New methodology for the synthesis of 25-hydroxyvitamin D conjugates

A new method for synthesizing regiospecific 3-position vitamin D conjugates is described. Reaction of either 25-dihydroxyvitamin D2 or 25-dihydroxyvitamin D3 with p-nitrophenylchloroformate resulted in conversion to the respective 3-p-nitrophenylcarbonates. Reaction of the p-nitrophenylcarbonates with amines produced the 3-carbamates in good yield. Careful selection of commercially available amines and non-acidic conditions made this pathway amenable to the preparation of fluorescent, chemiluminescent, or biotinylated conjugates. This strategy offers a general method for the preparation of vitamin D conjugates.     

Design and synthesis of a potent biotinylated Smac mimetic

A biotinylated Smac mimetic (2) was designed based upon our previously reported potent, conformationally constrained Smac mimetic (1). Smac mimetic (2) was synthesized and determined to bind to XIAP protein with a high-affinity (K_i value of 13 nM) and is therefore a useful pharmacological tool for probing the intracellular targets of this class of potent Smac mimetics.     

Facile solid-phase synthesis of biotinylated alkyl thiols

Biotinylated alkyl thiols with the capacity to graft avidin proteins are in increasing demand for the development of self-assembled monolayers on gold. Here we propose 2-Chlorotrityl Chloride solid-phase resin as a new platform to produce these functionalized alkyl thiols. Biotinylated alkyl thiols of non-obvious solution synthesis were obtained rapidly using this method and without previous purification steps.     

Chromatographic assay to study the activity of multiple enzymes involved in the synthesis and metabolism of dopamine and serotonin

Serotonin and dopamine are crucial regulators of signalling in the peripheral and central nervous systems. We present an ex-vivo, isocratic chromatographic method that allows for the measurement of tyrosine, L-3,4-dihydroxyphenylalanine (L-DOPA), dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), tryptophan, 5-hydroxytryptophan (5-HTP), serotonin and 5-hydroxy-3-indoleacetic acid (5-HIAA) in a model central nervous (CNS) system, to study the role of key enzymes involved in the synthesis and metabolism of serotonin and dopamine. By utilising a sample splitting technique, we could test a single CNS sample at multiple time points under various pharmacological treatments. In, addition, we were able to conduct this assay by utilising the endogenous biochemical components of the CNS to study the synthesis and metabolism of serotonin and dopamine, negating the requirement of additional enzyme activators or stabilisers in the biological matrix. Finally we utilised NSD-1015, an aromatic amino acid decarboxylase enzyme inhibitor used to study the synthesis of dopamine and serotonin to monitor alterations in levels of key neurochemicals. 3-hydroxybenzylhydrazine dihydrochloride (NSD-1015) was able to reduce levels of serotonin and dopamine, whilst elevating precursors L-DOPA and 5-HTP.     

Electric impedance method for evaluation of the release property of calcein-encapsulated liposomes

This paper is concerned with the study on development of a novel method for evaluation of the liposomes release property by measuring the electric impedance changes of liposome suspensions. Calcein/NaOH encapsulated liposomes (calcein-liposomes) were prepared with deionized water and were treated with ultrasonic irradiation in order to investigate the release property of the liposomes. To validate the proposed impedance measuring method, the calcein release rates were evaluated both by the impedance changes and the fluorescence intensity changes in calcein-liposome suspensions. With the comparison of these results obtained by the two methods, it is shown that the impedance method has much wider detecting concentration range than the fluorescence one. Furthermore, the impedance method can be efficiently used for evaluation of the release property on various ionic substances encapsulated within liposomes.     

Elucidation of post-PKS tailoring steps involved in landomycin biosynthesis

The functional roles of all proposed enzymes involved in the post-PKS redox reactions of the biosynthesis of various landomycin aglycones were thoroughly studied, both in vivo and in vitro. The results revealed that LanM2 acts as a dehydratase and is responsible for concomitant release of the last PKS-tethered intermediate to yield prejadomycin (10). Prejadomycin (10) was confirmed to be a general pathway intermediate of the biosynthesis. Oxygenase LanE and the reductase LanV are sufficient to convert 10 into 11-deoxylandomycinone (5) in the presence of NADH. LanZ4 is a reductase providing reduced flavin (FMNH) co-factor to the partner enzyme LanZ5, which controls all remaining steps. LanZ5, a bifunctional oxygenase-dehydratase, is a key enzyme directing landomycin biosynthesis. It catalyzes hydroxylation at the 11-position preferentially only after the first glycosylation step, and requires the presence of LanZ4. In the absence of such a glycosylation, LanZ5 catalyzes C5,6-dehydration, leading to the production of anhydrolandomycinone (8) or tetrangulol (9). The overall results provided a revised pathway for the biosynthesis of the four aglycones that are found in various congeners of the landomycin group.     

Niosomes from 80s to present: The state of the art

Efficient and safe drug delivery has always been a challenge in medicine. The use of nanotechnology, such as the development of nanocarriers for drug delivery, has received great attention owing to the potential that nanocarriers can theoretically act as “magic bullets” and selectively target affected organs and cells while sparing normal tissues. During the last decades the formulation of surfactant vesicles, as a tool to improve drug delivery, brought an ever increasing interest among the scientists working in the area of drug delivery systems. Niosomes are self assembled vesicular nanocarriers obtained by hydration of synthetic surfactants and appropriate amounts of cholesterol or other amphiphilic molecules. Just like liposomes, niosomes can be unilamellar or multilamellar, are suitable as carriers of both hydrophilic and lipophilic drugs and are able to deliver drugs to the target site. Furthermore, niosomal vesicles, that are usually non-toxic, require less production costs and are stable over a longer period of time in different conditions, so overcoming some drawbacks of liposomes.     

Chromatographic behaviour and purification of N1.5-glycosyl enkephalins

Summary N ^1.5-Glycosyl enkephalins are potent analgesics. Two enkephalin-related glycosyl peptides: [DMet², Pro⁵] enkephalin (N ^1.5 -glucopyranosyl] amide and [DMet², Pro⁵] enkephalin [N ^1.5 -galactosyl] amide have been prepared following the liquid phase procedure. The chromatographic behavior of both the final glycosyl enkephalins and their synthetic intermediates on reversed-phase columns has been tested. Semipreparative, reversed-phase, HPLC conditions have been developed in order to obtain a simple and rapid procedure for the purification of the two synthetic pentapeptides. Thus, using isocratic elution, injections of 10mg of crude material after gel filtration gave homogeneous (99.9%) glycosyl enkephalins.     

Lipase-catalyzed synthesis of novel galactosylated cholesterol

In an organic phase system,an enzymes lipase was used as a catalyst to synthesize galactosylated cholesterol,(5-cholesten-3b-yl)[(4-O-β-D-galactopyranosyl)D-glucitol-6]sebacate(CHS-SE-LA),which contains galactose residues.Its chemical structure was characterized by ESI-MS,and NMR.For HepG2 cells,the cellular fluorescence intensities of liposomes modified with CHS-SE-LA(GAL-FL) were as much as 2.6-fold(p 0.01) control liposomes(FL).Moreover,the presence of excess galactose significantly inhibited the uptake of GAL-FL suggesting ASGPR mediated uptake.In conclusion,the novel galactosylated ligand CHS-SE-LA was synthesized by lipase-catalyzation and revealed a great potential as drug carrier materials for hepatocyte-selective targeting.     

Efficient exosome extraction through the conjugation of superparamagnetic iron oxide nanoparticles for the targeted delivery in rat brain

Exosomes possess endogenous attributes and distinct biological functions, and thereby, their uses as drug nanocarriers have attracted increasing attention for biomedical practices. However, to achieve targeted therapeutic purposes, complicated extractions, as well as modifications of exosomes, are involved. Here, based on the use of superparamagnetic iron oxide nanoparticles conjugated exosome (Ex-SPIONs), a facile exosome extraction through magnetism was established. The produced Ex-SPIONs exhibited a uniform size distribution and desirable biocompatibility. Moreover, taking advantage of the magnetic properties of SPIONs, the targeted delivery of Ex-SPIONs was demonstrated in the rat brain. Therefore, the constructed SPIONs functionalized exosome shows promising therapeutic potentials, including the treatment of brain diseases.     

Chromatographic study of the synthesis of halogenated unsaturated polyesters

The molecular-weight distribution and functionality of polycondensation products of 1,4,5,6,7,7-hexa chloro(hexabromo)bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride, propylene glycol, and maleic anhydride were studied by size-exclusion chromatography. Conditions were examined for preparing oligoesters with more uniform composition and regular alternation of ester fragments and unsaturated units     

纳米高分子材料在医用载体方面的应用

医用纳米高分子作为药物、基因传递和控释的载体,是一种新型的控释体系,它与微米粒子载体的主要区别是超微小体积,它能穿过组织间隙并被细胞吸收,可通过人体最小的毛细血管,还可通过血脑屏障,因而作为新的控释体系而被广泛研究,具有广阔的发展前景,重点论述了纳米高分子控释系统在药物和基因载体方面的最新研究进展,并对其发展前景提出了展望。     

Total synthesis of (+)-alpha-onocerin in four steps via four-component coupling and tetracyclization steps

A remarkably short (four steps, 31% overall yield) enantioselective synthesis of the structurally unique C2-symmetric tetracyclic triterpene (+)-alpha-onocerin (1) has been developed. The brevity of this mechanism depends on the assembly of four fragments (two molecules of a chiral epoxy ketone and two molecules of vinyllithium) to generate the chiral bis-epoxide 4 in one step, and on the efficient formation of all four carbocyclic rings in one step by cation-olefin tetracyclization. New and general methodology for the conversion of vinyl tert-butyldimethylsilyl ethers to vinyl triflates with retention of E or Z olefinic geometry also was utilized in the synthesis of 1. A short enantioselective synthesis of a non-C2-symmetric diastereomer of 1 is also described which uses the new methodology.     

Testing for Drugs in Hair – a Review of Chromatographic Procedures

This article reviews the analysis of drugs and drug metabolites in hair by chromatographic procedures, including the pretreatment steps, and the extraction methods. The general tendency in the last years, to highly sophisticated techniques (GC–MS–NCI, HPLC–MS, GC–MS–MS) illustrates the constant fight for sensitivity.     

Recent advances in liposomal nanohybrid cerasomes as promising drug nanocarriers

Liposomes have been extensively investigated as possible carriers for diagnostic or therapeutic agents due to their unique properties. However, liposomes still have not attained their full potential as drug and gene delivery vehicles because of their insufficient morphological stability. Recently, a super-stable and freestanding hybrid liposomal cerasome (partially ceramic- or silica-coated liposome) has drawn much attention as a novel drug delivery system because its atomic layer of polyorganosiloxane surface imparts higher morphological stability than conventional liposomes and its liposomal bilayer structure reduces the overall rigidity and density greatly compared to silica nanoparticles. Cerasomes are more biocompatible than silica nanoparticles due to the incorporation of the liposomal architecture into cerasomes. Cerasomes combine the advantages of both liposomes and silica nanoparticles but overcome their disadvantages so cerasomes are ideal drug delivery systems. The present review will first highlights some of the key advances of the past decade in the technology of cerasome production and then review current biomedical applications of cerasomes, with a view to stimulating further research in this area of study.     

功能多肽在肿瘤治疗中的应用及研究进展

多肽具有生物相容性好,功能多样化,生物体内响应性高及合成修饰方法简单易行等优点,已被广泛用于构建靶向药物传递系统。以具有靶向功能和刺激响应性的多肽为基础构建的药物传递系统,能够将药物定向地运送到肿瘤区域。药物传递系统到达肿瘤组织后,在肿瘤组织特殊微环境或外源刺激下,实现药物的精准释放。这种具有特异性肿瘤靶向和刺激响应型的多肽载体可以最大程度地提高药物的抗肿瘤效果,降低药物的毒副作用。本文简要介绍了常用的靶向多肽和刺激响应型多肽,并讨论了基于功能型多肽的药物载体在肿瘤治疗方面的应用。     

Transmembrane Transport of Adenosine 5′-Triphosphate Using a Lipophilic Cholesteryl Derivative

The uptake of ATP in liposomes was achieved by using the lipophilic derivative cholesteryloxycarbonyl-ATP ( 1 ). Its hydrolysis leading to the release of ATP inside the vesicules (see scheme) was observed with the help of a pH gradient and monitored by ³¹P NMR spectroscopy. This is the first successful transfer of a nucleoside 5′-triphosphate across a membrane.     

Investigation of SPR and electrochemical detection of antigen with polypyrrole functionalized by biotinylated single-chain antibody: A review

An electrochemical label-free immunosensor based on a biotinylated single-chain variable fragment (Sc-Fv) antibody immobilized on copolypyrrole film is described. An efficient immunosensor device formed by immobilization of a biotinylated single-chain antibody on an electropolymerized copolymer film of polypyrrole using biotin/streptavidin system has been demonstrated for the first time. The response of the biosensor toward antigen detection was monitored by surface plasmon resonance (SPR) and electrochemical analysis of the polypyrrole response by differential pulse voltammetry (DPV). The composition of the copolymer formed from a mixture of pyrrole (py) as spacer and a pyrrole bearing a N-hydroxyphthalimidyl ester group on its 3-position (pyNHP), acting as agent linker for biomolecule immobilization, was optimized for an efficient immunosensor device. The ratio of py:pyNHP for copolymer formation was studied with respect to the antibody immobilization and antigen detection. SPR was employed to monitor in real time the electropolymerization process as well as the step-by-step construction of the biosensor. FT-IR demonstrates the chemical copolymer composition and the efficiency of the covalent attachment of biomolecules. The film morphology was analyzed by electron scanning microscopy (SEM).Results show that a well organized layer is obtained after Sc-Fv antibody immobilization thanks to the copolymer composition defined with optimized pyrrole and functionalized pyrrole leading to high and intense redox signal of the polypyrrole layer obtained by the DPV method. Detection of specific antigen was demonstrated by both SPR and DPV, and a low concentration of 1 pg mL⁻¹ was detected by measuring the variation of the redox signal of polypyrrole.     

Roles of adriamycin and adriamycin dimer in antitumor activity of the polymeric micelle carrier system

Adriamycin (ADR) dimer was prepared and its antitumor activity was evaluated with mouse colon adenocarcinoma 26 (C 26). As compared with original ADR, the dimer did not show significant antitumor activity, either in vitro or in vivo. Furthermore, polymeric micelles containing varied ratios of the dimer to the original ADR were prepared. Polymeric micelles with a higher dimer/ADR ratio (9.7) showed significant antitumor activity, but the effective dose shifted higher. Effective doses were found to largely depend on the concentration of the original ADR, rather than that of the dimer at the tumor sites. Therefore, it was presumed that the original ADR played a major role in antitumor activity, and the dimer played a supplementary role to contribute selective delivery of ADR to the tumor sites.