Discovery of Novel Thiazole-Based SIRT2 Inhibitors as Anticancer Agents: Molecular Modeling, Chemical Synthesis and Biological Assays.

The search and development of effective sirtuin small molecule inhibitors (SIRTIs) continues to draw great attention due to their wide range of pharmacological applications. Based on SIRTs' involvement in different biological pathways, their ligands were investigated for many diseases, such as cancer, neurodegenerative disorders, diabetes, cardiovascular diseases and autoimmune diseases. The elucidation of a substantial number of SIRT2-ligand complexes is steering the identification of novel and more selective modulators.

Investigations of Antioxidant and Anti-Cancer Activities of 5-Aminopyrazole Derivatives.

To further extend the structure-activity relationships (SARs) of 5-aminopyrazoles (5APs) and identify novel compounds able to interfere with inflammation, oxidative stress, and tumorigenesis, 5APs have been designed and prepared. Some chemical modifications have been inserted on cathecol function or in aminopyrazole central core; in detail: (i) smaller, bigger, and more lipophilic substituents were introduced in and positions of catechol portion (5APs ); (ii) a methyl group was inserted on C3 of the pyrazole scaffold (5APs ); (iii) a more flexible alkyl chain was inserted on N1 position (5APs ); (iv) the acylhydrazonic linker was moved from position 4 to position 3 of the pyrazole scaffold (5APs ). All new derivatives have been tested for radical scavenging (DPPH assay), anti-aggregating/antioxidant (in human platelets) and cell growth inhibitory activity (MTT assay) properties.

New Pyrazolyl Thioureas Active against the Genus.

To meet the urgent need for new antibacterial molecules, a small library of pyrazolyl thioureas (PTUs) was designed, synthesized and tested against difficult-to-treat human pathogens. The prepared derivatives are characterized by a carboxyethyl functionality on C4 and different hydroxyalkyl chains on N1. Compounds - were first evaluated against a large panel of Gram-positive and Gram-negative pathogens.

PTC596-Induced BMI-1 Inhibition Fights Neuroblastoma Multidrug Resistance by Inducing Ferroptosis.

Neuroblastoma (NB) is a paediatric cancer with noteworthy heterogeneity ranging from spontaneous regression to high-risk forms that are characterised by cancer relapse and the acquisition of drug resistance. The most-used anticancer drugs exert their cytotoxic effect by inducing oxidative stress, and long-term therapy has been demonstrated to cause chemoresistance by enhancing the antioxidant response of NB cells. Taking advantage of an in vitro model of multidrug-resistant (MDR) NB cells, characterised by high levels of glutathione (GSH), the overexpression of the oncoprotein BMI-1, and the presence of a mutant P53 protein, we investigated a new potential strategy to fight chemoresistance.

Further Quinolizidine Derivatives as Antiarrhythmic Agents- 3.

Fourteen quinolizidine derivatives, structurally related to the alkaloids lupinine and cytisine and previously studied for other pharmacological purposes, were presently tested for antiarrhythmic, and other cardiovascular effects on isolated guinea pig heart tissues in comparison to well-established reference drugs. According to their structures, the tested compounds are assembled into three subsets: (a) N-(quinolizidinyl-alkyl)-benzamides; (b) 2-(benzotriazol-2-yl)methyl-1-(quinolizidinyl)alkyl-benzimidazoles; (c) N-substituted cytisines. All compounds but two displayed antiarrhythmic activity that was potent for compounds , , , and (in ascending order).

Indole Antitumor Agents in Nanotechnology Formulations: An Overview.

The indole heterocycle represents one of the most important scaffolds in medicinal chemistry and is shared among a number of drugs clinically used in different therapeutic areas. Due to its varied biological activities, high unique chemical properties and significant pharmacological behaviors, indole derivatives have drawn considerable interest in the last decade as antitumor agents active against different types of cancers. The research of novel antiproliferative drugs endowed with enhanced efficacy and reduced toxicity led to the approval by U.

New Class of Benzodiazepinone Derivatives as Pro-Death Agents Targeting BIR Domains in Cancer Cells.

Inhibitor of Apoptosis Proteins (IAPs) are validated targets for cancer therapy, and the deregulation of their activities within the NF-κB pathway correlates with chemoresistance events, even after treatment with IAPs-antagonists in the clinic (Smac-mimetics). The molecule FC2 was identified as a NF-κB pathway modulator in MDA-MB-231 adenocarcinoma cancer cells after virtual screening of the Chembridge library against the Baculoviral IAP Repeat 1 (BIR1) domain of cIAP2 and XIAP. An improved cytotoxic effect is observed when FC2 is combined with Smac-mimetics or with the cytokine Tumor Necrosis Factor (TNF).

Microbiological Screening of 5-Functionalized Pyrazoles for the Future Development of Optimized Pyrazole-Based Delivery Systems.

The pyrazole ring represents a widely applied chemical scaffold in medicinal chemistry research and we have observed that the physicochemical and biological features of highly substituted pyrazoles can be successfully improved by their encapsulation in dendrimer nanoparticles (NPs). For the future development of new optimized antibacterial delivery systems, we report the synthesis and biological evaluation of 5-amino functionalized pyrazole library (compounds -). In detail, new derivatives - were differently decorated in C3, C4 and C5 positions.

Nanotechnology for Pediatric Retinoblastoma Therapy.

Retinoblastoma is a rare, sometimes hereditary, pediatric cancer. In high-income countries this disease has a survival rate approaching 100%, while in low- and middle-income countries the prognosis is fatal for about 80% of cases. Depending on the stage of the disease, different therapeutic protocols are applied.

The Development of FAK Inhibitors: A Five-Year Update.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase over-expressed in different solid cancers. In recent years, FAK has been recognized as a new target for the development of antitumor agents, useful to contrast tumor development and metastasis formation. To date, studies on the role of FAK and FAK inhibitors are of great interest for both pharmaceutical companies and academia.

The Development of BTK Inhibitors: A Five-Year Update.

Bruton's tyrosine kinase (BTK) represented, in the past ten years, an important target for the development of new therapeutic agents that could be useful for cancer and autoimmune disorders. To date, five compounds, able to block BTK in an irreversible manner, have been launched in the market, whereas many reversible BTK inhibitors (BTKIs), with reduced side effects that are more useful for long-term administration in autoimmune disorders, are under clinical investigation. Despite the presence in the literature of many articles and reviews, studies on BTK function and BTKIs are of great interest for pharmaceutical companies as well as academia.

Btk Inhibitors: A Medicinal Chemistry and Drug Delivery Perspective.

In the past few years, Bruton's tyrosine Kinase (Btk) has emerged as new target in medicinal chemistry. Since approval of ibrutinib in 2013 for treatment of different hematological cancers (as leukemias and lymphomas), two other irreversible Btk inhibitors have been launched on the market. In the attempt to overcome irreversible Btk inhibitor limitations, reversible compounds have been developed and are currently under evaluation.

Nanotechnology of Tyrosine Kinase Inhibitors in Cancer Therapy: A Perspective.

Nanotechnology is an important application in modern cancer therapy. In comparison with conventional drug formulations, nanoparticles ensure better penetration into the tumor mass by exploiting the enhanced permeability and retention effect, longer blood circulation times by a reduced renal excretion and a decrease in side effects and drug accumulation in healthy tissues. The most significant classes of nanoparticles (i.

Journey on Naphthoquinone and Anthraquinone Derivatives: New Insights in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by memory loss, cognitive impairment, and functional decline leading to dementia and death. AD imposes neuronal death by the intricate interplay of different neurochemical factors, which continue to inspire the medicinal chemist as molecular targets for the development of new agents for the treatment of AD with diverse mechanisms of action, but also depict a more complex AD scenario. Within the wide variety of reported molecules, this review summarizes and offers a global overview of recent advancements on naphthoquinone (NQ) and anthraquinone (AQ) derivatives whose more relevant chemical features and structure-activity relationship studies will be discussed with a view to providing the perspective for the design of viable drugs for the treatment of AD.

Multitarget Biological Profiling of New Naphthoquinone and Anthraquinone-Based Derivatives for the Treatment of Alzheimer's Disease.

Two series of naphthoquinone and anthraquinone derivatives decorated with an aromatic/heteroaromatic chain have been synthesized and evaluated as potential promiscuous agents capable of targeting different factors playing a key role in Alzheimer's disease (AD) pathogenesis. On the basis of the biological profiling, most of them exhibited a significant ability to inhibit amyloid aggregation, PHF6 tau sequence aggregation, acetylcholinesterase (AChE), and monoamine oxidase (MAO) B. In particular, naphthoquinone resulted as one of the best performing multitarget-directed ligand (MTDL) experiencing a high potency profile in inhibiting β-amyloid (Aβ) aggregation (IC = 3.

Whey proteins inhibit food intake and tend to improve oxidative balance in obese zucker rats.

Background/aims: Whey proteins (WP), obtained from milk after casein precipitation, represent a heterogeneous group of proteins. WP are reported to inhibit food intake in diet-induced experimental obesity; WP have been proposed as adjuvant therapy in oxidative stress-correlated pathologies. This work evaluates the effects of WP in comparison with casein, as a source of alimentary proteins, on food intake, weight growth and some indexes of oxidative equilibrium in Zucker Rats, genetically prone to obesity.

New Insights on Fak and Fak Inhibitors.

Background: Focal adhesion kinase (Fak) is a cytoplasmic protein tyrosine kinase overexpressed and activated in different solid cancers; it has shown an important role in metastasis formation, cell migration, invasion and angiogenesis and consequently it has been proposed as a potential target in cancer therapy, particularly in a metastatic phase. In recent years, different investigations have highlighted the importance of new Fak inhibitors as potential anti-cancer drugs, but other studies evidenced its role in different pathologies related to the cardiac function or viral infection.

Methods: An extensive bibliographic research (104 references) has been done concerning the structure of Fak, its importance in tumor development, but also in other pathologies currently under study.

Molecular Docking and QSAR Studies as Computational Tools Exploring the Rescue Ability of F508del CFTR Correctors.

Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. Different mutations involving the cystic fibrosis transmembrane regulator protein (CFTR) gene, which encodes the CFTR channel, are involved in CF. A number of life-prolonging therapies have been conceived and deeply investigated to combat this disease.

Quinolizidine-Derived Lucanthone and Amitriptyline Analogues Endowed with Potent Antileishmanial Activity.

Leishmaniases are neglected diseases that are endemic in many tropical and sub-tropical Countries. Therapy is based on different classes of drugs which are burdened by severe side effects, occurrence of resistance and high costs, thereby creating the need for more efficacious, safer and inexpensive drugs. Herein, sixteen 9-thioxanthenone derivatives (lucanthone analogues) and four compounds embodying the diarylethene substructure of amitriptyline (amitriptyline analogues) were tested in vitro for activity against and promastigotes.

Discovery of novel VX-809 hybrid derivatives as F508del-CFTR correctors by molecular modeling, chemical synthesis and biological assays.

Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. It is caused by different mutations in the cystic fibrosis transmembrane regulator protein (CFTR) gene, with F508del being the most common. During the last years, small-molecule therapy chosen to contrast CF relied on compounds that correct CFTR misfolding and ER retention (correctors such as VX-809), or defective channel gating (potentiators such as VX-770).

Synthesis and Structure-activity Relationship of Aminoarylthiazole Derivatives as Potential Potentiators of the Chloride Transport Defect in Cystic Fibrosis.

Background: Cystic fibrosis (CF) is the autosomal recessive disorder most common in Caucasian populations. It is caused by mutations in the cystic fibrosis transmembrane regulator protein (CFTR). CFTR is predominantly expressed at the apical plasma membranes of the epithelial cells lining several organs, and functions as a cAMP-regulated chloride/bicarbonate channel.

Differential modulation of SIRT6 deacetylase and deacylase activities by lysine-based small molecules.

Sirtuin 6 (SIRT6) is an NAD-dependent deacetylase regulating important functions: modulators of its enzymatic activity have been considered as possible therapeutic agents. Besides the deacetylase activity, SIRT6 also has NAD-dependent deacylase activity, whereby it regulates the secretion of cytokines and proteins. We identified novel SIRT6 modulators with a lysine-based structure: compound 1 enhances SIRT6 deacylase while inhibiting the deacetylase activity.

Schneider's first-rank symptoms as predictors of remission in antipsychotic-naive first-episode psychosis.

Objective: German psychiatrist Kurt Schneider proposed the concept of first-rank symptoms (FRS) of schizophrenia in 1959. However, their relevance for diagnosis and prediction of treatment response are still unclear. Most studies have investigated FRS in chronic or medicated patients.

Exploring the effectiveness of novel benzimidazoles as CB2 ligands: synthesis, biological evaluation, molecular docking studies and ADMET prediction.

Herein we continued our previous work on the development of CB2 ligands, reporting the design and synthesis of a series of benzimidazole-containing derivatives that were explored as selective CB2 ligands with binding affinity towards both CB1 and CB2 receptors. Seven out of eighteen compounds exhibited preferential binding ability to CB2 over CB1 receptors with potencies in the sub-micromolar or low micromolar range. In particular, we identified two promising hit compounds, the agonist 1-[2-(,-diethylamino)ethyl]-2-(4-ethoxybenzyl)-5-trifluoromethylbenzimidazole () (CB2: = 0.