Recent Advances on the Catalytic Asymmetric Allylic α-Alkylation of Carbonyl Derivatives Using Free Allylic Alcohols.

During the last years, the development of more sustainable and straightforward methodologies to minimize the generation of waste organic substances has acquired high importance within synthetic organic chemistry. Therefore, it is not surprising that many efforts are devoted to ameliorating already well-known successful methodologies, that is, the case of the asymmetric allylic allylation reaction of carbonyl compounds. The use of free alcohols as alkylating agents in this transformation represents a step forward in this sense since it minimizes waste production and the substrate manipulation. In this review, we aim to gather the most recent methodologies describing this strategy by paying special attention to the reaction mechanisms, as well as their synthetic applications.

Boron-Catalyzed, Diastereo- and Enantioselective Allylation of Ketones with Allenes.

The diastereo- and enantioselective allylation of ketones remains a synthetic challenge, with transition metal catalysis offering the most applied methods. Here, a boron-catalyzed allylation of ketones with allenes is presented. Excellent yield, regioselectivity, and diastereoselectivity were found across functionalized substrates. The reaction was further developed to accommodate an enantioenriched boron catalyst and thus gave asymmetric ketone allylation in good yield, diastereoselectivity, and enantioselectivity. Mechanistic studies supported a hydroboration-allylation-transborylation pathway.

Diastereoselective, Catalytic Access to Cross-Aldol Products Directly from Esters and Lactones.

High oxidation-state carbonyl coupling partners including esters and lactones were reacted with enones to give aldol-type products directly using two-fold organoborane catalysis. This new retrosynthetic disconnection to aldol-type products is compatible with enolisable coupling partners, without self-condensation, and couples the high reactivity of secondary dialkylboranes with the stability of pinacolboronic esters. Excellent chemoselectivity, substrate scope (including those containing reducible functionalities and free alcohols) and diastereocontrol were achieved to access both the syn- and anti-aldol-type products. Mechanistic studies confirmed the two-fold catalytic role of the single secondary borane catalyst for boron enolate formation and formation of an aldehyde surrogate from the ester or lactone coupling partner.

Nanomaterials and Nanostructures Hand-In-Hand with Biology.

The nanoparticle's synthesis had its tipping point at the beginning of the 21st century, opening up the possibility of manufacturing nanoparticles with almost every imaginable shape and size [...].

Strategies for the Biofunctionalization of Straining Flow Spinning Regenerated Bombyx mori Fibers.

High-performance regenerated silkworm (Bombyx mori) silk fibers can be produced efficiently through the straining flow spinning (SFS) technique. In addition to an enhanced biocompatibility that results from the removal of contaminants during the processing of the material, regenerated silk fibers may be functionalized conveniently by using a range of different strategies. In this work, the possibility of implementing various functionalization techniques is explored, including the production of fluorescent fibers that may be tracked when implanted, the combination of the fibers with enzymes to yield fibers with catalytic properties, and the functionalization of the fibers with cell-adhesion motifs to modulate the adherence of different cell lineages to the material. When considered globally, all these techniques are a strong indication not only of the high versatility offered by the functionalization of regenerated fibers in terms of the different chemistries that can be employed, but also on the wide range of applications that can be covered with these functionalized fibers.

Bacteria as Nanoparticle Carriers for Immunotherapy in Oncology.

The use of nanocarriers to deliver antitumor agents to solid tumors must overcome biological barriers in order to provide effective clinical responses. Once within the tumor, a nanocarrier should navigate into a dense extracellular matrix, overcoming intratumoral pressure to push it out of the diseased tissue. In recent years, a paradigm change has been proposed, shifting the target of nanomedicine from the tumoral cells to the immune system, in order to exploit the natural ability of this system to capture and interact with nanometric moieties. Thus, nanocarriers have been engineered to interact with immune cells, with the aim of triggering specific antitumor responses. The use of bacteria as nanoparticle carriers has been proposed as a valuable strategy to improve both the accumulation of nanomedicines in solid tumors and their penetration into the malignancy. These microorganisms are capable of propelling themselves into biological environments and navigating through the tumor, guided by the presence of specific molecules secreted by the diseased tissue. These capacities, in addition to the natural immunogenic nature of bacteria, can be exploited to design more effective immunotherapies that yield potent synergistic effects to induce efficient and selective immune responses that lead to the complete eradication of the tumor.

Janus-Type Mesoporous Silica Nanoparticles for Sequential Tumoral Cell and Mitochondria Targeting.

The development of nanoparticles has provided a powerful weapon in the fight against cancer due to the discovery of their selective accumulation in tumoral tissues, known as enhanced permeation and retention (EPR) effect (Peer et al, Nat Nanotechnol 2:751-760, 2007). Tumoral tissues require afastformation of blood vessels to sustain this rapid growth.

UVA-Degradable Collagenase Nanocapsules as a Potential Treatment for Fibrotic Diseases.

Peyronie and Dupuytren are pathologies characterized by the appearance of localized fibrotic lesions in an organ. These disorders originate from an excessive production of collagen in the tissue provoking dysfunction and functional limitations to the patients. Local administration of collagenase is the most used treatment for these fibrotic-type diseases, but a high lability of the enzyme limits its therapeutic efficacy. Herein, we present a novel methodology for the preparation of collagenase nanocapsules without affecting its enzymatic activity and capable of releasing the enzyme in response to an ultraviolet A (UVA) light stimulus. Polymeric coating around collagenase was formed by free-radical polymerization of acrylamide-type monomers. Their degradation capacity under UVA irradiation was provided by incorporating a novel photocleavable acrylamide-type crosslinker within the polymeric framework. This property allowed collagenase release to be triggered in a controlled manner by employing an easily focused stimulus. Additionally, UVA irradiation presents considerable benefits by itself due to its capacity to induce collagenase production in situ. An expected synergistic effect of collagenase nanocapsules in conjunction with UVA effect may present a promising treatment for these fibrotic diseases.

Evaluation of the penetration process of fluorescent collagenase nanocapsules in a 3D collagen gel.

One of the major limitations of nanomedicine is the scarce penetration of nanoparticles in tumoral tissues. These constrains have been tried to be solved by different strategies, such as the employ of polyethyleneglycol (PEG) to avoid the opsonization or reducing the extracellular matrix (ECM) density. Our research group has developed some strategies to overcome these limitations such as the employ of pH-sensitive collagenase nanocapsules for the digestion of the collagen-rich extracellular matrix present in most of tumoral tissues. However, a deeper understanding of physicochemical kinetics involved in the nanocapsules degradation process is needed to understand the nanocapsule framework degradation process produced during the penetration in the tissue. For this, in this work it has been employed a double-fluorescent labelling strategy of the polymeric enzyme nanocapsule as a crucial chemical tool which allowed the analysis of nanocapsules and free collagenase during the diffusion process throughout a tumour-like collagen matrix. This extrinsic label strategy provides far greater advantages for observing biological processes. For the detection of enzyme, collagenase has been labelled with fluorescein Isothiocyanate (FITC), whereas the nanocapsule surface was labelled with rhodamine Isothiocyanate (RITC). Thus, it has been possible to monitor the hydrolysis of nanocapsules and their diffusion throughout a thick 3D Collagen gel during the time, obtaining a detailed temporal evaluation of the pH-sensitive collagenase nanocapsule behaviour. These collagenase nanocapsules displayed a high enzymatic activity in low concentrations at acidic pH, and their efficiency to penetrate into tissue models pave the way to a wide range of possible nanomedical applications, especially in cancer therapy.

Inorganic Porous Nanoparticles for Drug Delivery in Antitumoral Therapy.

The use of nanoparticles in oncology to deliver chemotherapeutic agents has received considerable attention in the last decades due to their tendency to be passively accumulated in solid tumors. Besides this remarkable property, the surface of these nanocarriers can be decorated with targeting moieties capable to recognize malignant cells which lead to selective nanoparticle uptake mainly in the diseased cells, without affecting the healthy ones. Among the different nanocarriers which have been developed with this purpose, inorganic porous nanomaterials constitute some of the most interesting due to their unique properties such as excellent cargo capacity, high biocompatibility and chemical, thermal and mechanical robustness, among others. Additionally, these materials can be engineered to present an exquisite control in the drug release behavior placing stimuli-responsive pore-blockers or sensitive hybrid coats on their surface. Herein, the recent advances developed in the use of porous inorganic nanomedicines will be described in order to provide an overview of their huge potential in the look out of an efficient and safe therapy against this complex disease. Porous inorganic nanoparticles have been designed to be accumulated in tumoral tissues; once there to recognize the target cell and finally, to release their payload in a controlled manner.

Bacteria as Nanoparticles Carrier for Enhancing Penetration in a Tumoral Matrix Model.

One of the major concerns in the application of nanocarriers in oncology is their scarce penetration capacity in tumoral tissues, which drastically compromises the effctivity. Living organisms as cells and bacteria present the capacity to navigate autonomously following chemical gradients being able to penetrate deeply into dense tissues. In the recent years, the possibility to employ these organisms for the transportation of therapeutic agents and nanocarriers attached on their membrane or engulfed in their inner space have received huge attention. Herein, based on this principle, a new approach to deliver drug loaded nanoparticles achieving high penetration in tumoral matrices is presented. In this case, Escherichia coli (E. coli) bacteria wall is decorated with azide groups, whereas alkyne-strained groups are incorporated on the surface of mesoporous silica nanoparticles loaded with a potent cytotoxic compound, doxorubicin. Both functional groups form stable triazole bonds by click-type reaction allowing the covalent grafting of nanoparticles on living bacteria. Thus, the motility and penetration capacity of bacteria, which carried nanoparticles are evaluated in a 3D tumoral matrix model composed by a dense collagen extracellular matrix with HT1080 human fibrosarcome cells embedded. The results confirmed that bacteria are able to transport the nanoparticles crossing a thick collagen layer being able to destroy almost 80% of the tumoral cells located underneath. These findings envision a powerful strategy in nanomedicine applied for cancer treatment by allowing a homogeneous distribution of therapeutic agents in the malignancy.

Mesoporous Silica Nanoparticles as Theranostic Antitumoral Nanomedicines.

Nanoparticles have become a powerful tool in oncology not only as carrier of the highly toxic chemotherapeutic drugs but also as imaging contrast agents that provide valuable information about the state of the disease and its progression. The enhanced permeation and retention effect for loaded nanocarriers in tumors allow substantial improvement of selectivity and safety of anticancer nanomedicines. Additionally, the possibility to design stimuli-responsive nanocarriers able to release their payload in response to specific stimuli provide an excellent control on the administered dosage. The aim of this review is not to present a comprehensive revision of the different theranostic mesoporous silica nanoparticles (MSN) which have been published in the recent years but just to describe a few selected examples to offer a panoramic view to the reader about the suitability and effectiveness of these nanocarriers in the oncology field.

Direct Synthesis of N,N-Disubstituted Formamides by Oxidation of Imines Using an HFIP/UHP System.

The straightforward synthesis of N,N-disubstituted formamides using a combination of 1,1,1,3,3,3-hexafluoroispropanol (HFIP) and H2O2 is described. The unique features of HFIP allowed the utilization of a green oxidant such as H2O2, and the products, arising from an oxidation-rearrangement sequence, were obtained in good to high yields under smooth reaction conditions.

HFIP-Promoted Synthesis of Substituted Tetrahydrofurans by Reaction of Epoxides with Electron-Rich Alkenes.

In the present work, the employment of fluorinated alcohols, specifically 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), as solvent and promoter of the catalyst-free synthesis of substituted tetrahydrofuranes through the addition of electron-rich alkenes to epoxydes is described. The unique properties of this fluorinated alcohol, which is very different from their non-fluorinated analogs, allows carrying out this new straightforward protocol under smooth reaction conditions affording the corresponding adducts in moderate yields in the majority of cases. Remarkably, this methodology has allowed the synthesis of new tetrahydrofuran-based spiro compounds as well as tetrahydrofurobenzofuran derivatives. The scope and limitations of the process are also discussed. Mechanistic studies were also performed pointing towards a purely ionic or a SN2-type process depending on the nucleophilicity of the alkene employed.

Tumor Targeted Nanocarriers for Immunotherapy.

The paramount discovery of passive accumulation of nanoparticles in tumoral tissues triggered the development of a wide number of different nanoparticles capable of transporting therapeutic agents to tumoral tissues in a controlled and selective way. These nanocarriers have been endowed with important capacities such as stimuli-responsive properties, targeting abilities, or the capacity to be monitored by imaging techniques. However, after decades of intense research efforts, only a few nanomedicines have reached the market. The reasons for this disappointing outcome are varied, from the high tumor-type dependence of enhanced permeation and retention (EPR) effect to the poor penetration capacity of nanocarriers within the cancerous tissue, among others. The rapid nanoparticle clearance by immune cells, considered another important barrier, which compromises the efficacy of nanomedicines, would become an important ally in the fight against cancer. In the last years, the fine-tuned ability of immune cells to recognize and engulf nanoparticles have been exploited to deliver immunoregulating agents to specific immune cell populations selectively. In this work, the recent advances carried out in the development of nanocarriers capable of operating with immune and tumoral cells in order to orchestrate an efficient antitumoral response will be presented. The combination of nanoparticles and immunotherapy would deliver powerful weapons to the clinicians that offer safer and more efficient antitumoral treatments for the patients.

Oxidation of Electron-Rich Arenes Using HFIP-UHP System.

The straightforward oxidation of electron-rich arenes, namely, phenols, naphthols, and anisole derivatives, under mild reaction conditions, is described by means of the use of an environmentally benign HFIP-UHP system. The corresponding quinones or hydroxylated arenes were obtained in moderate to good yields.

Impact of Omega-3 Fatty Acids Among Other Nonpharmacological Interventions on Behavior and Quality of Life in Children with Compromised Conduct in Spain.

The aim of this study was to assess the impact of omega-3 fatty acid supplementation among other nonpharmacological treatments on mental health and quality of life (QOL) of children with behavioral disorders. An observational multicenter study of 6- to 12-year-old children with behavior-related problems was performed in Spain with a three-month follow-up assessment. The Kidscreen-10 and Strengths and Difficulties Questionnaires (SDQ) were used to assess effectiveness of each intervention. Characteristics of study population were compared with those of the general population. Subanalyses of two homogenous subgroups, who received versus did not receive dietary supplementation with omega-3 fatty acids, were performed. The study included 942 children (69.1% male) with a mean (SD) age of 8.5 (1.8) years. Overall, patients' health status and QOL significantly improved at three months (p < .001). Scores on the SDQ also improved, with significant reductions on all subscales (p < .05). Comparison of SDQ results with the same-age general population showed higher overall scores in the study population (8.5 [5.5] vs. 18.6 [8.1], respectively) and on all the subscales (p < .001 in all cases). The omega-3 fatty acid supplementation subgroup presented greater improvements in each category of SDQ (p < .05), except for the emotion subscale. Omega-3 fatty acid supplementation alone or in combination with other nonpharmacological treatments is effective in improving children's mental health. Overall, nonpharmacological recommendations currently made by pediatricians seem to be effective in improving the perceived health status and patients' QOL and in the reduction of health problems, especially hyperactivity/inattention and conduct problems.

Overcoming the stability, toxicity, and biodegradation challenges of tumor stimuli-responsive inorganic nanoparticles for delivery of cancer therapeutics.

Introduction: Stimuli-responsive nanomaterials for cancer therapy have attracted much interest recently due to their potential for improving the current standard of care. Different types of inorganic nanoparticles are widely employed for the development of these strategies, but in some cases safety concerns hinder their clinical translation. This review aims to provide an overview of the challenges that inorganic nanoparticles face regarding their stability, toxicity, and biodegradability, as well as the strategies that have been proposed to overcome them. Areas covered: The available information about the in vitro and in vivo biocompatibility, as well as the biodegradability of the following nanoparticles, is presented and discussed: superparamagnetic iron oxide nanoparticles, gold nanoparticles, graphene and mesoporous nanoparticles made of silicon or silicon oxide. The toxicology of inorganic nanoparticles is greatly affected by many physicochemical parameters, and their surface modification emerges as the main intervention to improve their biocompatibility and tailor their performance for specific biomedical applications. Expert opinion: Even though many different studies have been performed regarding the biological behavior of inorganic nanoparticles, long-term in vivo data is still scarce, limiting our capacity to evaluate the proposed nanomaterials for clinical use. The role of biodegradability in different therapeutic contexts is also discussed.

Use of Dietary Supplements among Spanish Pediatricians in Daily Practice: A Cross-Sectional Survey Study.

A cross-sectional survey study was designed to gather information on the use of dietary supplements by Spanish pediatricians. The study questionnaire was completed by 433 pediatricians (62% men, mean age 52.5 years) throughout the country. They also provided data on 10 of their patients (n = 4304) in which synbiotics, immune stimulants, and omega-3 polyunsaturated fatty acids (PUFAs) had been prescribed. Synbiotics were used by 92% of pediatricians, immune stimulants by 80.4%, and omega-3 PUFAs by 75.1%. Synbiotics were mainly used combined with antibiotics (92.6%) and for gastrointestinal disorders (91.2%), immune stimulants to enhance defenses and cold prevention (87.1%), and omega-3 PUFAs to improve symptoms of attention-deficit hyperactivity disorder (ADHD) (84.8%) and concentration (80.1%). Confidence and previous experience with the product (51.6%), composition and indications of the product (43.1%), and tolerability (39.9%) were main factors involved in decision-making. Children treated with omega-3 supplements were significantly older (mean age 7.6 (3.0) years) than those treated with synbiotics (3.9 (3.9) years) or immune stimulants (3.4 (2.8) years) (P < 0.001). Short duration of treatment (<1 month) was significantly more common in the synbiotics group (90.5%), whereas longer duration of treatment (>3 months) was more frequent in the omega-3 group (79.1%). In the immune stimulants group, 60.4% of patients were treated for a period between 1 and 3 months. Clinical improvement was rated by participants as "a lot" in 39% of cases and as "quite" improvement in 50.6%. The overall level of satisfaction was rated as "very satisfied" by 52.1% of participants and as "quite satisfied" by 40.9%. The results show that the use of dietary supplements to improve different conditions, particularly minor disorders, is a widespread clinical practice among Spanish pediatricians. Administration regimens for the three types of supplements, synbiotics, immune stimulants, and omega-3 PUFAs, were consistent with guideline recommendations.

Targeting strategies for improving the efficacy of nanomedicine in oncology.

The use of nanoparticles as drug carriers has provided a powerful weapon in the fight against cancer. These nanocarriers are able to transport drugs that exhibit very different nature such as lipophilic or hydrophilic drugs and big macromolecules as proteins or RNA. Moreover, the external surface of these carriers can be decorated with different moieties with high affinity for specific membrane receptors of the tumoral cells to direct their action specifically to the malignant cells. The selectivity improvement yielded by these nanocarriers provided a significative enhancement in the efficacy of the transported drug, while the apparition of side effects in the host was reduced. Additionally, it is possible to incorporate targeting moieties selective for organelles of the cell, which improves even more the effect of the transported agents. In the last years, more sophisticated strategies such as the use of switchable, hierarchical or double targeting strategies have been proposed for overcoming some of the limitations of conventional targeting strategies. In this review, recent advances in the development of targeted nanoparticles will be described with the aim to present the current state of the art of this technology and its huge potential in the oncological field.