Flow through diffusion cell method: A novel approach to study in vitro enzymatic degradation of a starch‐based ternary semi‐interpenetrating network for gastrointestinal drug delivery

A ter‐polymeric semi‐IPN has been synthesized by aqueous polymerization of methacrylamide in the presence of polyethylene glycol (PEG) and natural polysaccharides starch, and its enzymatic degradation has been studied in the phosphate buffer medium of pH 6.8 at the physiological temperature 37°C. With the increase in content of enzyme in the external solution and starch in the hydrogel, the degradation is enhanced while the extent of degradation is lowered with the increase in the amount of PEG in the hydrogel. The initial water content also affects the degradability of the polymer matrix. The degradation follows Michaelis–Menten kinetics and K_M was found to be 3.92 × 10^?5 mol dm^?3. The hydrogel exhibits different degradation behavior when studied by “traditional degradation method” (TDM) and “flow through diffusion cell” (FTDC) method. The degradability is suppressed in FTDC method because of the absorption of amylase molecules onto filler particles. Finally the nature and size of the filler particles also affects the degradation behavior of hydrogels. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 100: 2975–2984, 2006     

In vitro enzymatic degradation kinetics of polymeric blends of crosslinked starch and carboxymethyl cellulose

Hydrophilic blend matrices of crosslinked starch and carboxymethyl cellulose were synthesized and their susceptibilities to enzymatic degradation were assessed by taking α‐amylase as a model enzyme. The polymeric blends were characterized by FT‐IR spectroscopy, differential scanning calorimetry and scanning electron microscopy. The influence of the chemical compositions of the blends, and the pH values and temperatures of the α‐amylase solutions was investigated by studying the swelling and degradation kinetics of the blends. The impact of the concentrations of the enzyme solutions on the degradation profiles was also examined. The blends were found to exhibit a mixed type of degradation mechanism, ie both diffusion and surface erosion. Copyright © 2005 Society of Chemical Industry     

Cationic copolymers of α,β‐poly‐(N‐2‐hydroxyethyl)‐DL‐aspartamide (PHEA) and α,β‐polyasparthylhydrazide (PAHy): synthesis and characterization

In the present study the derivatization of two water‐soluble synthetic polymers, α,β‐poly(N‐2‐hydroxyethyl)‐DL ‐aspartamide (PHEA) and α,β‐polyasparthylhydrazide (PAHy), with glycidyltrimethylammonium chloride (GTA) is described. This reaction permits the introduction of positive charges in the macromolecular chains of PHEA and PAHy in order to make easier the electrostatic interaction with DNA. Different parameters affect the reaction of derivatization, such as GTA concentration and reaction time. PHEA reacts partially and slowly with GTA; on the contrary the reaction of PAHy with GTA is more rapid and extensive. The derivatization of PHEA and PAHy with GTA is a convenient method to introduce positive groups in their chains and it permits the preparation of interpolyelectrolyte complexes with DNA. © 2000 Society of Chemical Industry     

One‐step production of 2,3‐butanediol from starch by secretory over‐expression of amylase in Klebsiella pneumoniae

BACKGROUND: 2,3‐Butanediol (2,3‐BD) is a valuable chemical that can be biosynthesized from many kinds of substrates. For commercial biological production of 2,3‐BD, it is desirable to use cheap substrate without pretreatment, such as starch. However, there have been few reports on the production of 2,3‐BD directly from starch. RESULTS: In this work, gene malS coding for α‐amylase (EC 3.2.1.1) precursor was inserted into plasmid pUC18K, and secretory over‐expression of α‐amylase was achieved by engineered Klebsiella pneumoniae. The extracellular recombinant amylase accelerated the hydrolyzation of starch, and one‐step production of 2,3‐BD from starch was carried out by engineered K. pneumoniae. A 2,3‐BD concentration of 3.8 g L^?1 and yield of 0.19 g 2,3‐BD g^?1 starch were obtained after 24 h fermentation. CONCLUSION: The one‐step production of 2,3‐BD from starch was achieved by secretory over‐expression of amylase in K. pneumoniae. This would simplify the process and reduce the production cost considerably by enabling use of starch with minimal pretreatment. Copyright © 2008 Society of Chemical Industry     

Poly‐α,β‐(3‐hydroxypropyl)‐DL‐aspartamide: A new drug carrier

Poly‐α,β‐(3‐hydroxypropyl)‐DL ‐aspartamide (PHPA) was synthesized by the ring‐open reaction of polysuccinimide (PSI) and 3‐hydroxypropylamine. The polymer was characterized by ¹H‐NMR, ¹³C‐NMR, FTIR, and GPC. Mark–Houwink coefficients were obtained from viscometry and GPC measurements, K = 5.53 × 10⁻³ and α = 0.78 in water. The acute toxicity of PHPA was examined and it revealed no death in ICR mice up to the dose treated of 15.3 kg/kg, and hematological parameters showed no significant difference between treated and control animals. The potential use of PHPA as a drug carrier was also investigated. In a typical case, a contraceptive drug, norethindrone (NET), was bonded to PHPA, and the drug sustained released as long as 120 days an in vitro test. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 77: 2411–2417, 2000     

Sodium Iodide/tert‐Butyl(dimethyl)silyl Chloride‐Induced Isomerization of 2,3‐Allenols to 2(E)‐Enals

Through an unexpected CC bond migration, 2(E)‐enals were efficiently prepared highly stereoselectively in moderate to good yields via the sodium iodide/tert‐butyl(dimethyl)silyl chloride (NaI/TBSCl)‐mediated reaction of the easily available 2,3‐allenols. Based on a careful mechanistic study, including control experiments and deuterium‐labeling experiments, an electron‐withdrawing substituent group in the 4 position has been proven to be crucial and a possible mechanism has been proposed.

     

Palladium(II)‐Catalyzed Aerobic Intermolecular Cyclization of Acrylic Acid with Alkenes to α‐Methylene‐γ‐butyrolactones

The methodology in this article is a palladium(II)/copper(II)‐ or palladium(II)‐catalyzed intermolecular cyclization of acrylic acid with alkenes to produce α‐methylene‐γ‐butyrolactone derivatives using molecular oxygen as an environmentally benign oxidant. In this system, the carboxylato, especially trifluoroacetato, or trimethylacetato ligand, plays a quite important role to afford a high catalytic activity by suppressing the deposition of palladium(0) black.     

Asymmetric penta‐armed poly(ε‐caprolactone)s with short‐chain phosphazene core: synthesis,characterization, and in vitro degradation

A novel hydroxyl‐terminated short‐chain penta‐armed phosphazene was prepared. This penta‐armed compound was studied as an initiator for the synthesis of asymmetric penta‐armed poly(ε‐caprolactone)s in the presence of stannous octoate. The effect of molar ratio of monomer to initiator was investigated. Thermal analysis revealed that the penta‐armed poly(ε‐caprolactone)s possessed lower melting point and crystallinity than linear ones. The penta‐armed poly(ε‐caprolactone)s with long chain‐length exhibited higher onset decomposition temperature and maximum decomposition temperature than linear ones owing to the presence of the phosphazene core. The in vitro degradation of linear and penta‐armed PCL was performed in phosphate buffer solution at 37 and 55 °C. Copyright © 2005 Society of Chemical Industry     

Titanium‐Mediated Direct Carbon‐Carbon Double Bond Formation to α‐Trifluoromethyl Acids: A New Contribution to the Knoevenagel Reaction and a High‐Yielding and Stereoselective Synthesis of α‐Trifluoromethylacrylic Acids

An efficient strategy for a high‐yielding and stereoselective synthesis of α‐trifluoromethyl unsaturated carboxylic acids directly from the reactions of 3,3,3‐trifluoropropanoic acid (CF₃CH₂COOH) with various aryl aldehydes in the presence of titanium tetrachloride (TiCl₄) is reported here for the first time, which is a valuable expansion for the classical Knoevenagel reaction. Because these compounds may have potential applications in organic electronics and can be easily converted to the corresponding fluorinated alcohols and amino acids with excellent bioactivity, this route should be a good choice for the preparation of α‐trifluoromethyl‐containing derivatives.     

Access to Both Enantiomers of α‐Chloro‐β‐keto Esters with a Single Chiral Ligand: Highly Efficient Enantioselective Chlorination of Cyclic β‐Keto Esters Catalyzed by Chiral Copper(II) and Zinc(II) Complexes of a Spiro‐2,2′‐bischroman‐Based Bisoxazoline Ligand

The spiro‐2,2′‐bichroman‐based chiral bisoxazoline ligands (SPANbox) were found to be highly efficient in copper(II)‐ and zinc(II)‐catalyzed asymmetric chlorinations of cyclic β‐keto esters with N‐chlorosuccinimide (NCS) as the chlorination reagent, to give the corresponding α‐chloro‐β‐keto esters in excellent yields in 5–30 min with ee values up to 97%. The copper(II) triflate and zinc(II) triflate complexes of a single SPANbox ligand demonstrated complementary results to each other with respect to the enantioselection, affording both antipodes of the chlorinated product enantiomers with good to excellent optical purities.     

Immobilization of malto‐oligosaccharide forming α‐amylase from Bacillus subtilis KCC103: properties and application in starch hydrolysis

BACKGROUND: A malto‐oligosaccharide forming α‐amylase from Bacillus subtilis KCC103 immobilized in calcium alginate beads was repeatedly used in batch processes of starch hydrolysis. The degree of starch degradation and operational stability of the immobilized system were optimized by varying the physical characteristics and composition of the beads. The products formed from hydrolysis of various starches by α‐amylase immobilized in different supports were analyzed. RESULTS: Immobilized beads prepared from 3% (w/v) alginate and 4% (w/v) CaCl₂ were suitable for up to 10 repeated uses, losing only 25% of their efficiency. On addition of 1% silica gel to alginate prior to gelation, the operational stability of the immobilized enzyme was enhanced to 20 cycles of operation, retaining > 90% of the initial efficiency. Distribution of malto‐oligosaccharides in the starch hydrolyzate depended on the type of starch, reaction time and mode of immobilization. Soluble starch and potato starch formed a wide range of malto‐oligosaccharides (G1–G5). Starches from wheat, rice and corn formed a narrow range of smaller oligosaccharides (G1–G3) as the major products. CONCLUSION: The immobilized beads of α‐amylase from KCC103 prepared from alginate plus silica gel showed high efficiency and operational stability for hydrolysis of starch. This immobilized system is useful for production of malto‐oligosaccharides applied in the food and pharmaceutical industries. Since this KCC103 amylase can be produced at low cost utilizing agro‐residues in a short time and immobilized enzyme can be recycled, the overall cost of malto‐oligosaccharide production would be economical for industrial application. Copyright © 2008 Society of Chemical Industry     

N‐Heterocyclic Carbene‐Mediated Organocatalytic Transfer of Tin onto Aldehydes: New Access to α‐Silyloxyalkylstannanes and γ‐Silyloxyallylstannanes

A new, highly efficient and mild N‐heterocyclic carbene (NHC)‐mediated organocatalytic procedure for the transfer of tin from tributyl(trimethylsilyl)stannane (Bu₃SnSiMe₃) onto aldehydes for the preparation of α‐silyloxyalkylstannanes and γ‐silyloxyallylstannanes has been developed.     

Highly Enantioselective Phase‐Transfer Catalytic α‐Alkylation of α‐tert‐Butoxycarbonyllactams: Construction of β‐Quaternary Chiral Pyrrolidine and Piperidine Systems

A new enantioselective α‐alkylation of α‐tert‐butoxycarbonyllactams for the construction of β‐quaternary chiral pyrrolidine and piperidine core systems is reported. α‐Alkylations of N‐methyl‐α‐tert‐butoxycarbonylbutyrolactam and N‐diphenylmethyl‐α‐tert‐butoxycarbonylvalerolactam under phase‐transfer catalytic conditions (solid potassium hydroxide, toluene, −40 °C) in the presence of (S,S)‐3,4,5‐trifluorophenyl‐3,3′,5,5′‐tetrahydro‐2,6‐bis(3,4,5‐trifluorophenyl)‐4,4′‐spirobi[4H‐dinaphth[2,1‐c:1′,2′‐e]azepinium] bromide [(S,S)‐NAS Br] (5 mol%) afforded the corresponding α‐alkyl‐α‐tert‐butoxycarbonyllactams in very high chemical (up to 99%) and optical yields (up to 98% ee). Our new catalytic systems provide attractive synthetic methods for pyrrolidine‐ and piperidine‐based alkaloids and chiral intermediates with β‐quaternary carbon centers.     

Synthesis and characterization of degradable copoly(ester–amide)s: Poly(trans‐4‐hydroxy‐L‐proline‐co‐ε‐caprolactam)

Novel copolyesteramides were synthesized by reacting trans‐4‐hydroxy‐N‐benzyloxycarbonyl‐L ‐proline (N‐CBz‐Hpr) with ε‐caprolactam (CLM) in the presence of stannous octoate [Sn(II) Oct.] as a catalyst. Various techniques, including ¹H‐NMR, IR, DSC, and viscosity, were used to elucidate structural characteristics and thermal properties of the resulting copolymers. Data showed that the optimal reaction condition for the synthesis of the copolymers was obtained by using 3 wt % Sn(II) Oct. at 170°C for 24 h. The DSC analysis demonstrated amorphous structure for most of the copolymers. The glass‐transition temperature of the copolymers shifts to a higher temperature with increasing Hpr/CLM molar ratio. In vitro degradation of these poly(N‐CBz‐Hpr‐co‐CLM)s was evaluated by weight loss measurements. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 86: 1615–1621, 2002     

The One‐Pot Wittig Reaction: A Facile Synthesis of α,β‐Unsaturated Esters and Nitriles by Using Nanocrystalline Magnesium Oxide

Nanocrystalline magnesium oxide was found to be an effective heterogeneous, solid base catalyst for the one‐pot Wittig reaction to afford α,β‐unsaturated esters and nitriles in excellent yields with high E‐stereoselectivity in the presence of triphenylphosphine under mild conditions.     

Ionic Liquid, 1‐n‐Butyl‐3‐methylimidazolium Bis(trifluoromethanesulfonyl)imide,Resulted in the First Catalyst‐Free Aminohalogenation of Electron‐Deficient Alkenes

The 2‐Ns‐based aminohalogenation of α,β‐unsaturated ketones has been achieved in an ionic liquid, 1‐n‐butyl‐3‐methylimidazolium bis(trifluoromethanesulfonyl)imide {[bmim][N(SO₂CF₃)₂]}. [Bmim][N(SO₂CF₃)₂] was found to be superior not only to classical organic solvents but also to its counterpart, [bmim][BF₄], which was proven to be successful in the TsNCl₂‐based aminohalogenation but failed to give any product for this reaction. The present process takes the advantage of 2‐NsNCl₂ as the stable nitrogen/halogen source in a one‐pot operation without the use of any metal catalysts, it is convenient to perform without special protection of inert gases. Eight examples were examined with good to excellent stereoselectivity (1:5 to one isomer) and modest to good chemical yields (53–72 %).     

Gelatin based pH‐sensitive hydrogels for colon‐specific oral drug delivery: Synthesis,characterization, and in vitro release study

Based on gelatin (Gltn) and acrylic acid (AAc), biodegradable pH‐sensitive hydrogel was prepared using gamma radiation as super clean source for polymerization and crosslinking. Incorporation of PAAc in the prepared hydrogel was confirmed by Fourier transform infrared spectroscopy (FTIR). The effect of PAAc content on the morphological structure of the prepared hydrogel swollen at pH 1, 5, and 7 was examined using scanning electron microscopy (SEM). The results showed the dependence of the porous structure of the prepared hydrogels on AAc content and the pH of the swelling medium. Swelling properties of gelatin/acrylic acid copolymer hydrogels with different AAc contents were investigated at different pH values. Swelling data showed that the prepared hydrogels possessed pronounced pH sensitivity. In vitro release studies were performed to evaluate the hydrogel potential as drug carrier using ketoprofen as a model drug. Experimental data showed that the release profile depends on both hydrogel composition and pH of the releasing medium. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Ruthenium(II)‐Catalyzed Protocol for Preparation of Diverse α,β‐ and β,β‐Dihaloenones from Diazodicarbonyls

Efficient one‐step syntheses of α,β‐ and β,β‐dihaloenones were achieved by ruthenium(II)‐catalyzed reactions between cyclic or acyclic diazodicarbonyl compounds and oxalyl chloride or oxalyl bromide in moderate to good yields. This methodology offers several significant advantages, which include ease of handling, mild reaction conditions, one‐step reaction, and the use of an effective and non‐toxic catalyst. The synthesized compounds were further transformed into highly functionalized novel molecules bearing aromatic rings on the enone moiety using the Suzuki reaction.

     

Chemical Synthesis of Rare Natural Bile Acids: 11α‐Hydroxy Derivatives of Lithocholic and Chenodeoxycholic Acids

A method for the preparation of 11α‐hydroxy derivatives of lithocholic and chenodeoxycholic acids, recently discovered to be natural bile acids, is described. The principal reactions involved were (1) elimination of the 12α‐mesyloxy group of the methyl esters of 3α‐acetate‐12α‐mesylate and 3α,7α‐diacetate‐12α‐mesylate derivatives of deoxycholic acid and cholic acid with potassium acetate/hexamethylphosphoramide; (2) simultaneous reduction/hydrolysis of the resulting △¹¹‐3α‐acetoxy and △¹¹‐3α,7α‐diacetoxy methyl esters with lithium aluminum hydride; (3) stereoselective 11α‐hydroxylation of the △¹¹‐3α,24‐diol and △¹¹‐3α,7α,24‐triol intermediates with B₂H₆/tetrahydrofuran (THF); and (4) selective oxidation at C‐24 of the resulting 3α,11α,24‐triol and 3α,7α,11α,24‐tetrol to the corresponding C‐24 carboxylic acids with NaClO₂ catalyzed by 2,2,6,6‐tetramethylpiperidine 1‐oxyl free radical (TEMPO) and NaClO. In summary, 3α,11α‐dihydroxy‐5β‐cholan‐24‐oic acid and 3α,7α,11α‐trihydroxy‐5β‐cholan‐24‐oic acid have been synthesized and their nuclear magnetic resonance (NMR) spectra characterized. These compounds are now available as reference standards to be used in biliary bile acid analysis.     

Bis(3,5‐dimethylphenyl)‐(S)‐pyrrolidin‐2‐ylmethanol: an Improved Organocatalyst for the Asymmetric Epoxidation of α,β‐Enones

The asymmetric epoxidation of α,β‐enones by the readily available bis(3,5‐dimethylphenyl)‐(S)‐pyrrolidin‐2‐ylmethanol and tert‐butyl hydroperoxide (TBHP) is described. Stereoelectronic substitution on the aryl moiety of diaryl‐2‐pyrrolidinemethanols was found to significantly affect the efficiency with respect to the previously reported (S)‐diphenyl‐2‐pyrrolidinemethanol. Improved reactivity and enantioselectivity were achieved with bis(3,5‐dimethylphenyl)‐(S)‐pyrrolidin‐2‐ylmethanol at reduced catalyst loading (20 mol %) with ees up to 94% for chalcone epoxides under mild reaction conditions, whereas (S)‐diphenyl‐2‐pyrrolidinemethanol afforded a maximum ee of 80%. Interestingly, the methodology is applicable to the epoxidation of more challenging aliphatic or enolizable enones with good control of the asymmetric induction (up to 87% ee).