A bis(pyrazolyl)methane derivative against clinical Staphylococcus aureus strains isolated from otitis externa.

OBJECTIVE: The purpose of this study was to evaluate the in vitro antibacterial effects of a p-Cymene-based bis(pyrazolyl)methane derivative (SC-19) to advance in developing alternative therapeutic compounds to fight against bacterial isolates from patients with otitis externa (OE). METHODS: Eighteen swab specimens were collected from patients aged over 18 years diagnosed with OE within at least 7 days of symptom onset, contaminated by only one bacterium type: Pseudomonas aeruginosa (n = 5); Staphylococcus aureus (n = 8); Klebsiella aerogenes (n = 2); Serratia marcescens (n = 1); Morganella morganii (n = 2). To appraise antibacterial activity, minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC), minimum biofilm inhibitory concentration (MBIC), and minimum biofilm eradication concentration (MBEC) assays were run at different SC-19 concentrations. RESULTS: When using SC-19, S. aureus strains showed less bacterial growth, but no bactericidal effect was observed. The MIC and MBC of SC-19 were 62.5 and 2000 µg/ml against S. aureus and were >2000 µg/ml against the other isolates obtained from OE, respectively. In addition, the MBICs and MBECs of SC-19 against S. aureus were 125 and >2000 µg/ml, respectively. CONCLUSION: Nowadays the acquired antibiotic resistance phenomenon has stimulated research into novel and more efficient therapeutic agents. Hence, we report that, helped by the structural diversity fostered herein by a range of bis(pyrazolyl)methane derivatives, SC-19 can be a promising alternative therapeutic option for treating OE caused by S. aureus given the observed effects on both planktonic state and biofilm. LEVEL OF EVIDENCE: IV.

Tuning the Cytotoxicity of Bis-Phosphino-Amines Ruthenium(II) Para-Cymene Complexes for Clinical Development in Breast Cancer.

Despite some limitations such as long-term side effects or the potential presence of intrinsic or acquired resistance, platinum compounds are key therapeutic components for the treatment of several solid tumors. To overcome these limitations, maintaining the same efficacy, organometallic ruthenium(II) compounds have been proposed as a viable alternative to platinum agents as they have a more favorable toxicity profile and represent an ideal template for both, high-throughput and rational drug design. To support the preclinical development of bis-phoshino-amine ruthenium compounds in the treatment of breast cancer, we carried out chemical modifications in the structure of these derivatives with the aim of designing less toxic and more efficient therapeutic agents. We report new bis-phoshino-amine ligands and the synthesis of their ruthenium counterparts. The novel ligands and compounds were fully characterized, water stability analyzed, and their in vitro cytotoxicity against a panel of tumor cell lines representative of different breast cancer subtypes was evaluated. The mechanism of action of the lead compound of the series was explored. In vivo toxicity was also assessed. The results obtained in this article might pave the way for the clinical development of these compounds in breast cancer therapy.

The Effect of WS2 Nanosheets on the Non-Isothermal Cold- and Melt-Crystallization Kinetics of Poly(l-lactic acid) Nanocomposites.

In the present work, hybrid nanocomposite materials were obtained by a solution blending of poly(l-lactic acid) (PLLA) and layered transition-metal dichalcogenides (TMDCs) based on tungsten disulfide nanosheets (2D-WS2) as a filler, varying its content between 0 and 1 wt%. The non-isothermal cold- and melt-crystallization and melting behavior of PLLA/2D-WS2 were investigated. The overall crystallization rate, final crystallinity, and subsequent melting behavior of PLLA were controlled by both the incorporation of 2D-WS2 and variation of the cooling/heating rates. In particular, the analysis of the cold-crystallization behavior of the PLLA matrix showed that the crystallization rate of PLLA was reduced after nanosheet incorporation. Unexpectedly for polymer nanocomposites, a drastic change from retardation to promotion of crystallization was observed with increasing the nanosheet content, while the melt-crystallization mechanism of PLLA remained unchanged. On the other hand, the double-melting peaks, mainly derived from melting-recrystallization-melting processes upon heating, and their dynamic behavior were coherent with the effect of 2D-WS2 involved in the crystallization of PLLA. Therefore, the results of the present study offer a new perspective for the potential of PLLA/hybrid nanocomposites in targeted applications.

Polyester Polymeric Nanoparticles as Platforms in the Development of Novel Nanomedicines for Cancer Treatment.

Many therapeutic agents have failed in their clinical development, due to the toxic effects associated with non-transformed tissues. In this context, nanotechnology has been exploited to overcome such limitations, and also improve navigation across biological barriers. Amongst the many materials used in nanomedicine, with promising properties as therapeutic carriers, the following one stands out: biodegradable and biocompatible polymers. Polymeric nanoparticles are ideal candidates for drug delivery, given the versatility of raw materials and their feasibility in large-scale production. Furthermore, polymeric nanoparticles show great potential for easy surface modifications to optimize pharmacokinetics, including the half-life in circulation and targeted tissue delivery. Herein, we provide an overview of the current applications of polymeric nanoparticles as platforms in the development of novel nanomedicines for cancer treatment. In particular, we will focus on the raw materials that are widely used for polymeric nanoparticle generation, current methods for formulation, mechanism of action, and clinical investigations.

Fast Addition of s-Block Organometallic Reagents to CO2 -Derived Cyclic Carbonates at Room Temperature, Under Air, and in 2-Methyltetrahydrofuran.

Fast addition of highly polar organometallic reagents (RMgX/RLi) to cyclic carbonates (derived from CO2 as a sustainable C1 synthon) has been studied in 2-methyltetrahydrofuran as a green reaction medium or in the absence of external volatile organic solvents, at room temperature, and in the presence of air/moisture. These reaction conditions are generally forbidden with these highly reactive main-group organometallic compounds. The correct stoichiometry and nature of the polar organometallic alkylating or arylating reagent allows straightforward synthesis of: highly substituted tertiary alcohols, ß-hydroxy esters, or symmetric ketones, working always under air and at room temperature. Finally, an unprecedented one-pot/two-step hybrid protocol is developed through combination of an Al-catalyzed cycloaddition of CO2 and propylene oxide with the concomitant fast addition of RLi reagents to the in situ and transiently formed cyclic carbonate, thus allowing indirect conversion of CO2 into the desired highly substituted tertiary alcohols without need for isolation or purification of any reaction intermediates.

Screening and Preliminary Biochemical and Biological Studies of [RuCl(p-cymene)(N,N-bis(diphenylphosphino)-isopropylamine)][BF4] in Breast Cancer Models.

Breast cancer is the second leading cause of cancer death worldwide. Despite progress in drug discovery, identification of the correct population is the limiting factor to develop new compounds in the clinical setting. Therefore, the aim of this study is to evaluate the effects of a new metallodrug, [RuCl(p-cymene)(N,N-bis(diphenylphosphino)-isopropylamine)][BF4] (pnpRu-14), as a lead pnp-Ru compound by screening and preliminary biochemical and biological studies in different breast cancer subtypes. The results show that complex pnpRu-14 is much more effective in promoting in vitro cytotoxic effects on HER2+ and RH+/HER2- breast cancer than the reference metallodrugs cisplatin, carboplatin, or RAPTA-C. It is important to highlight that pnpRu-14 shows an impressive cytotoxicity against BT474 cells. Caspase-dependent apoptosis is the mechanism of action for these compounds. In addition, treatment of SKBR3, BT474, T47D, and MCF7 cancer cells with pnpRu-14 caused an accumulation of cells in the G0/G1 phase cells. The human serum albumin, DNA, and H1 histones binding properties of the lead compound are reported. Pharmacokinetic and biodistribution studies show a quick absorption of pnpRu-14 in serum with no significant accumulation in any of the tested organs. This work provides evidence to support the preclinical and clinical development of pnpRu-14 in breast cancer.

Poly(Cyclohexene Phthalate) Nanoparticles for Controlled Dasatinib Delivery in Breast Cancer Therapy.

The effect on the activity in breast cancer models of the small tyrosine kinase inhibitor dasatinib (DAS), either alone or in combination with other antitumoral agents, has been recently explored. However, DAS is characterized by its low and highly pH-dependent solubility, which could lead to poor uptake of the drug limiting its tumoral efficacy. Thus far, the development of safe and efficient delivery vehicles of DAS to improve the therapeutic efficacy minimizing the toxicity profile is still required. In this work, a biodegradable and biocompatible polyester is assessed, for the first time, as raw material for the generation of polymeric nanoparticles (NPs). NPs of 100 nm with a narrow polydispersity were formulated for the encapsulation of DAS. The enzymatic and cellular degradation of the new drug delivery system has been studied, and the toxicity and blood compatibility evaluated for its potential clinical use. The new material used for the generation of nanoparticles led to encapsulate DAS in an efficient manner with quicker release DAS profile when compared with the FDA-approved biopolymer Polylactide. The new DAS-loaded polymeric nanocarrier gave a superior efficacy when compared to free DAS with no difference in the mechanism of action. The new NPs shown to be a promising DAS delivery system to be further evaluated for breast cancer treatment.

Trastuzumab-Targeted Biodegradable Nanoparticles for Enhanced Delivery of Dasatinib in HER2+ Metastasic Breast Cancer.

Dasatinib (DAS) is a multikinase inhibitor that acts on several signaling kinases. DAS is used as a second-line treatment for chronic accelerated myeloid and Philadelphia chromosome-positive acute lymphoblastic leukemia. The therapeutic potential of DAS in other solid tumours is under evaluation. As for many other compounds, an improvement in their pharmacokinetic and delivery properties would potential augment the efficacy. Antibody-targeted biodegradable nanoparticles can be useful in targeted cancer therapy. DAS has shown activity in human epidermal growth factor receptor 2 (HER2) positive tumors, so conjugation of this compound with the anti-HER2 antibody trastuzumab (TAB) with the use of nanocarriers could improve its efficacy. TAB-targeted DAS-loaded nanoparticles were generated by nanotechnology. The guided nanocarriers enhanced in vitro cytotoxicity of DAS against HER2 human breast cancer cell lines. Cellular mechanistic, release studies and nanoparticles stability were undertaken to provide evidences for positioning DAS-loaded TAB-targeted nanoparticles as a potential strategy for further development in HER2-overexpressing breast cancer therapy.

Synthesis and structural characterization of amido scorpionate rare earth metals complexes.

The reactivity of hybrid scorpionate/cyclopentadienyl ligands in the form of the protio derivatives as a mixture of two regioisomers, namely bpzcpH [1-{2,2-bis(3,5-dimethylpyrazol-1-yl)-1,1-diphenylethyl}-1,3-cyclopentadiene and 2-{2,2-bis(3,5-dimethylpyrazol-1-yl)-1,1-diphenylethyl}-1,3-cyclopentadiene] and bpztcpH [1-{2,2-bis(3,5-dimethylpyrazol-1-yl)-1-tert-butylethyl}-1,3-cyclopentadiene and 2-{2,2-bis(3,5-dimethylpyrazol-1-yl)-1-tert-butylethyl}-1,3-cyclopentadiene], with the tris(silylamide) precursors [M{N(SiHMe2)2}3(thf)x] of rare earth metals (including the group 3 metals scandium and yttrium) is related to the atomic radii of the metal centres. The reaction with the precursor containing the smallest ion, [Sc{N(SiHMe2)2}3(thf)], did not proceed even heating at reflux temperature in toluene. The reaction with the precursors that contain a medium-sized metal ion, i.e., [M{N(SiHMe2)2}3(thf)2] (M = Y, Lu), proceeded only at high temperature and gave good yields of the silylenediamide-containing derivatives [M{κ(2)-NN-Me2Si(NSiHMe2)2}(bpzcp)] (M = Y , Lu ) and [M{κ(2)-NN-Me2Si(NSiHMe2)2}(bpztcp)] (M = Y , Lu ) by an double activation of Si-H and Si-N bonds. However, the reaction with the precursors that contained the largest metal ions, i.e., [M{N(SiHMe2)2}3(thf)2] (M = Nd, Sm), proceeded rapidly at room temperature to afford the bis(silylamide) complexes [M{N(SiHMe2)2}2(bpzcp)] (M = Nd , Sm ) and [M{N(SiHMe2)2}2(bpztcp)] (M = Nd , Sm ). Additionally, the alkyl heteroscorpionate yttrium and lutetium complexes [M(CH2SiMe3)2(NNCp)] (M = Y, Lu) reacted with an excess of HN(SiHMe2)2 to give the mixed alkyl/amide derivatives [M{N(SiHMe2)2}(CH2SiMe3)(bpzcp)] (M = Y , Lu ) and [M{N(SiHMe2)2}(CH2SiMe3)(bpztcp)] (M = Y , Lu ). The structures of the complexes were determined by spectroscopic methods and the X-ray crystal structures of , and were also established.