Encapsulation of isohexenylnaphthazarins in cyclodextrins

Naturally occurring isohexenylnaphthazarins (IHN), such as Alkannin, Shikonin (A/S) and their derivatives, are potent pharmaceutical substances with a wide spectrum of biological activity. In the present study, inclusion complexes of alkannin and shikonin commercial samples and IHN derivatives in the form of an oily extract of Alkanna tinctoria roots were formed with beta-cyclodextrin (CD) and beta-HPCD. These complexes were investigated to evaluate the effect of complexation on their aqueous solubility, decoloration, and also the percentage of polymeric A/S and IHN derivatives enclosed in the CDs cavity, since these decrease the active monomeric IHN. Both beta-CD and beta-HPCD increased the aqueous solubility of A/S and IHN derivatives and thus inclusion complexes can be used as drug delivery systems for A/S in both internal (capsules, tablets) and external hydrophilic pharmaceutical and cosmetic preparations (creams, gels, sprays) with enhanced bioavailability. The inclusion complexes formed had a pale purple colour, contributing to the partial decoloration of the A/S and thus of the fi nal pharmaceutical preparations. Finally, CDs selectively included more monomeric and less polymeric IHN, compared with the initial each time sample that is encapsulated; thus inclusion complexes may present enhanced biological activity.     

Study on polymerization of the pharmaceutical substances isohexenylnaphthazarins

Polymerization of naturally occurring isohexenylnaphthazarins (IHN), such as alkannin, shikonin (A/S) and their derivatives, which are potent pharmaceutical substances, significantly affects their use in pharmaceuticals, cosmetics and as food colorants, because it leads to reduction of the lustre of their red coloration, a decrease in their solubility and reduces the active monomeric IHN derivatives. In the present study, the influence of several crucial variables (processing and storage) was experimentally investigated on IHN polymerization by size exclusion chromatography (SEC). Temperature and solvent polarity increased significantly the concentration of hydroxynaphthoquinone (HNQ) polymers, while air and light exposure conditions did not significantly affect IHN polymerization. Low temperatures are proposed for all processes of industrial production of pharmaceutical preparations containing IHN and HNQ. An optimization of the industrial conditions used for the preparation of pharmaceutical and cosmetic preparations containing IHN, maximizing the active monomeric IHN fraction, was performed.     

Structure determination of oligomeric alkannin and shikonin derivatives

Monomeric alkannin and shikonin (A/S) are potent pharmaceutical substances with a wide spectrum of biological activity and comprise the active ingredients for several pharmaceutical preparations. Therefore, the determination of the impurities, degradation products or byproducts in alkannin and shikonin samples is of great importance. Oligomeric alkannin and shikonin are formed during biosynthesis of these bioactive secondary metabolites in Boraginaceaous root plants, during tissue culture production of A/S, during alkaline hydrolysis of A/S esters and also thermal treatment of A/S. In the present study, a dimeric alkannin/shikonin compound was isolated by size exclusion chromatography from alkannin and shikonin commercial samples and its structure was determined by one- and two-dimensional NMR spectroscopy. The structure of the most abundant oligomeric species in these samples, a dimeric naphthoquinone, was established for the fi rst time, indicating that coupling of the side chain of one naphthoquinone unit with the aromatic ring of a second naphthoquinone leads to dimer formation. This type of coupling allows further oligomerization by leaving one isohexenyl side chain available at the second monomer unit.     

Kinetic and theoretical studies on the mechanism of alkaline hydrolysis of DNA

The reaction mechanism of alkaline hydrolysis of DNA has been investigated by kinetic analysis and density-functional-theory calculation. The rates of hydrolysis of thymidine 3'-monophosphate esters (including thymidylyl(3'-5')thymidine (Tp-OT)) monotonically decrease as the leaving groups get poorer. According to the theoretical calculation in which the solvent effects are incorporated, no intermediate is formed in the course of the reaction. In the alkaline hydrolysis of the activated Tp-OT analogues having good leaving groups, the 3',5'-cyclic monophosphate of thymidine is concurrently formed through the intramolecular attack by the 5'-alkoxide ion. In the hydrolysis of the native dinucleotide, however, this side reaction does not occur, since the transition state leading to the departure of its poor leaving group cannot be formed due to conformational restraint. These arguments are supported by the theoretical analysis on the hydrolysis of both dimethyl phosphate and its O(bridging)-->S substituted analogue.     

An Efficient Method for Determination of the Degree of Substitution of Cellulose Esters of Long Chain Aliphatic Acids

The determination of the degree of substitution (DS) of fatty acid cellulose esters, representing a broad range of substituents (C₆, C₁₂, C₁₈ and C₂₂), was performed by alkaline hydrolysis of the ester groups and the quantification of fatty acids by gas chromatography-mass spectrometry (GC-MS) as their trimethylsilyl derivatives. The method was optimized and compared with established techniques for the DS determination (elemental analysis and alkaline hydrolysis/titrimetry). The results demonstrated that alkaline hydrolysis/GC-MS is a rapid, reliable and powerful method for analysis of fatty acid cellulose esters, particularly when different acyl substituents are present.     

Analytical utility of 2-halopyridinium salts,part III paper electrophoretic characterization of alcohols as 2-alkoxy-1-methylpyridinium p-toluenesulphonates

Summary A method using high-voltage paper electrophoresis to separate 2-alkoxy-l-methylpyridinium p-toluenesulphonates derived from alcohols is described. Various primary and secondary alcohols are characterized by the relative mobilities of the corresponding 2-alkoxyl-l-methylpyridinium cations using orthoboric acid-orthophosphoric acid-ethylene glycol buffer as electrolyte. The method proved to be useful for the detection and identification of alcohols present as impurities in solvents. A procedure is outlined that permits identification of the alkoxy groups of esters. The procedure utilizes the alkaline hydrolysis of esters, reaction of the alcohols so formed with 2-fluoro-1-methylpyridinium p-toluenesulphonate followed by electrophoresis of the derived 2-alkoxy-1-methylpyridinium p-toluenesulphonates. Nanomole quantities of the separated compounds have been made detectable on the pherograms using Dragendorff's reagent.Part II, Ref. [1]     

Effect of pH on the aluminum salts hydrolysis during coagulation process: formation and decomposition of polymeric aluminum species

Effect of pH on the aluminum chloride hydrolysis at low concentration was investigated in detail by electrospray ionization (ESI) mass spectrometry. In particular, formation and decomposition processes of polymeric aluminum species were discussed. When coagulant AlCl(3) was diluted to normal coagulant dose (1.5 x 10(-4) mol/L), hydrolysis occurred immediately. Monomeric and dimeric aluminum species were the main products at pH 4.0. With pH increasing, hydrolysis and polymerization processes were accelerated. Monomeric and dimeric aluminum species hydrolyzed and polymerized into small polymeric aluminum species (Al(3)-Al(5) species) at pH 4.8. Through aggregation and self-assembly, the small polymeric aluminum species polymerized into median polymeric species (Al(6)-Al(10) species) at pH 5.0. In the same way, small and median polymeric aluminum species further aggregated into large polymeric species (Al(11)-Al(21) species). When pH was up to 5.8, metastable median and large polymers species decomposed into small aluminum species, then further disaggregated into dimeric species. With pH increased to 6.4, majority of aluminum species formed to Al(OH)(3) amorphous flocs. Accordingly, coagulant hydrolysis mechanism from polymerization toward decomposition was proposed. Furthermore, formation and decomposition of polymeric aluminum species in AlCl(3) solution followed the "Core-links" model, while those of Keggin-Al(13) species in polyaluminum solution was based on the "Cage-like" model.     

Hydrolysis of esters of certain substitutes of 1,3,5-triazine

The mechanism of hydrolysis of esters of triazine substitutes was studied. It was shown that hydrolysis of l-menthyl esters in both alkaline and acid media at 80–120° C takes place with cleavage of the bond between the oxygen and carbon of triazine. The bond between the oxygen and carbon of alcohol is broken at 180–200° C in acid medium. The kinetics of alkaline hydrolysis of triazine esters was studied, and it was established that the stability of the latter increases in relation to the influence of the substitute in triazine in the order: C₆H₅ < NHC₆H₅ < NHC₂H₅ < N(C₂H₅)₂. A number of new C-substitutes of triazine was synthesized.We thank Prof. A. I. Korolev for the proposal, and the attention he gave to this work.     

Crosslinking‐induced morphology change of latex nanoparticles: A study of RAFT‐mediated polymerization in aqueous dispersed media using amphiphilic double‐brush copolymers as reactive surfactants

Amphiphilic double‐brush copolymers (DBCs) with each graft site quantitatively carrying both a hydrophilic poly(ethylene oxide) (PEO) graft and a hydrophobic polystyrene (PSt) graft are synthesized by sequential reversible addition‐fragmentation chain transfer (RAFT) polymerization and ring‐opening metathesis polymerization (ROMP). These DBCs are used as both surfactants and polyfunctional RAFT agents in the radical polymerization of St in aqueous dispersed media. Miniemulsions with narrowly dispersed St‐based nanodroplets are readily obtained after ultrasonication of the reaction mixtures. Without the presence of crosslinker, chain‐extension polymerization of St from the DBCs yields well‐defined polymeric latexes with narrow size distributions. However, with the presence of divinylbenzene (DVB) as the crosslinker, vesicular polymeric nanoparticles are formed as the major product. Such crosslinking‐induced change in morphology of the resulting latex nanomaterials may be ascribed to the increase of interfacial curvature in the heterophase systems during crosslinking polymerization. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 3250–3259     

Enzymatic hydrolysis of esterified diarrhetic shellfish poisoning toxins and pectenotoxins

Okadaic acid (OA) and dinophysistoxins-1 and -2 (DTX1, DTX2), the toxins responsible for incidents of diarrhetic shellfish poisoning (DSP), can occur as complex mixtures of ester derivatives in both plankton and shellfish. Alkaline hydrolysis is usually employed to release parent OA/DTX toxins, and analyses are conducted before and after hydrolysis to determine the concentrations of nonesterified and esterified toxins. Recent research has shown that other toxins, including pectenotoxins and spirolides, can also exist as esters in shellfish, but these toxins cannot survive alkaline hydrolysis. A promising alternative approach is enzymatic hydrolysis. In this study, two enzymatic methods were developed for the hydrolysis of 7-O-acyl esters, “DTX3,” and the carboxylate esters of OA, “diol-esters.” Porcine pancreatic lipase induced complete conversion of DTX3 to OA and DTXs within one hour for reference solutions. The presence of mussel tissue matrix reduced the rate of hydrolysis, but an optimized lipase concentration resulted in greater than 95% conversion within four hours. OA-diol-ester was hydrolyzed by porcine liver esterase and was completely converted to OA in less than 30 min, even in the presence of mussel tissue matrix. Esters and OA/DTX toxins were all monitored by LC–MS. Further experiments with pectenotoxin esters indicated that enzymatic hydrolysis could also be applied to esters of other toxins. Enzymatic hydrolysis has excellent potential as an alternative to the conventional alkaline hydrolysis procedure used in the preparation of shellfish samples for the analysis of toxins.     

乙烯系单体自由基聚合的阻聚效应——Ⅸ.受阻胺-醌类电荷转移络合物对甲基丙烯酸甲酯自由基聚合的阻聚及历程

用膨胀计法研究了西氯苯醌(CA)、苯醌(BQ)与受阻胺二异丙胺(DIPA)、2,2,6,6-四甲基-4-羟基哌啶(TMP)形成的电荷转移络合物(CTC)对偶氮二异丁腈(AIBN)引发的甲基丙烯酸甲酯(MMA)自由基聚合阻聚效应。结果表明,CA-DIPA、CA-TMP、BQ-DIPA和BQ-TMP对MMA的自由基聚合均产生较单独的醌或胺更显著的阻聚能力。其中以CA-DIPA阻聚效果更佳。比较了MMA在苯或乙腈中的溶液聚合,得类似结果。初步讨论了受阻胺-醌电荷转移络合物对MMA自由基聚合的阻聚反应机理。     

Solid-phase extraction for purification of alkannin/shikonin samples and isolation of monomeric and dimeric fractions

Isohexenylnaphthazarins (IHN), commonly known as alkannins and shikonins (A/S), are potent pharmaceutical substances with a wide spectrum of wound healing, antimicrobial, anti-inflammatory, and antitumor activity. Purification of A/S is crucial for their use in pharmaceuticals and for biological experimentation. Dimeric and oligomeric A/S derivatives co-exist with the active monomeric ones in most of the samples produced either by (semi)-synthesis or biotechnologically or isolated from natural products. Oligomeric A/S derivatives have not been studied for biological activity hitherto and a method to isolate them is essential.     

THE STRUCTURE OF THE ACTIVE MATERIAL IN HEMATOPORPHYRIN DERIVATIVE

Abstract The structure of the active material in hematoporphyrin derivative is shown to be a condensation polymer of hematoporphyrin linked by ether functional groups. When a mixture of the monoacetates and the diacetate of hematoporphyrin is treated with dilute sodium hydroxide solution a polymeric fraction is formed which constitutes the active material of hematoporphyrin derivative. This fraction is stable to basic hydrolysis using conditions which are shown to hydrolyse porphyrin esters, but is hydrolysed by acidic conditions which cleave porphyrin ethers as well as esters. When hematoporphyrin diacetate is similarly treated with base a polymeric fraction is formed which is hydrolysed by both acidic and basic conditions showing it to be ester linked. This ester linked polymer is unstable in aqueous solution at pH 7 and converts to the polyether within 2 days at room temperature.     

Mechanochemical solid-state polymerization (XI): effect of water-insoluble pharmaceutical aids on drug release from mechanically synthesized polymeric prodrugs

We discuss here the effect of water-insoluble pharmaceutical aids on the nature of drug release from composite polymeric prodrugs synthesized by mechanochemical solid-state polymerization. Magnesium stearate (Mgst) and hydrogen castor oil (HCO) were used as water-insoluble pharmaceutical aids. Composite polymeric prodrugs were synthesized by the mechanochemical solid-state polymerization of a vinyl monomer of 5-fluorouracil (I) in the presence of Mgst or HCO. The molecular weight of the resulting polymeric prodrugs increased with increasing the content of Mgst or HCO. Prodrug hydrolysis was carried out in a heterogeneous system in phosphate buffer at pH 6.8 and 37 degrees C. The rate of drug release from the composite polymeric prodrug containing Mgst (Poly-Mgst) was faster than that from polymeric prodrug containing no pharmaceutical aids (Poly-Non), while hydrolysis of the composite polymeric prodrug containing HCO (Poly-HCO) was slower than Poly-Non. Scanning electron microscope (SEM) photos showed the surface of Poly-HCO was smoother than that of Poly-Non and Poly-Mgst. It was suggested that the slower drug release from Poly-HCO may be responsible for the smaller specific surface area than that of Poly-Non. It was also shown that the rate of drug release from the composite polymeric prodrugs decreases with increasing the content of Mgst or HCO. Hence, novel composite polymeric prodrugs with a variety of drug release rates can be prepared by mechanochemical solid-state polymerization in a totally dry process.     

室温自交联丙烯酸酯乳液的制备与表征

使用3种含不饱和双键硅氧烷,乙烯基三(β-甲氧基乙氧基)硅烷(A172)、乙烯基三乙氧基硅烷(VTES)和γ-甲基丙烯酰氧丙基三甲氧基硅烷(A174)为功能单体,采用半连续乳液聚合法制备了室温自交联丙烯酸酯乳液,探讨了硅氧烷功能单体在不同pH条件下水解情况以及其种类和用量对乳液及乳胶膜性能的影响.结果表明,pH在7～9之间时硅氧烷功能单体水解最慢;A172在pH为8.4时5h内就水解完全;增加VTES和A174的用量均能提高乳胶膜的交联度、力学性能和耐水性.控制聚合过程的pH值以抑制硅氧烷功能单体的水解并调节乳液成膜时的pH值以加速硅氧烷功能单体的水解从而增强胶膜的交联程度,发现酸性或碱性条件下得到乳胶膜比中性条件下胶膜的力学和耐水性能均有不同程度的提高,并且在酸性条件下胶膜的性能提高最多.对比使用A174和VTES制备的胶膜,发现这种方法对含有A174胶膜的效果不明显,而含VTES胶膜的性能提高最为显著.     

The Immobiline family: from "vacuum" to "plenum" chemistry.

We list here a total of 17 acrylamido acids and bases as potential buffers and titrants for isoelectric focusing separations in immobilized pH gradients. The chemistry of these compounds is reviewed and general guidelines are given for their proper use. In particular, it is shown that the most delicate compounds are the basic species, since they can undergo several degradation pathways, including: (i) spontaneous hydrolysis to acrylic acid and a diamine; (ii) spontaneous autopolymerization to oligomers and n-mers; (iii) oxidation to N-oxides during the persulfate polymerization step. A hydrophobicity scale has been constructed, by partitioning the deprotonated species in water/1-octanol phases. A scale of resistance to alkaline hydrolysis for the basic acrylamido buffers is also given, followed by general consideration on the structure/stability relationship of these chemicals.     

Synthesis and applications of acid-labile acrylic polymers

A variety of acrylic and methacrylic acetal esters were synthesized by reaction of unsaturated carboxylic acids with vinyl ethers. The acetal esters were converted by radical polymerization and GTP to acid-labile homo- and copolymers. Coatings of these polymeric acetal esters containing photosensitive acid-generating compounds are useful in image-formation through chemical amplification. Thus, poly(tetrahydropyranyl methacrylate-co-benzyl methacrylate) can be used in positive working deep UV microlithography. Poly(tetrahydropyranyl acrylate), coated in a thin layer over a tacky elastomer, provides a high resolution, water-developable negative working tonable composition. Several polymeric and nonpolymeric acetal esters can be used for positive working electrostatic imaging through changes in electrical conductivity.     

Quantitative determination of esters by saponification in dimethyl sulphoxide

A method is given for the quantitative determination of esters which makes use of the unusually rapid rate of their alkaline hydrolysis in aqueous dimethyl sulphoxide medium. Only 5 min heating on a steam-bath is needed for quantitative hydrolysis of most esters, and many react completely in 5 min at room temperature. When hydrolysis is complete, the excess of base is titrated with standard acid, using a visual indicator.     

Peculiarities of the preparation of copolymers of acrylamide with sodium acrylate in inverse emulsions

The polymerization of acrylamide (AA) in inverse emulsions in the presence of saponifying agents (NaOH and Na₂CO₃) and potassium persulphate at 30–50° has been investigated. The rates of the polymerization and alkaline hydrolysis increase with increasing concentration of saponifying agents, AA, initiator and temperature. The molecular weight of copolymers decreases with increasing concentration of saponifying agents for polymerization in water-toluene emulsions and in aqueous solutions. It has been shown that the alkaline hydrolysis in inverse emulsions polymerization of AA is a second-order reaction, with rate proportional to both the amide and the alkaline agent concentrations. The effective overall energies of activation of the alkaline hydrolysis were 57.5 (in the presence of NaOH) and 57.0 kJ/mol (in the presence of Na₂CO₃).