différentes voies de synthèse: une voie de macrocyclisation directe et une voie de cyclooligomérisation. Notre partie expérimentale porte sur la préparation des précurseurs de ces deux voies de synthèse. En effet, nous avons préparé des monomères conjugués ou non-conjugués à partir de produits commerciaux, l'acide ß- trans -hydromuconique et le 3-amino-1-propanol. Ces précurseurs réagissent soit par cyclooligomérisation, dans le cas du monomère, soit par macrocyclisation directe, dans le cas du précurseur di-, tri- et tétramère linéaire. Nous avons également étudié les avantages et les inconvénients des deux méthodes qui sont très influencées par la conjugaison des systèmes. La discussion portera aussi sur la nature des structures tubulaires obtenues à la lumière de résultats de modélisation moléculaire, de cristallographie, de spectroscopie RMN, LC/MS et d'observation au microscope optique et électronique