Silver and Gold Complexes with NHC-Ligands Derived from Caffeine: Catalytic and Pharmacological Activity.

N-heterocyclic carbene (NHC) silver(I) and gold(I) complexes have found different applications in various research fields, as in medicinal chemistry for their antiproliferative, anticancer, and antibacterial activity, and in chemistry as innovative and effective catalysts. The possibility of modulating the physicochemical properties, by acting on their ligands and substituents, makes them versatile tools for the development of novel metal-based compounds, mostly as anticancer compounds. As it is known, chemotherapy is commonly adopted for the clinical treatment of different cancers, even though its efficacy is hampered by several factors. Thus, the development of more effective and less toxic drugs is still an urgent need. Herein, we reported the synthesis and characterization of new silver(I) and gold(I) complexes stabilized by caffeine-derived NHC ligands, together with their biological and catalytic activities. Our data highlight the interesting properties of this series as effective catalysts in A3-coupling and hydroamination reactions and as promising anticancer, anti-inflammatory, and antioxidant agents. The ability of these complexes in regulating different pathological aspects, and often co-promoting causes, of cancer makes them ideal leads to be further structurally functionalized and investigated.

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.

Complexes of Ruthenium(II) as Promising Dual-Active Agents against Cancer and Viral Infections.

Poor responses to medical care and the failure of pharmacological treatment for many high-frequency diseases, such as cancer and viral infections, have been widely documented. In this context, numerous metal-based substances, including cisplatin, auranofin, various gold metallodrugs, and ruthenium complexes, are under study as possible anticancer and antiviral agents. The two Ru(III) and Ru(II) complexes, namely, BOLD-100 and RAPTA-C, are presently being studied in a clinical trial and preclinical studies evaluation, respectively, as anticancer agents. Interestingly, BOLD-100 has also recently demonstrated antiviral activity against SARS-CoV-2, which is the virus responsible for the COVID-19 pandemic. Over the last years, much effort has been dedicated to discovering new dual anticancer-antiviral agents. Ru-based complexes could be very suitable in this respect. Thus, this review focuses on the most recent studies regarding newly synthesized Ru(II) complexes for use as anticancer and/or antiviral agents.

NHC-Ag(I) and NHC-Au(I) Complexes with N-Boc-Protected α-Amino Acidate Counterions Powerfully Affect the Growth of MDA-MB-231 Cells.

N-Heterocyclic carbene (NHC) metal complexes are attracting scientists' interest as an alluring class of metallodrugs. Indeed, the versatile functionalization of NHC ligands makes them optimal scaffolds to be developed in medicinal chemistry. Besides, amino acids are great biological ligands for metals, such as silver and gold, even though their use is still under-investigated. Aiming to shed light on the anticancer properties of this kind of complex, we investigated a series of silver and gold complexes, stabilized by NHC ligands and bearing carboxylate salts of tert-butyloxycarbonyl (Boc)-N-protected glycine and l-phenylalanine as anionic ligands. The most active complexes, AuM1Gly and AuM1Phe, powerfully affect the growth of MDA-MB-231 breast cancer cells, with IC50 values in the low nanomolar range. Further studies demonstrated the blockade of the human topoisomerase I activity and actin polymerization reaction at 0.001 µM. These unique features make these complexes very interesting and worthy to be used for future in vivo studies.

Activity and Selectivity of Novel Chemical Metallic Complexes with Potential Anticancer Effects on Melanoma Cells.

Human malignant melanoma cells from lymph node metastatic site (MeWo) were selected for testing several synthesized and purified silver(I) and gold(I) complexes stabilized by unsymmetrically substituted N-heterocyclic carbene (NHC) ligands, called L20 (N-methyl, N'-[2-hydroxy ethylphenyl]imidazol-2-ylide) and M1 (4,5-dichloro, N-methyl, N'-[2-hydroxy ethylphenyl]imidazol-2-ylide), having halogenide (Cl- or I-) or aminoacyl (Gly=N-(tert-Butoxycarbonyl)glycinate or Phe=(S)-N-(tert-Butoxycarbonyl)phenylalaninate) counterion. For AgL20, AuL20, AgM1 and AuM1, the Half-Maximal Inhibitory Concentration (IC50) values were measured, and all complexes seemed to reduce cell viability more effectively than Cisplatin, selected as control. The complex named AuM1 was the most active just after 8 h of treatment at 5 µM, identified as effective growth inhibition concentration. AuM1 also showed a linear dose and time-dependent effect. Moreover, AuM1 and AgM1 modified the phosphorylation levels of proteins associated with DNA lesions (H2AX) and cell cycle progression (ERK). Further screening of complex aminoacyl derivatives indicated that the most powerful were those indicated with the acronyms: GlyAg, PheAg, AgL20Gly, AgM1Gly, AuM1Gly, AgL20Phe, AgM1Phe, AuM1Phe. Indeed, the presence of Boc-Glycine (Gly) and Boc-L-Phenylalanine (Phe) showed an improved efficacy of Ag main complexes, as well as that of AuM1 derivatives. Selectivity was further checked on a non-cancerous cell line, a spontaneously transformed aneuploid immortal keratinocyte from adult human skin (HaCaT). In such a case, AuM1 and PheAg complexes resulted as the most selective allowing HaCaT viability at 70 and 40%, respectively, after 48 h of treatment at 5 µM. The same complexes tested on 3D MeWo static culture induced partial spheroid disaggregation after 24 h of culture, with almost half of the cells dead.

Synthesis of Novel N-Heterocyclic Carbene-Ruthenium (II) Complexes, "Precious" Tools with Antibacterial, Anticancer and Antioxidant Properties.

Ruthenium N-heterocyclic carbene (Ru-NHC) complexes show interesting physico-chemical properties as catalysts and potential in medicinal chemistry, exhibiting multiple biological activities, among them anticancer, antimicrobial, antioxidant, and anti-inflammatory. Herein, we designed and synthesized a new series of Ru-NHC complexes and evaluated their biological activities as anticancer, antibacterial, and antioxidant agents. Among the newly synthesized complexes, RANHC-V and RANHC-VI are the most active against triple-negative human breast cancer cell lines MDA-MB-231. These compounds were selective in vitro inhibitors of the human topoisomerase I activity and triggered cell death by apoptosis. Furthermore, the Ru-NHC complexes' antimicrobial activity was studied against Gram-positive and -negative bacteria, revealing that all the complexes possessed the best antibacterial activity against the Gram-positive Staphylococcus aureus, at a concentration of 25 µg/mL. Finally, the antioxidant effect was assessed by DPPH and ABTS radicals scavenging assays, resulting in a higher ability for inhibiting the ABTS•+, with respect to the well-known antioxidant Trolox. Thus, this work provides encouraging insights for further development of novel Ru-NHC complexes as potent chemotherapeutic agents endowed with multiple biological properties.

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.

Biological Activities of Ruthenium NHC Complexes: An Update.

Ruthenium N-heterocyclic carbene (NHC) complexes have unique physico-chemical properties as catalysts and a huge potential in medicinal chemistry and pharmacology, exhibiting a variety of notable biological activities. In this review, the most recent studies on ruthenium NHC complexes are summarized, focusing specifically on antimicrobial and antiproliferative activities. Ruthenium NHC complexes are generally active against Gram-positive bacteria, such as Bacillus subtilis, Staphylococcus aureus, Micrococcus luteus, Listeria monocytogenes and are seldom active against Gram-negative bacteria, including Salmonella typhimurium, Pseudomonas aeruginosa and Escherichia coli and fungal strains of Candida albicans. The antiproliferative activity was tested against cancer cell lines of human colon, breast, cervix, epidermis, liver and rat glioblastoma cell lines. Ruthenium NHC complexes generally demonstrated cytotoxicity higher than standard anticancer drugs. Further studies are needed to explore the mechanism of action of these interesting compounds.

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.

Exploring the anticancer and antioxidant properties of Vicia faba L. pods extracts, a promising source of nutraceuticals.

Background: Pulse crops are considered the major sources of proteins, dietary fiber, micronutrients, and bioactive phytochemicals. Among the numerous pulse crops, broad beans (Vicia faba L.) have received particular attention due to their nutraceutical, functional and economic importance. Our attention was mainly focused on the broad bean pods (VFs), which are the primary by-product of the domestic and industrial processing of broad beans and an attractive source of valuable ingredients. Methods: In order to investigate the VFs properties, the flours from broad beans of three different harvest periods were extracted with acetone, methanol and 70% aqueous ethanol and the dried extracts were analyzed, qualitatively and quantitatively, and tested for their antioxidant through DPPH and ABTS assay and anticancer activities using the MTT assay and immunofluorescence analysis. Results: The VF extracts demonstrated a good in vitro radical scavenging activity from the first stage of collection of all the V. faba L. extracts. Additionally, the extracts were tested for their cytotoxicity against a panel of cancer and normal cells and the outcomes indicated the ethanol extract as the most active against the melanoma cell line Sk-Mel-28, without affecting the viability of the normal cells. Finally, we found out that the ethanol extract interfered with the microtubules organization, leading to the cancer cells death by apoptosis.

Electrospun Membranes Designed for Burst Release of New Gold-Complexes Inducing Apoptosis of Melanoma Cells.

Two non-commercial metallic Au-based complexes were tested against one of the most aggressive malignant melanomas of the skin (MeWo cells), through cell viability and time-lapse live-cell imaging system assays. The tests with the complexes were carried out both in the form of free metallic complexes, directly in contact with the MeWo cell line culture, and embedded in fibers of Polycaprolactone (PCL) membranes produced by the electrospinning technique. Membranes functionalized with complexes were prepared to evaluate the efficiency of the membranes against the melanoma cells and therefore their feasibility in the application as an antitumoral patch for topical use. Both series of tests highlighted a very effective antitumoral activity, manifesting a very relevant cell viability inhibition after both 24 h and 48 h. In the case of the AuM1 complex at the concentration of 20 mM, melanoma cells completely died in this short period of time. A mortality of around 70% was detected from the tests performed using the membranes functionalized with AuM1 complex at a very low concentration (3 wt.%), even after 24 h of the contact period. The synthesized complexes also manifest high selectivity with respect to the MeWo cells. The peculiar structural and morphological organization of the nanofibers constituting the membranes allows for a very effective antitumoral activity in the first 3 h of treatment. Experimental points of the release profiles were perfectly fitted with theoretical curves, which easily allow interpretation of the kinetic phenomena occurring in the release of the synthesized complexes in the chosen medium.

N-Heterocyclic Carbene (NHC) Silver Complexes as Versatile Chemotherapeutic Agents Targeting Human Topoisomerases and Actin.

In recent years, the number of people suffering from cancer has risen rapidly and the World Health Organization and U.S. and European governments have identified this pathology as a priority issue. It is known that most bioactive anticancer molecules do not target a single protein but exert pleiotropic effects, simultaneously affecting multiple pathways. In our study, we designed and synthesized a new series of silver N-heterocyclic carbene (NHC) complexes [(NHC)2 Ag]+ [AgX2 ]- (X=iodide or acetate). The new complexes were active against two human breast cancer cell lines, MCF-7 and MDA-MB-231. These compounds showed multiple target actions as anticancer, by inhibiting in vitro the activity of the human topoisomerases I and II and interfering with the cytoskeleton dynamic, as also confirmed by in silico studies. Moreover, the antimicrobial activity of these silver complexes was studied against Gram-positive/negative bacteria. These dual properties provide a two-tiered approach, making these compounds of interest to be further deepened for the development of new chemotherapeutic agents.

Triclosan: A Small Molecule with Controversial Roles.

Triclosan (TCS), a broad-spectrum antimicrobial agent, has been widely used in personal care products, medical products, plastic cutting boards, and food storage containers. Colgate Total® toothpaste, containing 10 mM TCS, is effective in controlling biofilm formation and maintaining gingival health. Given its broad usage, TCS is present ubiquitously in the environment. Given its strong lipophilicity and accumulation ability in organisms, it is potentially harmful to biohealth. Several reports suggest the toxicity of this compound, which is inserted in the class of endocrine disrupting chemicals (EDCs). In September 2016, TCS was banned by the U.S. Food and Drug Administration (FDA) and the European Union in soap products. Despite these problems, its application in personal care products within certain limits is still allowed. Today, it is still unclear whether TCS is truly toxic to mammals and the adverse effects of continuous, long-term, and low concentration exposure remain unknown. Indeed, some recent reports suggest the use of TCS as a repositioned drug for cancer treatment and cutaneous leishmaniasis. In this scenario it is necessary to investigate the advantages and disadvantages of TCS, to understand whether its use is advisable or not. This review intends to highlight the pros and cons that are associated with the use of TCS in humans.

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.

Newly Synthesized Imino-Derivatives Analogues of Resveratrol Exert Inhibitory Effects in Breast Tumor Cells.

Breast cancer represents the most frequently diagnosed malignancy in women worldwide. Various therapeutics are currently used in order to halt the progression of breast tumor, even though certain side effects may limit the beneficial effects. In recent years, many efforts have been addressed to the usefulness of natural compounds as anticancer agents due to their low toxicity. Resveratrol, a stilbene found in grapes, berries, peanuts and soybeans, has raised a notable interest for its antioxidant, anti-inflammatory, and antitumor properties. Here, we report the design, the synthesis and the characterization of the anticancer activity of a small series of imino N-aryl-substituted compounds that are analogues of resveratrol. In particular, the most active compound, named 3, exhibited anti-tumor activity in diverse types of breast cancer cells through the inhibition of the human topoisomerase II and the induction of apoptotic cell death. Therefore, the abovementioned compound maybe considered as a promising agent in more comprehensive treatments of breast cancer.

α-ω Alkenyl-bis-S-Guanidine Thiourea Dihydrobromide Affects HeLa Cell Growth Hampering Tubulin Polymerization.

Cancer is going to be the first cause of mortality worldwide in the 21th century. It is considered a multifactorial disease that results from the combined influence of many genetic aberrations, leading to abnormal cell proliferation. As microtubules are strongly implicated in cellular growth, they represent an important target for cancer treatment. The well-known microtubule-targeting agents (MTAs) including paclitaxel, colchicine and vinca alkaloids are commonly used in the treatment of various cancers. However, adverse effects and drug resistance are major limitations in their clinical use. To find new candidates able to induce microtubule alteration with reduced toxic effects or drug resistance, we studied a small new series of derivatives that present imidazolinic, guanidinic, thioureidic and hydrazinic groups (1-9). All the compounds were tested for their antitumor activity against a panel of six tumoral cell models. In particular, compound 8 (nonane-1,9-diyl-bis-S-amidinothiourea dihydrobromide) showed the lowest IC50 value against HeLa cells, together with a low cytotoxicity for normal cells. This compound was able to induce the apoptotic mitochondrial pathway and inhibited tubulin polymerization with a similar efficacy to vinblastine and nocodazole. Taken together, these promising biological properties make compound 8 useful for the development of novel therapeutic approaches in cancer treatment.

Is the Way to Fight Cancer Paved with Gold? Metal-Based Carbene Complexes with Multiple and Fascinating Biological Features.

Herein, we report the synthesis and the multiple anti-tumor properties of new gold and silver carbene complexes. The chemical modifications, grounded on our previous studies, led us to identify a good lead complex, gold-based, whose biological features are very exciting and promising in the anti-cancer research and could be further developed. Indeed, the bis-[4,5-dichloro-(N-methyl-N'(2-hydroxy-2-phenyl)ethyl-imidazole-2-ylidene)gold(I)]+[dichloro-gold]- (AuL7) complex possesses the ability to interfere with at least three important and different intracellular targets, namely the human topoisomerases I and II and tubulin, which are able to modulate metabolic processes not directly correlated each other. We proved that the modifications of the ligands structure in AuL7, with respect to another already published complex, i.e., bis-[4,5-dichloro-(N-methyl-N'(cyclopentane-2ol)-imidazole-2-ylidine)gold(I)]+[dichloro-gold]- (AuL4), produce a different behavior toward tubulin-polymerization process, since AuL7 is a tubulin-polymerization inhibitor and AuL4 a stabilizer, with the final same result of hampering the tumor growth. Taken together, our outcomes designate AuL7 as a promising compound for the development of multi-targeted anti-cancer therapies.

Carbazole Derivatives as Kinase-Targeting Inhibitors for Cancer Treatment.

Protein Kinases (PKs) are a heterogeneous family of enzymes that modulate several biological pathways, including cell division, cytoskeletal rearrangement, differentiation and apoptosis. In particular, due to their crucial role during human tumorigenesis and cancer progression, PKs are ideal targets for the design and development of effective and low toxic chemotherapeutics and represent the second group of drug targets after G-protein-coupled receptors. Nowadays, several compounds have been claimed to be PKs inhibitors, and some of them, such as imatinib, erlotinib and gefitinib, have already been approved for clinical use, whereas more than 30 others are in various phases of clinical trials. Among them, some natural or synthetic carbazole-based molecules represent promising PKs inhibitors due to their capability to interfere with PK activity by different mechanisms of action including the ability to act as DNA intercalating agents, interfere with the activity of enzymes involved in DNA duplication, such as topoisomerases and telomerases, and inhibit other proteins such as cyclindependent kinases or antagonize estrogen receptors. Thus, carbazoles can be considered a promising this class of compounds to be adopted in targeted therapy of different types of cancer.

From coins to cancer therapy: Gold, silver and copper complexes targeting human topoisomerases.

Cancer is a complex issue and, even though the prevention basics and therapy have been implemented, it is still the second leading death cause worldwide. With the hope to discover new powerful and safer molecules to fight cancer, many researchers focused their attention on metal-based compounds, starting from the most famous and successfully employed anticancer drug, i.e. cisplatin. The current article aims to report the most recent discoveries about the use of gold, silver and copper complexes as antitumor agents, highlighting their influences on important enzymes, namely human topoisomerases. The latter are fundamental for the cell life and, if overexpressed, strongly implicated in cancer onset and progression. The identification of lead complexes targeting human topoisomerases and gifted with the appropriate chemical and pharmacological properties represents a fecund starting point to obtain new and more effective anticancer molecules.

Inhibition of Human Topoisomerase†II by N,N,N-Trimethylethanammonium Iodide Alkylcarbazole Derivatives.

Chemotherapy is used for the treatment of all stages of breast cancer, including the metastatic stage of the disease. Treatment regimens are generally tailored for each patient's particular situation. However, chemotherapeutic agents are the leading cause of serious drug-related adverse effects; moreover, drug resistance often occurs. In this study, we designed and synthesized a new series of N-alkylcarbazoles derived from ellipticine, an alkaloid with a carbazole skeleton initially used in the treatment of metastatic breast cancer and later dismissed because of poor aqueous solubility and severe side effects. After evaluating the binding modes of our class of newly synthesized compounds with human topoisomerase II (hTopo II), we performed hTopo II decatenation assays, identifying compound 4 f (2-(4-((3-chloro-9H-carbazol-9-yl)pentyl)piperazin-1-yl)-N,N,N-trimethylethanammonium iodide) as a good inhibitor. Moreover, 4 f and 4 g (2-(4-((3-chloro-9H-carbazol-9-yl)hexyl)piperazin-1-yl)-N,N,N-trimethylethanammonium iodide) showed a good anti-proliferative activity toward breast cancer cells, causing apoptosis by activation of the caspase pathway. Interestingly, the activity of these two compounds on triple-negative MDA-MB-231 cells, which tend to be highly metastatic and aggressive, is strictly connected to the observed inhibition of hTopo II.