Protecting-group-free synthesis of clevudine (L-FMAU), a treatment of the hepatitis B virus.

Unnatural nucleoside analogues are valuable research and clinical tools as antiproliferative, antibacterial or antiviral agents. In this context, clevudine (L-FMAU), a reverse transcriptase inhibitor, is currently used for the treatment of the hepatitis B virus. Herein, we describe a new strategy for the preparation of clevudine. Starting from 2-deoxy-2-fluoro-D-galactopyranose, we developed the shortest and highest yield synthesis of this unnatural L-nucleoside. Key steps involve an iodine-promoted cyclization and oxidative cleavage to access the L-arabinofuranosyl scaffold.

Polyfluoroglycoside Synthesis via Simple Alkylation of an Anomeric Hydroxyl Group: Access to Fluoroetoposide Analogues.

In this work, we have developed a new approach for the synthesis of fluoroglycoside analogues. This strategy used a simple alkylation protocol and allowed the installation of a simple aglyconic alkane with the ß configuration. Moreover, the glycosylation of fluorinated glucoside analogues with 4'-demethylepipodophyllotoxin furnished novel fluoroetoposide analogues. In these cases, the α anomers were formed as major products with an S configuration at the C-4 of the aglycone.

A glycan-based plasmonic sensor for prostate cancer diagnosis.

Prostate cancer affects thousands of men who undergo clinical screening tests every year. The main biomarker used for the diagnosis of prostate cancer, prostate specific antigen (PSA), presents limitations that justify investigating new biomarkers to improve reliability. Antibodies against the tumor-associated carbohydrate antigen (Tn), or TACA, develop early in carcinogenesis, making them an interesting alternative as a target for prostate cancer diagnostics. In this work, the Tn antigen was synthesized and immobilized on a surface plasmon resonance sensor coated with a polydopamine/polyethylene oxide mixed layer used both as an anchoring surface for Tn capture moieties and to minimize surface fouling. The sensor could be regenerated and reused at least 60 times without any significant loss in sensitivity. Anti-Tn antibodies were detected in the 0-10 nM concentration range with detection limits of 0.1 and 0.3 nM in spiked buffer solutions and diluted human blood serum samples, respectively. Finally, as a proof-of-concept, this carbohydrate-based sensor was used to successfully discriminate blood serum samples from prostate cancer-free and prostate cancer patients.

Synthetic development of sugar amino acid oligomers towards novel podophyllotoxin analogues.

In this work, we have developed an approach for the synthesis of sugar amino acid oligomers based on the glucosamine scaffold. We found that the solid-phase approach was unsuccessful for the preparation of sugar amino acid oligomers and the limitation of the liquid-phase approach revolved around the low solubility of larger oligomers. Nevertheless, this strategy allowed the coupling of alkynylated carbohydrate amino acids with podophyllotoxin-bearing an azide functional group yielding novel podophyllotoxin analogues. Due to their low solubility, the antiproliferative study revealed no anticancer activity of these newly synthesized analogues.

Exploring the Chemistry of Non-sticky Sugars: Synthesis of Polyfluorinated Carbohydrate Analogues of d-Allopyranose.

There is a growing interest in the preparation of polyfluorinated carbohydrates. A limited number of fluorohexopyranosides have been used in biological investigations because of the synthetic challenge they present. Hence, we report the synthesis of fluorinated homodimer, fluorodisaccharides, C-terminal fluoroglycopeptides, lipoic acid fluoroglycoconjugate and trifluoroallopyranoside derivatives functionalized at C-6. Our strategy uses levoglucosan as inexpensive starting material and facilitates an approach to complex carbohydrate analogues with multiple C-F bonds. The challenge of our synthetic route centered around an efficient preparation of crucial 1,6-anhydro-2,4-dideoxy-difluoroglucopyranose and focused on achieving a difficult glycosylation of the trifluoroallopyranose donor. The results clearly highlight challenges related to the preparation of polyhalogenated complex organic molecules and pave the way to access novel medically relevant tools.

Diversity-Oriented Synthesis of Diol-Based Peptidomimetics as Potential HIV Protease Inhibitors and Antitumor Agents.

Peptidomimetic HIV protease inhibitors are an important class of drugs used in the treatment of AIDS. The synthesis of a new type of diol-based peptidomimetics is described. Our route is flexible, uses d-glucal as an inexpensive starting material, and makes minimal use of protection/deprotection cycles. Binding affinities from molecular docking simulations suggest that these compounds are potential inhibitors of HIV protease. Moreover, the antiproliferative activities of compounds 33 a, 35 a, and 35 b on HT-29, M21, and MCF7 cancer cell lines are in the low micromolar range. The results provide a platform that could facilitate the development of medically relevant asymmetrical diol-based peptidomimetics.

Randomized, Placebo- and Active-Controlled Crossover Study of the Safety and Efficacy of THVD-102, a Fixed-dose Combination of Oxybutynin and Pilocarpine, in Subjects With Primary Focal Hyperhidrosis.

BACKGROUND: While muscarinic antagonists (anticholinergics) have shown efficacy in treating primary focal hyperhidrosis (PFH), side effects - most commonly dry mouth - are intolerable for most patients. THVD-102, a fixed-dose combination product has been developed combining oxybutynin, a muscarinic antagonist, and pilocarpine, a muscarinic agonist. The pilocarpine is at a dose level and release profile optimized to correct salivary flow impaired by oxybutynin yet not interfere with the therapeutic muscarinic antagonist effect of oxybutynin upon the sweat glands. OBJECTIVES: This study evaluated safety, efficacy, dry mouth and quality of life with THVD-102 (oxybutynin 7.5 mg / pilocarpine 7.5 mg) in subjects with axillary and / or palmar PFH. METHODS: After a 21-day open label treatment period with oxybutynin 5 mg twice daily to determine susceptibility of subjects to develop dry mouth, eligible subjects were randomized to 1 of 6 sequences of 3 study treatments (THVD-102, oxybutynin 7.5 mg, and placebo) in sequential 21day double-blind crossover treatment periods, each preceded by a washout period of at least 7 days. RESULTS: A total of 24 subjects were randomized and 19 finished all crossover treatments. Changes from baseline to end of treatment in symptoms associated with PFH were statistically significant for both THVD-102 versus placebo and for oxybutynin versus placebo as assessed by multiple measures. Beneficial trends, not statistically significant, for gravimetric measurements were also observed. There were no statistically significant differences between THVD-102 and oxybutynin in PFH efficacy. Fewer subjects reported moderate to severe dry mouth while receiving THVD-102 compared to oxybutynin and more subjects categorized their dry mouth as none or mild while receiving THVD-102 compared to oxybutynin. Differences in reported dry mouth were statistically significant. CONCLUSION: THVD-102 was generally well-tolerated. Both THVD-102 and oxybutynin 7.5 mg twice daily were effective in treating PFH. THVD-102 was associated with significantly reduced dry mouth compared to oxybutynin. J Drugs Dermatol. 2017;16(2):127-132..

Squaramide Tethered Clindamycin, Chloroquine, and Mortiamide Hybrids: Design, Synthesis, and Antimalarial Activity.

Malaria remains one of the major health problems in the world. In this work, a series of squaramide tethered chloroquine, clindamycin, and mortiamide D hybrids have been synthesized to assess their in vitro antiplasmodial activity against 3D7 (chloroquine-sensitive) and Dd2 strains of Plasmodium falciparum. The most active compound, a simple chloroquine analogue, displayed low nanomolar IC50 value against both strains (3 nM for 3D7 strain and 18 nM for Dd2 strain). Moreover, all molecular hybrids incorporating the hydroxychloroquine scaffold showed the most potent activities, exemplified with a chloroquine dimer, IC50 = 31 nM and 81 nM against 3D7 and Dd2 strains, respectively. These results highlight the first time use of clindamycin and mortiamide D as antimalarial molecular hybrids and establish these valuable hits for future optimization.

Synthetic Multicomponent Nanovaccines Based on the Molecular Co-assembly of ß-Peptides Protect against Influenza A Virus.

Peptides with the ability to self-assemble into nanoparticles have emerged as an attractive strategy to design antigen delivery platforms for subunit vaccines. While toll-like receptor (TLR) agonists are promising immunostimulants, their use as soluble agents is limited by their rapid clearance and off-target inflammation. Herein, we harnessed molecular co-assembly to prepare multicomponent cross-ß-sheet peptide nanofilaments exposing an antigenic epitope derived from the influenza A virus and a TLR agonist. The TLR7 agonist imiquimod and the TLR9 agonist CpG were respectively functionalized on the assemblies by means of an orthogonal pre- or post-assembly conjugation strategy. The nanofilaments were readily uptaken by dendritic cells, and the TLR agonists retained their activity. Multicomponent nanovaccines induced a robust epitope-specific immune response and completely protected immunized mice from a lethal influenza A virus inoculation. This versatile bottom-up approach is promising for the preparation of synthetic vaccines with customized magnitude and polarization of the immune responses.

Synthesis of C-terminal glycopeptides via oxime resin aminolysis.

Natural glycopeptides have been shown to possess interesting biological activities. In this work, we have developed a general solid-phase approach to C-terminal glycopeptides. Taking advantage of oxime resin ester bond nucleophile susceptibility, we optimised the nucleophilic cleavage step with glycosylamines and demonstrated the generality and scope of this method. In addition, this reaction has high functional group tolerance and can be used for the preparation of longer C-terminal glycopeptides, demonstrated with the synthesis of a glycododecapeptide in one single step. The results pave the way to access efficiently novel medically relevant compounds.

Pulmonary hemodynamic effects of dipyridamole infusion in patients with normal and elevated pulmonary artery systolic pressure receiving PB127.

BACKGROUND: Intravenous administration of microspheres used as ultrasound contrast agents may potentially alter pulmonary hemodynamics. PB127 (POINT Biomedical Corp., San Carlos, CA) is an investigational ultrasound perfusion-imaging agent used in conjunction with dipyridamole to diagnose coronary artery disease. The effects of PB127 alone or in combination with dipyridamole on pulmonary hemodynamics have not been described. METHODS: We studied 20 patients, including 10 with elevated screening pulmonary artery systolic pressure (>35 mm Hg). Doppler-derived pulmonary hemodynamics were determined before and after continuous infusion of PB127 (0.175 mg/kg diluted in 5% dextrose) or 5% dextrose. Patients then received dipyridamole (0.56 mg/kg) and hemodynamics were again assessed. RESULTS: During PB127/dextrose infusion, there were no significant changes in pulmonary hemodynamics compared with baseline. After dipyridamole, there were small increases in pulmonary artery systolic pressure and in pulmonary flow and a reduction in pulmonary vascular resistance. These changes occurred in patients with normal and elevated pulmonary artery systolic pressure. CONCLUSION: PB127 infusion does not alter pulmonary hemodynamics. Mild alterations of pulmonary hemodynamics occur after dipyridamole administration.

Geo-environments of the northwest Orinoco Delta, Venezuela

El Delta del Orinoco es un complejo de humedades y ecosistemas acuáticos tropicales de aguas poco profundas en la planicie costera del oriente de Venezuela, el cual en su mayor parte aún no ha sido desarrollado. Es un sistema dinámico y complejo, vulnerable a las actividades humanas. Este artículo resume resultados de cartografía geo-ambiental en el noroeste del delta. Los geo-ambientes son unidades de recursos terrestres y acuáticos que se definen por las características y los procesos físicos, químicos, hidrológicos, y biológicos que los establecen, mantienen y modifican. Más de 20 geo-ambientes se definieron y delinearon en el formato del Sistema de Información Geográfica (SIG) mediante análisis integrado de información de sensores remotos, estadística y campo. Las unidades cartográficas se agruparon en cinco sistemas geomórfico/ecológicos: 1)costa con influencia marina, 2) canal distributario e isla con influencia marina, 3) fluvio/marino transicional, 4) canal distributario, y 5) cuenca interdistributaria. Los más extensos son las cuencas interdistributarias y los sistemas de canales distributarios, los cuales cubren respectivamente el 44 por ciento y el 15 por ciento del área cartografiada. Aunque el Delta del Orinoco esta sin desarrollar en su mayor parte, la actividad humana en el noroeste del delta, especialmente la construcción de la represa de Volcán, ha modificado considerablemente los geo-ambientes en esta región. La distribución que se determinó y las características de los geo-ambientes proporcionaron una base para el diseño de planes estratégicos para el desarrollo prudente y sustentable en esta parte del complejo ecosistema del Delta del Orinoco