Mono- and di-acylated imidazolidine-2-thione derivatives: synthesis, cytotoxicity evaluation and computational studies

Imidazolidine-2-thione substructure represents a pharmaceutically attractive scaffold, being included in different antimicro- bial, anticancer and pesticide agents. To further evaluate the pharmaceutical potential of this chemical moiety, imidazolidine- 2-thione was reacted with atypical Vilsmeier adducts, obtained by the condensation between dimethylacetamide and various acyl chlorides endowed with different electronic and steric properties. The formation of mono-acylated or di-acylated thio- urea derivatives emerged to be affected by the nature of the considered acyl chloride reagent. Computational semi-empirical simulations were carried out to rationalize the relevant factor influencing the outcome of the reaction. As acylthioureas are pharmacologically relevant compounds, the chemical versatility of mono-acylated derivatives were evaluated by reacting benzoyl imidazolidin-2-thione with acyl chlorides. A small library of asymmetric di-acylthioureas was prepared and the obtained derivatives did not show any cytotoxicity on SKOV-3 and MCF-7 cancer cell lines. Additionally, in silico studies predicted good pharmacokinetics properties and promising drug-like characteristics for mono- and di-acylated thioureas. These considerations further support the value of the prepared compounds as interesting non-cytotoxic chemical scaffold useful in the medicinal chemistry field

The High Resolution Structure of GDP-4-keto-6-deoxy-D-mannose epimerase/reductase

GDP-4-keto-6-deoxy-D-mannose epimerase/reductase is a bifunctional enzyme involved in the biosynthesis of cell-surface structures, such as blood group antigens. Each subunit in the homodimeric enzyme consists of two domains. The N-terminal domain displays a Rossmann-fold topology and binds the NADP+ coenzyme. The C-terminal domain is held to bind the substrate. The holo-enzyme structure has been refined at 1.45 Å resolution, based on synchrotron data, to a final R-factor of 0.127 (Rfree = 0.167). The refined protein model highlights several residues involved in coenzyme recognition and binding and suggests that the enzyme belongs to the short-chain dehydrogenase protein homology family. Implications of the catalytic mechanism are discussed

Regioselective Synthesis, Structural Characterization, and Antiproliferative Activity of Novel Tetra-Substituted Phenylaminopyrazole Derivatives

A small library of highly functionalized phenylaminopyrazoles, bearing different substituents at position 1, 3 and 4 of the pyrazole ring, was prepared by the one pot condensation of active methylene reagents, phenylisothiocyanate and substituted hydrazine (namely, methyl- and benzyl-hydrazine). The identified reaction conditions proved to be versatile and efficient. Fur-thermore, the evaluation of alternative stepwise protocols affected the chemo- and re-gio-selectivity outcome of the one-pot procedure. The chemical identity of two N-methyl pyrazole isomers, selected as prototypes of the whole series, was unambiguously identified by means of NMR and mass spectrometry studies. Additionally, semiempirical calculations provided a structural rationale for the different chromatographic behaviour of the two isomers. The prepared tetra-substituted phenylaminopyrazoles were tested in cell-based assays on a panel of cancer and normal cell lines. The tested compounds did not show any cytotoxic effect on the selected cell lines, thus supporting their pharmaceutical potentials

Novel Au Carbene Complexes as Promising Multi-Target Agents in Breast Cancer Treatment

Over the past decade, metal complexes based on N-heterocyclic carbenes (NHCs) have attracted great attention due to their wide and exciting applications in material sciences and medicinal chemistry. In particular, the gold-based complexes are the focus of research efforts for the development of new anticancer compounds. Literature data and recent results, obtained by our research group, reported the design, the synthesis and the good anticancer activity of some silver and gold complexes with NHC ligands. In particular, some of these complexes were active towards some breast cancer cell lines. Considering this evidence, here we report some new Au-NHC complexes prepared in order to improve solubility and biological activity. Among them, the compounds 1 and 6 showed an interesting anticancer activity towards the breast cancer MDA-MB-231 and MCF-7 cell lines, respectively. In addition, in vitro and in silico studies demonstrated that they were able to inhibit the activity of the human topoisomerases I and II and the actin polymerization reaction. Moreover, a downregulation of vimentin expression and a reduced translocation of NF-kB into the nucleus was observed. The interference with these vital cell structures induced breast cancer cells’ death by triggering the extrinsic apoptotic pathway

Multidrug Resistance (MDR): A Widespread Phenomenon in Pharmacological Therapies

Multidrug resistance is a leading concern in public health. It describes a complex phenotype whose predominant feature is resistance to a wide range of structurally unrelated cytotoxic compounds, many of which are anticancer agents. Multidrug resistance may be also related to antimicrobial drugs, and is known to be one of the most serious global public health threats of this century. Indeed, this phenomenon has increased both mortality and morbidity as a consequence of treatment failures and its incidence in healthcare costs. The large amounts of antibiotics used in human therapies, as well as for farm animals and even for fishes in aquaculture, resulted in the selection of pathogenic bacteria resistant to multiple drugs. It is not negligible that the ongoing COVID-19 pandemic may further contribute to antimicrobial resistance. In this paper, multidrug resistance and antimicrobial resistance are underlined, focusing on the therapeutic options to overcome these obstacles in drug treatments. Lastly, some recent studies on nanodrug delivery systems have been reviewed since they may represent a significant approach for overcoming resistance

Novel Au Carbene Complexes as Promising Multi-Target Agents in Breast Cancer Treatment

Over the past decade, metal complexes based on N-heterocyclic carbenes (NHCs) have attracted great attention due to their wide and exciting applications in material sciences and medicinal chemistry. In particular, the gold-based complexes are the focus of research efforts for the development of new anticancer compounds. Literature data and recent results, obtained by our research group, reported the design, the synthesis and the good anticancer activity of some silver and gold complexes with NHC ligands. In particular, some of these complexes were active towards some breast cancer cell lines. Considering this evidence, here we report some new Au-NHC complexes prepared in order to improve solubility and biological activity. Among them, the compounds 1 and 6 showed an interesting anticancer activity towards the breast cancer MDA-MB- 231 and MCF-7 cell lines, respectively. In addition, in vitro and in silico studies demonstrated that they were able to inhibit the activity of the human topoisomerases I and II and the actin polymerization reaction. Moreover, a downregulation of vimentin expression and a reduced translocation of NF-kB into the nucleus was observed. The interference with these vital cell structures induced breast cancer cells’ death by triggering the extrinsic apoptotic pathway

Metal Complexes with Schiff Bases: Data Collection and Recent Studies on Biological Activities

Metal complexes play a crucial role in pharmaceutical sciences owing to their wide and significant activities. Schiff bases (SBs) are multifaceted pharmacophores capable of forming chelating complexes with various metals in different oxidation states. Complexes with SBs are extensively studied for their numerous advantages, including low cost and simple synthetic strategies. They have been reported to possess a variety of biological activities, including antimicrobial, anticancer, antioxidant, antimalarial, analgesic, antiviral, antipyretic, and antidiabetic ones. This review summarizes the most recent studies on the antimicrobial and antiproliferative activities of SBs-metal complexes. Moreover, recent studies regarding mononuclear and binuclear complexes with SBs are described, including antioxidant, antidiabetic, antimalarial, antileishmanial, anti-Alzheimer, and catecholase activities

A Comprehensive Review on the State of the Art of Breast Cancers in Italy

: Breast cancer (BC) currently represents one of the most prevalent cancers among women worldwide and the leading cause of cancer death among women, also negatively affecting the quality of life (QoL) in patients. Over the past two decades, BC research has led to extraordinary advances in our understanding of the disease, resulting in more effective treatments. However, its occurrence is still increasing. Several new treatments are now under development worldwide, but they are not devoid of well-- known side effects, and a great number of patients develop endocrine resistance. Nevertheless, the design and synthesis of more suitable strategies and new drugs to treat breast cancers, overcome resistance and side effects, and obtain better therapeutic outcomes are needed. In this review, we summarize the therapies and the clinical studies currently ongoing in Italy for the treatment of BCs, mainly HER2+ MBC, HER2-low MBC, and TNBC, focusing on the most recent ones, also in consideration of diverse facets, including some aspects related to QoL. Finally, some studies related to the usefulness of physical activity in BC will be cited

5,8-Dimethyl-9H-carbazole Derivatives Blocking hTopo I Activity and Actin Dynamics

Over the years, carbazoles have been largely studied for their numerous biological properties, including antibacterial, antimalarial, antioxidant, antidiabetic, neuroprotective, anticancer, and many more. Some of them have gained great interest for their anticancer activity in breast cancer due to their capability in inhibiting essential DNA-dependent enzymes, namely topoisomerases I and II. With this in mind, we studied the anticancer activity of a series of carbazole derivatives against two breast cancer cell lines, namely the triple negative MDA-MB-231 and MCF-7 cells. Compounds 3 and 4 were found to be the most active towards the MDA-MB-231 cell line without interfering with the normal counterpart. Using docking simulations, we assessed the ability of these carbazole derivatives to bind human topoisomerases I and II and actin. In vitro specific assays confirmed that the lead compounds selectively inhibited the human topoisomerase I and interfered with the normal organization of the actin system, triggering apoptosis as a final effect. Thus, compounds 3 and 4 are strong candidates for further drug development in multi-targeted therapy for the treatment of triple negative breast cancer, for which safe therapeutic regimens are not yet available

The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From Structure‐Based Virtual Screening to In Vivo Biological Activity

A mismatch between β‐oxidation and the tricarboxylic acid cycle (TCA) cycle flux in mitochondria produces an accumulation of lipid metabolic intermediates, resulting in both blunted metabolic flexibility and decreased glucose utilization in the affected cells. The ability of the cell to switch to glucose as an energy substrate can be restored by reducing the reliance of the cell on fatty acid oxidation. The inhibition of the carnitine system, limiting the carnitine shuttle to the oxidation of lipids in the mitochondria, allows cells to develop a high plasticity to metabolic rewiring with a decrease in fatty acid oxidation and a parallel increase in glucose oxidation. We found that 3‐(2,2,2‐ trimethylhydrazine)propionate (THP), which is able to reduce cellular carnitine levels by blocking both carnitine biosynthesis and the cell membrane carnitine/organic cation transporter (OCTN2), was reported to improve mitochondrial dysfunction in several diseases, such as Huntington’s disease (HD). Here, new THP‐derived carnitine‐lowering agents (TCL), characterized by a high affinity for the OCTN2 with a minimal effect on carnitine synthesis, were developed, and their biological activities were evaluated in both in vitro and in vivo HD models. Certain compounds showed promising biological activities: reducing protein aggregates in HD cells, ameliorating motility defects, and increasing the lifespan of HD Drosophila melanogaster