Butyltin(IV) Benzoates: Inhibition of Thioredoxin Reductase,Tumor Cell Growth Inhibition,and Interactions with Proteins

Thioredoxin reductase (TrxR) is overexpressed in cancer cells and is therefore a putative cancer target. Inhibition of this enzyme is considered an important strategy for the development of new chemotherapeutic agents with a specific mechanism of action. Organotin compounds have been described as experimental antitumor agents, yet their mechanism of action remains largely unknown. Based on the outcome of a virtual screening study, various di‐ and tri‐n‐butyltin(IV) carboxylates were synthesized, and their biological properties were evaluated. All synthesized compounds were able to inhibit TrxR selectively within the micromolar range and showed potent antitumor activity against HT‐29 and MCF‐7 cancer cell lines. Moreover, tin(IV) organometallics were found to strongly induce apoptosis in the BJAB lymphoma cell line. Mass spectrometry and atomic absorption spectroscopy experiments revealed metal binding to proteins, and efficient cellular uptake was observed using a di‐n‐butyltin(IV) complex as an example.     

Identification of Hck Inhibitors As Hits for the Development of Antileukemia and Anti‐HIV Agents

Hematopoietic cell kinase (Hck) is a member of the Src family of non‐receptor protein tyrosine kinases. High levels of Hck are associated with drug resistance in chronic myeloid leukemia. Furthermore, Hck activity has been connected with HIV‐1. Herein, structure‐based drug design efforts were aimed at identifying novel Hck inhibitors. First, an in‐house library of pyrazolo[3,4‐d]pyrimidine derivatives, which were previously shown to be dual Abl and c‐Src inhibitors, was analyzed by docking studies within the ATP binding site of Hck to select the best candidates to be tested in a cell‐free assay. Next, the same computational protocol was applied to screen a database of commercially available compounds. As a result, most of the selected compounds were found active against Hck, with K_i values ranging from 0.14 to 18.4 μM , confirming the suitability of the computational approach adopted. Furthermore, selected compounds showed an interesting antiproliferative activity profile against the human leukemia cell line KU‐812, and one compound was found to block HIV‐1 replication at sub‐toxic concentrations.     

Multifunctional Silk?Tropoelastin Biomaterial Systems

New multifunctional, degradable, polymeric biomaterial systems would provide versatile platforms to address cell and tissue needs in both in vitro and in vivo environments. While protein-based composites or alloys are the building blocks of biological organisms, similar systems have not been largely exploited, to date, to generate ad hoc biomaterials able to control and direct biological functions by recapitulating their inherent structural and mechanical complexities. Therefore, we have recently proposed silk tropoelastin material platforms that are able to conjugate a mechanically robust and durable protein, silk, to a highly flexible and biologically active protein, tropoelastin. This review focuses on the elucidation of the interactions between silk and tropoelastin to control the structure of the material its properties, and ultimately functions. In addition, an approach is provided for novel material designs to provide tools to control biological outcomes through surface roughness, elasticity, and net charge for neuronal and mesenchymal stem-cell-based tissue engineering.     

New Evidence for Cross Talk between Melatonin and Mitochondria Mediated by a Circadian-Compatible Interaction with Nitric Oxide

Extending our previous observations, we have shown on HaCat cells that melatonin, at ~10⁻⁹ M concentration, transiently raises not only the expression of the neuronal nitric oxide synthase (nNOS) mRNA, but also the nNOS protein synthesis and the nitric oxide oxidation products, nitrite and nitrate. Interestingly, from the cell bioenergetic point of view, the activated NO-related chemistry induces a mild decrease of the oxidative phosphorylation (OXPHOS) efficiency, paralleled by a depression of the mitochondrial membrane potential. The OXPHOS depression is apparently balanced by glycolysis. The mitochondrial effects described have been detected only at nanomolar concentration of melatonin and within a time window of a few hours’ incubation; both findings compatible with the melatonin circadian cycle.     

β-Cyclodextrin Inclusion Complex to Improve Physicochemical Properties of Pipemidic Acid: Characterization and Bioactivity Evaluation

The aptitude of cyclodextrins (CDs) to form host-guest complexes has prompted an increase in the development of new drug formulations. In this study, the inclusion complexes of pipemidic acid (HPPA), a therapeutic agent for urinary tract infections, with native β-CD were prepared in solid state by kneading method and confirmed by FT-IR and ¹H NMR. The inclusion complex formation was also characterized in aqueous solution at different pH via UV-Vis titration and phase solubility studies obtaining the stability constant. The 1:1 stoichiometry was established by a Job plot and the inclusion mechanism was clarified using docking experiments. Finally, the antibacterial activity of HPPA and its inclusion complex was tested on P. aeruginosa, E. coli and S. aureus to determine the respective EC_50s and EC_90s. The results showed that the antibacterial activity of HPPA:β-CD against E. coli and S. aureus is higher than that of HPPA. Furthermore, HPPA and HPPA:β-CD, tested on human hepatoblastoma HepG2 and MCF-7 cell lines by MTT assay, exhibited, for the first time, antitumor activities, and the complex revealed a higher activity than that of HPPA. The use of β-CD allows an increase in the aqueous solubility of the drug, its bioavailability and then its bioactivity.     

Alder ene functionalization of polyisobutene oligomer and styrene-butadiene-styrene triblock copolymer

The Alder ene functionalization reaction of double bonds containing macromolecules such as polyisobutene oligomer (PIB) and a styrene-butadiene-styrene triblock copolymer (SBS) samples with maleic anhydride (MAH) or diethyl maleate (DEM) as enophiles is described. The analysis of the products by means of different techniques assesses the addition of the polar molecules to the reactive vinylidene units of the polymer with functional degrees (FD) depending on the type of enophile and polymer reactivity. The role of the reaction conditions and the use as Lewis acids as catalysts are discussed in terms of their influence on the addition reaction extent and on the polymer molecular weight.     

Co- and Ni-exchanged ferrierite: The contribution of synchrotron X-ray diffraction data to siting of TMIs

High-silica zeolites exchanged with transition metal ions (TMIs) are the subject of great interest for their unusual catalytic activity and selectivity. Structural information like coordination and accessibility of TMIs in zeolites are important factors for understanding their catalytic activity. Siting of TMIs in zeolites is typically obtained by spectroscopic (EXAFS, EPR, UV–vis and IR) and computational methods, as in the case of Co-ferrierite. However, some controversy exists in the literature concerning the model for incorporation of bare Co ions in ferrierite. We show here that the results of our synchrotron X-ray powder diffraction studies on Co- and Ni-exchanged ferrierite (Si/Al = 8.5) are in a good agreement with the model of Co siting based on an indirect spectroscopic approach and help to validate this model. By direct structural evidences, a possible explanation for the larger catalytic activity of Co sites in the main channels of ferrierite can be inferred. A combination of data from in situ XRD continuous monitoring of the Co ion migration during calcination and crystal-chemical considerations allows to device a strategy for the design of optimised co-cations containing Co-ferrierite catalysts.     

Novel Therapeutic Opportunities in Neoadjuvant Setting in Urothelial Cancers: A New Horizon Opened by Molecular Classification and Immune Checkpoint Inhibitors

Muscle invasive bladder cancer (MIBC) is a widespread malignancy with a worse prognosis often related to a late diagnosis. For early-stage MIBC pts, a multidisciplinary approach is mandatory to evaluate the timing of neoadjuvant chemotherapy (NAC) and surgery. The current standard therapy is platinum-based NAC (MVAC-methotrexate, vinblastine, doxorubicin, and cisplatin or Platinum–Gemcitabine regimens) followed by radical cystectomy (RC) with lymphadenectomy. However, preliminary data from Vesper trial highlighted that dose-dense NAC MVAC is endowed with a good pathological response but shows low tolerability. In the last few years, translational-based research approaches have identified several candidate biomarkers of NAC esponsiveness, such as ERCC2, ERBB2, or DNA damage response (DDR) gene alterations. Moreover, the recent consensus MIBC molecular classification identified six molecular subtypes, characterized by different sensitivity to chemo- or targeted or immunotherapy, that could open a novel procedure for patient selection and also for neoadjuvant therapies. The Italian PURE-01 phase II Trial extended data on efficacy and resistance to Immune Checkpoint Inhibitors (ICIs) in this setting. In this review, we summarize the most relevant literature data supporting NAC use in MIBC, focusing on novel therapeutic strategies such as immunotherapy, considering the better patient stratification and selection emerging from novel molecular classification.