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How five different isoforms of N,N,N-Tris(tert-butoxycarbonyl)-L-arginine whose reactivity in esterification reactions was subsequently investigated were obtained
No full textL-arginine, nowadays, is more and more used to functionalize scaffolds for producing delivery systems with high transfection activity and low toxicity. For these purposes it is better to be protected to basic nitrogen atoms. A well known protective residue is tert-butoxycarbonyl group (BOC) and three protocols of BOC-protection selected by us assured that the widely cited (E)-αN,ωN,ω’N-tris(tert-butyloxycarbonyl)-L-arginine would be the only product obtainable. Surprisingly we achieved also other four isoforms (Figure 1) [1]. With the first tested procedure [2] αN,ωN,ω’N-Tris(tert-butyloxycarbonyl)-L-arginine was never obtained. The second one [3] provided the goal compound but in mixture with the Z rotamer while the third protocol [4] led to a single very pure isoform in high yield but with an unreported symmetrical structure. Since BOC protection is transient this discovery would seem of poor interest but investigations about the behavior of each one of the isoforms obtained in esterification reactions, whose results have been described in details in another work by us presented in this context, shown that their reactivity depends on their structure. With this work we reported a thorough description of this unexpected results and the meticulous NMR investigation performed with particular care for double bonds geometry and position which confirmed the structures.
References: 1. S. Alfei, S. Castellaro, Res. Chem. Intermediat. 44, 1811 (2018) DOI: 10.1007/s11164-017-3199-6. 2. H. Konno, K. Kubo, H. Makabe, E. Toshiro, N. Hinoda, K. Nosakaa, K: Akaji, Tetrahedron 63, 9502 (2007) doi:10.1016/j.tet.2007.06.082.3. J. Izdebski, T. Gers, D. Kunce, P. Markovsky, J. Pept. Sci. 11, 60 (2005) doi: 10.1002/psc.585.4. M. A. Jones, A. D. Hislop, J. S. Snaith, Org. Biomol. Chem. 4, 3769 (2006) doi: 10.1039/b611170
Bis-Triphenyl Phosphonium-Based Nano Vesicles Demonstrated Potent and Selective Antibacterial Effects on Clinically Relevant Superbugs
No full textThe increasing emergence of multidrug resistant (MDR) pathogens, due to antibiotics misuse, leads to obstinate infections, with high morbidity and high-cost hospitalizations. To oppose these MDR superbugs, new antimicrobial options are necessary. Quaternary phosphonium salts (QPSs) have demonstrated appealing antibacterial properties, and a triphenyl phosphonium salt, recently reported by us, has shown excellent bacteriostatic effects against MDR isolates of Enterococcus and Staphylococcus genus. Here, aiming at finding new antibacterial devices active towards a broader spectrum of clinically relevant bacteria, responsible of severe human infections, we synthesized a water-soluble, sterically hindered quaternary phosphonium salt (BPPB). It incorporates two tri-phenyl phosphonium groups linked by a C12 alkyl chain, thus embodying the characteristics of molecules known as bola-amphiphiles, capable to self-forming spherical nano-vesicles in solution. BPPB was characterized by ATR-FTIR, NMR and UV spectroscopy, FIA-MS (ESI), elemental analysis and potentiometric titrations. DLS analyses evidenced spherical vesicles of about 45 nm in solution, having a positive zeta potential (+18 mV). For the first time, the antibacterial effects of BPPB were assessed against fifty clinical isolates of both Gram-positive and Gram-negative species. Exceptional antibacterial effects were observed on all strains tested, involving highly worrying species included in ESKAPE bacteria. The lowest MICs were 0.250 μg/mL, while the highest ones (32 μg/mL) were those observed on MDR Gram-negative metallo-β-lactamase-producing bacteria and/or species resistant also to colistin, carbapenems, cefiderocol, so that intractable with current available antibiotics. Moreover, when administered to HepG2 human hepatic and COS-7 monkey kidney cells, BPPB showed very high selectivity for all Gram-positive isolated tested and for clinically relevant Gram-negative superbugs such as S. maltophylia, A. baumannii and E. coli, thus being very promising to be clinically developed
Characterization of water soluble dendrimer formulations of an insoluble thiocarbamate derivative with moderate anti HIV-1 activity: an overview
No full textDrug delivery is an engineered technology focused on the development of Drug Delivery Systems (DDSs) able to transport, release and maintain for long time the useful load of therapeutics in the body as needed for safe playing out the desired therapeutic effects. Nanosized dendritic polycationic polymers such as commercially available PAMAMs, are the most exploited materials for preparing smart DDSs, but unfortunately, the excessive cationic feature of the inner framework results in a high level of cytotoxicity. Nowadays, not charged amino acid-modified dendrimer scaffolds are considered as better solutions. These dendrimers have a more controlled number of nitrogen atoms and can be protonated at physiological pH. In order to improve the water solubility of the thiocarbamate non-nucleoside HIV-1 reverse transcriptase inhibitor 1 (Figure 1)1 five prodrugs were prepared by its entrapment inside not PAMAM amino acids-modified core-shell hydrophilic2 (Figure 2) and amphiphilic3 (Figure 3) dendrimers. As detailed in this communication an overview, organized in tables, graphs and NMR spectra of the physicochemical properties which identified obtained dendriplexes (DPXs) was provided. As estimated by NMR analysis, DPXs showed good load capacity. Mean size of their particles is suitable for avoiding rapid renal clearance while the release profile of the drug is favourable to a low spreading of drug in blood and to a massive release only within the cell. DPXs are soluble in water, EtOH and MeOH, have proper but not excessive cationic character and an optimal buffer capacity for enhanced cellular up take and pH-responsive endosomal escape once inside the cell. References: [1] A. Spallarossa, A. Ranise, et al., Eur. J. Med. Chem. 2009, 44, 1650-1663. [2] S. Alfei, S. Catena, 2018, submitted to Polym. Advan. Technol. 2018: https://doi.org/10.1002/pat.4396. [3] S. Alfei, S. Catena, 2018, submitted to Polym. Int. 2018, https://doi.org: 10.1002/pi.5680
Hydrophilic and amphiphilic water-soluble dendrimer formulations of a not-soluble thiocarbamate derivative with moderate anti HIV activity for biomedical applications.
No full textThe engineered technology known as Drug delivery concerns the approaches, formulations, technologies and systems for transporting therapeutics in the body and delivering them as needed. Advanced controlled Drug Delivery Systems (DDSs) able to release an effective load of drug and to maintain its concentration for long time in a limited area around the target site have been developed. These “smart” DDSs allowed to reduce dosages, administrations frequency and drugs toxicity and to improve therapeutic efficacy. Nanosized and dendritic polycationic polymers such as PAMAMs are the most exploited materials for getting advanced smart DDSs and can covalently bind or encapsulate drugs. However, the high number of protonable nitrogen atoms widespread on the whole matrix involves high cytotoxicity. The modern research is increasingly oriented towards the use of not charged dendrimer scaffolds decorated with biocompatible amino acids protonable at physiological pH. Thiocarbamate 1 (Figure 1) is a non-nucleoside HIV-1 reverse transcriptase inhibitor (EC50 = 27 μM) characterized by a free carboxylic group and endowed with poor water solubility.1 With the aim at improving both its solubility and activity, derivative 1 was physically incorporated inside not-toxic amino acid-modified core-shell hydrophilic (2,3)2 and amphiphilic (4-6)3 dendrimers. The encapsulation procedure is a straightforward protocol that involves stirring derivative 1 and the starting dendrimer at r.t. in methanol (Figure 1). The obtained dendriplexes (DPXs 7-11) showed a very good DL%, a proper particle size, an adequate buffer capacity and above all were well soluble in water. Therefore, they represent an appealing and promising crew of new smart DDSs for safe in vivo clinical administrations of 1.
References:
[1] A. Spallarossa, A. Ranise, et al., Eur. J. Med. Chem. 2009, 44, 1650-1663.
[2] S. Alfei, S. Catena, 2018, submitted to Polym. Advan. Technol. 2018: https://doi.org/10.1002/pat.4396.
[3] S. Alfei, S. Catena, 2018, submitted to Polym. Int. 2018, https://doi.org: 10.1002/pi.5680
Aspects of recent trend of perinatal mortality, infant mortality and nanimortality in a mean Marches Commune.
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N,N,N-Tris(tert-butoxycarbonyl)-L-arginine: five isoforms whose obtainment depends on procedure and a scrupulous NMR confirmation of their structures.
No full textL-arginine is often covalently linked to delivery systems for increasing their transfection activity and reducing toxicity and its basic nitrogen atoms need protection for example with tert-butoxycarbonyl group. Following three reported protocols which assured the goal of obtaining the widely cited αN,ωN,ω’N-tris(tert-butyloxycarbonyl)-L-arginine, surprisingly we achieved also other four isoforms (Figure 1). With the first selected procedure [1] αN,ωN,ω’N-Tris(tert-butyloxycarbonyl)-L-arginine was never obtained. The second one [2] provided the desired compound but as a mixture of geometric isomers E/Z while the third [3] protocol led to a single very pure isoform in high yield but with an unreported symmetrical structure. Since BOC protection is transient this discovery would seem of poor interest but results obtained from following investigations about the behavior of each one of the isoforms obtained in the esterification reactions of our interest shown that their reactivity depends on their structure. With this work we reported a detailed description of this unexpected results and the NMR investigation performed with particular care for double bonds geometry and position which confirmed the structures.
[1] H. Konno, K. Kubo, H. Makabe, E. Toshiro, N. Hinoda, K. Nosakaa, K: Akaji, Tetrahedron 63, 9502 (2007) doi:10.1016/j.tet.2007.06.082
[2] J. Izdebski, T. Gers, D. Kunce, P. Markovsky, J. Pept. Sci. 11, 60 (2005) doi: 10.1002/psc.585
[3] M. A. Jones, A. D. Hislop, J. S. Snaith, Org. Biomol. Chem. 4, 3769 (2006) doi: 10.1039/b611170
A NANOSPHERICAL DENDRIMERIC GALLATE ESTER FOR LONG TERM PRESERVATION OF ESSENTIAL OILS: AN INTEGRATED CHEMOMETRIC ASSISTED FT-IR STUDY
No full textEssential oils (EOs) are hydrophobic concentrated liquids from plants made of volatile chemical compounds. EOs are very popular in the food, cosmetic and pharmaceutical industry as aromas, fragrances and alternative therapeutic devices [1, 2]. EOs are susceptible to degradation reactions, especially of oxidative type, triggered by temperature, light and oxygen availability. A loss of quality and alterations of sensory and pharmacological properties may occur, causing the production of smelly or even harmful compounds, responsible for allergic reactions and skin irritation [3-5]. For preventing and delaying EOs’ spoilage, synthetic preservatives as 2,6-bis(1,1-dimetiletil)-4-metilphenol (BHT) or t-butil-4-hydrohyanisole (BHA) are commonly adopted; but, in addition to a limited efficiency due mainly to poor solubility in oils, they may cause health diseases [6]. Natural polyphenols as gallic acid (GA) are nowadays proposed as safer alternatives, but their efficiency is limited by their low compatibility with hydrophobic material again, or by the occurrence of probable side reactions with oils constituents. Recently, a hydrophobic and biodegradable GA-enriched dendrimer (GAD) (Fig. 1.a) characterised by a nanospherical morphology (Fig. 1.b) and endowed with a remarkable antioxidant activity was synthetized [7]. Further studies currently being completed, have shown that GAD, with respect to free GA, possesses also more efficient antibacterial properties against several antibiotics-resistant G+ strains, inhibits platelet aggregation and ROS accumulation thus representing an excellent alternative to conventional drugs to combat infections and thrombus formation [8]. In this study, based on integrated results obtained from the due investigations, GAD is advised also as an innovative and semi-synthetic preservative additive.
a)
b)
Figure 1. Intuitive representation of GA-enriched dendrimer (GAD) structure (a); SEM images of GAD spherical nanoparticles (b). Scale bars represent 300 nm.
In this regard, GAD proved a much more efficient preservative power than free GA and, unlike GA, it never acts as a pro-oxidant. Besides classic oxidation indexes, the desired information was obtained by FT-IR spectroscopy assisted by multivariate analysis (MVA). For further confirmation of the so obtained results, interpretations of FT-IR data by considering the area of some selected informative bands and iodometric titrations to determine the hydro peroxide value (PV) were also performed [9].
References
[1] Yamamoto S., SOFW J., 2008, 134, 8.
[2] Jiang Y., Wu N., Fu Y.-J., Wang W., Luo M., Zhao C.-J., Zu Y.-G., and Liu Y.-L., Environ. Toxicol. Pharmacol., 2011, 32, 63.
[3] Hagvall L., Skold M., Brared-Christensson J., Borje A., and Karlberg A.-T., Contact Dermatitis, 2008, 59, 143.
[4] Skold M., Hagvall L., and Karlberg A.-T., Contact Dermatitis, 2008, 58, 9.
[5] Brared-Christensson J., Matura M., Gruvberger B., Bruze M., and Karlberg A.-T., Contact Dermatitis, 2010, 62, 32.
[6] Hirose M., Takesada Y., Tanaka H., Tamano S., Kato T., and Shirai T., Carcinogenesis, 1998, 19, 207.
[7] Alfei S., Catena S., and Turrini F., Drug Deliv. Trans. Res., under review.
[8] Alfei S., Signorello M. A., Schito A., Catena S., and Turrini F., results not yet published
[9] Alfei S., Oliveri P., and Malegori C., New J. Chem., under review
Successful Dendrimer and Liposome-Based Strategies to Solubilize an Antiproliferative Pyrazole Otherwise Not Clinically Applicable
No full textWater-soluble formulations of the pyrazole derivative 3-(4-chlorophenyl)-5-(4-nitrophenylamino)-1H-pyrazole-4-carbonitrile (CR232), which were proven to have in vitro antiproliferative effects on different cancer cell lines, were prepared by two diverse nanotechnological approaches. Importantly, without using harmful organic solvents or additives potentially toxic to humans, CR232 was firstly entrapped in a biodegradable fifth-generation dendrimer containing lysine (G5K). CR232-G5K nanoparticles (CR232-G5K NPs) were obtained with high loading (DL%) and encapsulation efficiency (EE%), which showed a complex but quantitative release profile governed by Weibull kinetics. Secondly, starting from hydrogenated soy phosphatidylcholine and cholesterol, we prepared biocompatible CR232-loaded liposomes (CR232-SUVs), which displayed DL% and EE% values increasing with the increase in the lipids/CR232 ratio initially adopted and showed a constant prolonged release profile ruled by zero-order kinetics. When relevant, attenuated total reflectance Fourier transformed infrared spectroscopy (ATR-FTIR) and nuclear magnetic resonance (NMR) spectroscopy, scanning electron microscopy (SEM) and dynamic light scattering (DLS) experiments, as well as potentiometric titrations completed the characterization of the prepared NPs. CR232-G5K NPs were 2311-fold more water-soluble than the pristine CR232, and the CR232-SUVs with the highest DL% were 1764-fold more soluble than the untreated CR232, thus establishing the success of both our strategies
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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