Functional monomers and polymers, 54. Synthesis of poly-β-alanine from β-alanine 4-acyl-2-nitrophenyl esters

A series of active β-alanine 4-acyl-2-nitrophenyl esters with different lengths of alkyl groups was prepared, and their polycondensation was studied in various solvents. The results of the polycondensation of these esters with triethylamine at room temperature show that the conversion and the degree of polycondensation of the resulting poly(β-alanine)s depend on the chain length of the alkyl groups. No polymer was obtained in both protic and dipolar aprotic solvents such as methanol and DMSO, whereas nonpolar solvents such as diethyl ether, carbon tetrachloride, or benzene were found to be suitable for the polycondensation. The effect of a variety of amines on the polycondensation was examined for β-alanine 4-dodecanoyl-2-nitrophenyl ester ( 4e ) in diethyl ether solution.     

Structure formation and hydrogen bonding in all-aliphatic segmented copolymers with uniform hard segments

Fully aliphatic segmented poly(ether ester amide) copolymers with uniform hard segments prepared by melt polycondensation of α,ω-hydroxyl end-functionalized polytetrahydrofuran and short glycine or β-alanine bisester–bisoxalamide units hold promise for biomedical applications. For polymers with the hard block contents varying from 10% to 27%, differential scanning calorimetry and atomic force microscopy reveal a highly phase-separated morphology, with ribbon-like nanocrystals dispersed in the soft segment matrix. To relate the polymer properties to the structure of the hard segment, the monomers were prepared and studied by optical and X-ray diffraction measurements. It was shown that the glycine and β-alanine carbonyl ester groups are tilted away from the oxalamide plane, which can affect the degradation rate via hydrolysis of the ester bond.     

Preparation and crystalline structure of random copolymers of glycine and β-alanine

Copolymers of glycine and β-alanine within a range of amount-of-substance compositions from 3:1 to 1:9 were prepared by polycondensation of mixtures of the respective pentachlorophenyl ester hydrobromides. Number-average molecular weights between 2 500 and 9 000 were obtained, the lower values corresponding to those copolymers with a higher content in glycine. Sequence distributions were evaluated by means of 50,3 MHz ¹³C NMR spectroscopy and the crystalline structure was examined by wide-angle X-ray diffraction. Random copolymers having similar contents in glycine and β-alanine were found to crystallize in a bidimensional hexagonal lattice (a = 4,79 Å) with chains packed in a similar manner as they do in the crystalline structure of polyglycine II. On the contrary, a heterogeneous product consisting of homopolymer and random copolymer fractions results from mixtures which are enriched in one of the two amino acids. The random copolymer poly(glycine-ran-β-alanine) adopts a packing scheme similar to that found for the helical form of the alternating copolymer nylon 2/3. Chains are hexagonally arranged and interlinked by a three-dimensional network of hydrogen bonds as described for the well known model of polyglycine II, although in the present case no order along the chain axis should be expected.     

Functional monomers and polymers, 69. Synthesis of poly(β-alanine) in the functional reversed micelle

The effects of temperature and solvents on the polycondensation of active β-alanine 4-acyl-2-nitrophenyl esters 1a–g , having alkyl groups with different chain lengths, were studied. Nonpolar solvents were found to be well suited for the polycondensation, which was inhibited by the presence of a small amount of methanol. The reaction was found to be affected also by the temperature, the optimum temperature being 25°C. The results can be explained by assuming an aggregation of the active esters. This was checked with the model compounds 3, 4a and 4b , which correspond to the (dehydrobrominated) active ester 1e . The apparent mean aggregation numbers of the model compounds were determined in cyclohexane and in methanol by an osmotic method. The results led to the suggestion that the aggregation plays an important role in the polycondensation.     

Studies on functional micelles, 6. Micellar effect in the preparation of poly(β-alanine) from thio-β-alanine S-alkyl esters

The S-dodecyl ( 1e ), S-decyl ( 1d ), and S-octyl esters of thio-β-alanine ( 1c ) were condensed in the presence of a base in aqueous media to give poly(β-alanine) in yields of 44, 24, und 2%, respectively. The degrees of polycondensation of the obtained poly(β-alanine) were 13, 12, and 20, respectively. S-hexyl ester ( 1b ) and S-ethyl ester ( 1a ) gave no polymer. The process of this polycondensation reaction was explained by a proposed matrix reaction on the micelle surface.     

Functional monomers and polymers, 89. Synthesis of poly(β-alanine) in the functional reversed micelle

Active β-alanine 4-acyl-2-nitrophenyl esters ( 5a—j ) containing ω-phenyl- or ω-cyclohexyl acyl groups were prepared and their polycondensation was studied, which can take place in the reversed micelle to give poly(β-alanine). Non-polar solvents were suitable for the polycondensation, while no polymer was formed in protic and dipolar aprotic solvents. Esters having long linear acyl groups ( 5n—o ) were also reactive enough to give the polymer. However, the esters containing phenyl and cyclohexyl groups ( 5a—j ) were much more reactive and gave the polymer in high yield even if the linear acyl chain was only short.     

Heterochain polymers based on natural amino acids. Synthesis and enzymatic hydrolysis of regular poly(ester amide)s based on bis(L-phenylalanine) α,ω-alkylene diesters and adipic acid

Novel biodegradable regular poly(ester amide)s were synthesized by polycondensation of p-toluenesulfonic acid salts of bis(phenylalanine) α,ω-alkylene diesters ( 1 ) with bis(p-nitrophenyl) adipate under mild conditions in organic solvents in the presence of triethyl amine as acid acceptor. Enzymatic hydrolysis (α-chymotrypsinolysis) of the starting salts 1 , the model bis(ester acetamide)s 2 and the obtained poly(ester amide)s 3 was investigated at 37°C and pH 8 using potentiometric titration. It was established that the hydrolysis rate increased with elongation of the α,ω-alkylene chain. A strong noncovalent immobilization of the enzyme on the polymeric surface was observed.     

Activation of mouse peritoneal adherent cells with N-acyl muramyl dipeptide derivatives.

The effect of N-acyl derivatives of muramyl dipeptide (N-acetyl muramyl-L-alanyl-D-isoglutamine) on the activation of peritoneal adherent cells (PAC) in vivo and on the stimulation of nonspecific host resistance against Escherichia coli infection was examined in comparison with the effect of 6-O-stearoyl muramyl dipeptide. N-acyl muramyl dipeptide derivatives increased the release of hydrogen peroxide (H2O2) by PAC from mice treated 1 day before upon stimulation with phorbol myristate acetate, and their activities did not depend on the chain length or kinds of fatty acids introduced. The results obtained using N-stearoyl muramyl dipeptide analogs indicated that the acyl moiety combined to muramic acid played a more important role in the ability of PAC to release H2O2 than did the peptide moiety. PAC from mice treated with N-stearoyl muramyl dipeptide, N-(3-hydroxy-2-docosylhexacosanoyl) muramyl dipeptide, and 6-O-stearoyl muramyl dipeptide 1 day before, including 20 to 42% polymorphonuclear leukocytes, released large amount of H2O2, and most of the H2O2 released was due to the attribution of polymorphonuclear leukocytes. The cytostatic activity of PAC from mice treated with these three compounds reached a maximum on day 3 after injection, and the cytolytic activity of PAC was induced by N-stearoyl muramyl dipeptide on day 3 and by 6-O-stearoyl muramyl dipeptide on day 1 after injection. In contrast to the above results, N-acyl muramyl dipeptide derivatives did not stimulate nonspecific host resistance against E. coli infection in mice when compared to 6-O-stearoyl muramyl dipeptide.     

Amino acid based bioanalogous polymers. Novel regular poly(ester urethane)s and poly(ester urea)s based on bis(L-phenylalanine) α,ω-alkylene diesters

Novel biodegradable regular poly(ester urethane)s 2 (η_red ≤ 0,62 dL/g) were synthesized for the first time by polycondensation of di-p-toluenesulfonic acid salts of bis(phenylalanine) α,ω-alkylene diesters 1 with di-p-nitrophenyl trimethylenedicarbonate (4) under mild conditions in organic solvents in the presence of triethylamine as acid acceptor. The first synthesis of homopoly(ester urea)s 3 (η_red ≤ 0,33 dL/g) was carried out by polycondensation of 1 with di-p-nitrophenyl carbonate (5) under the same conditions. Preliminary in vitro evaluation of specific and nonspecific hydrolysis of the polymers obtained has been brought about using potentiometric titration.     

Synthesis and conformational study of poly(ε-N-benzyloxycarbonyl-L-lysyl-L-valyl-ε-N-benzyloxycarbonyl-L-lysine) in the solid state and in solution

Poly(ε-N-benzyloxycarbonyl-L -lysyl-L -valyl-ε-N-benzyloxycarbonyl-L -lysine) ( 6 ) was synthesized via the p-nitrophenyl active ester method. The dipeptide and the active ester of the tripeptide were obtained by using tert-butoxycarbonyl-N-ε-benzyloxycarbonyl-L -lysine succinimido ester and dicyclohexylcarbodiimide as condensing agents, respectively. Polymer 6 was investigated in the solid state by IR and X-ray diffraction measurements and in trifluoroethanol solution by UV, CD, and IR spectroscopy. The results obtained in the solid state indicate the occurrence of the β-conformation and some other unidentified conformation. No useful information was obtained from the study of the trifluoroethanol solution of 6 . Once more it was found that the introduction of valyl residues in a chain, containing residues which are α-helix formers, seems to favour the β-structure.     

Functional monomers and polymers, 62. Synthesis of polypeptides from dipeptide 4-acyl-2-nitrophenyl esters

A series of active glycylglycine 4-acyl-2-nitrophenyl esters having different chain length of the acyl groups (that is, 4-acetyl-, 4-hexanoyl-, and 4-dodecanoyl-2-nitrophenyl esters) was prepared, and their polycondensation was studied in various solvents at 30°C. In general, the yield of the polycondensates was high in nonpolar solvents, while the reaction in polar solvents was accompanied by formation of the cyclodimeric product. D ,L -Alanyl-D ,L -alanine, glycyl-D ,L -alanine and D,L-alanylglycine 4-dodecanoyl-2-nitrophenyl esters were also prepared and their polycondensation was tried.     

Synthesis and Characterization of Poly(glycolic acid‐alt‐6‐aminohexanoic acid) and Poly(glycolic acid‐alt‐11‐aminoundecanoic acid)

Summary: Poly(ester amide)s derived from glycolic acid and ω‐amino acid units, such as aminohexanoic or aminoundecanoic acids, are synthesized by a thermal polycondensation reaction that involves the formation of metal halide salts. Polymerization kinetics of different metal salts are studied by isothermal and nonisothermal methods and the corresponding parameters compared. The condensation reaction begins in the solid state for the aminohexanoic derivatives, although a rapid liquefaction is observed. On the other hand, the melting temperatures of the sodium and the potassium chloroacetylaminoundecanoate salts are lower than the reaction temperatures, and consequently polycondensation proceeds fully in the liquefied state. These polymers are characterized by an alternate disposition of ester and amide groups and can be obtained with high molecular weights and short polymerization times. Thermal properties (glass transition and melting temperatures) of the two new polymers are determined and compared. Thermal stability is also investigated; the results indicated that decomposition temperatures were always far from both reaction and polymer fusion temperatures.

DSC heating scans performed at different rates for potassium chloroacetylaminoundecanote.     

Polypeptides containing adenine and uracil residues

Amino acids containing uracil, adenine and imidazole residues were prepared and polymerized by reacting with phosgene in ethylene carbonate. The polymers did not have a simple polypeptidic structure but were soluble in aqueous dimethylformamide and interacted with complementary polynucleotides. Alternative polymerization of amino acids by N,N′-carbonyldiimidazole in aqueous neutral buffers proceeded with very low conversion but pure polypeptides resulted from the reaction. The following amino acids were prepared: β-adenin-9-yl-α-alanine ( 1a ), N-methyl-β-(adenin-9-yl)-α-alanine ( 1b ), β-(uracil-1-yl)-α-alanine, ( 2a ), N-methyl-β-(uracil-1-yl)-α-alanine ( 2b ), β-(5,6-trimethyleneuracil-1-yl)-α-alanine ( 3 ), and β-(imidazol-1-yl)-α-alanine.     

Synthesis and enzymatic degradation of poly(ester-amide) stereocopolymers derived from alanine

Poly(ester-amide)s with L -alanine contents of 100 (LalaS-100), 90, 80, 70, 50, 30 and 0 were prepared by interfacial polycondensation of the mixture of 1,6-hexanediol diester of L - and D -alanine with sebacoyl chloride. The enzymatic degradation of the poly(ester-amide)s was followed by the weight loss in a buffer solution (pH 7.2) of proteolytic enzymes (proteinase-K, papain and α-chymotrypsin) and lipase enzymes (R. delemar, P. cepacia and C. rugosa) at 37°C. The former enzymes degrade LalaS-100 much faster than the latter. Above all proteinase-K degrades it most rapidly and the weight loss is about 78% after 8 h of incubation. It was found that the degradation with the proteolytic enzymes is not caused by hydrolysis of the semi-peptide linkage but of the ester linkage. The effect of the stereochemical composition on the enzymatic degradation was examined using proteinase-K and papain, which degrades LalaS-100 (100% L ) as opposed to LalaS-0 (100% D ). In contrast, the highest rate of degradation was observed for LalaS-90.     

Synthesis and rheological study of some maleic acid and fumaric acid stereoregular polyesters, 4. Synthesis of random,multi-block and alternating unsaturated copolyesters from fumaric,maleic and phthalic acid potassium salts and 1,4-dibromobutane

The reaction of dicarboxylic acid potassium salts with dibromo derivatives in 1-methyl-2-pyrrolidone at moderate temperature was applied to the synthesis of high-molecular-weight co- and terpolyesters containing fumaric, maleic, phthalic and succinic ester residues and tetramethylene groups. Co- and terpolyesters with a random structure were obtained from the reaction of binary or ternary mixtures of salts with 1,4-dibromobutane. While the composition in ester residues of the organic phase varies continuously during the first 6 h of the polycondensation reaction, that of the copolyesters obtained after 24 h is determined by the composition of the initial mixture of salts. The relative amounts of cyclic n-mers produced in the course of the reaction and those of the different possible dimers were evaluated from GPC analyses of the reaction products. Multi-block copolyesters were prepared either by the reaction of a potassium salt with a mixture of 1,4-dibromobutane and a low-molecular-weight α-ω-dibromopolyester or by the coupling reaction of two low-molecular-weight α,ω-dibromopolyesters with succinic acid potassium salt. The reaction of bis(4-bromobutyl) phthalate and fumaric or maleic acid potassium salt produced the corresponding alternating copolyesters. Physico-chemical and compositional data of the prepared unsaturated copolyesters are given.     

Amino acid based bioanalogous polymers. Synthesis of novel poly(urethane amide)s based on N,N′-(trimethylenedioxydicarbonyl)bis(phenylalanine)

The feasibility of synthesizing high-molecular-weight amino acid based bioanalogous polymers (AABBPs)-poly(urethane amide)s (PUA) — via polycondensation (PC) of di-p-nitrophenyl ester of N,N′-(trimethylenedioxydicarbonyl)bis(L-phenylalanine) ( 3 ) with diamines or their derivatives under mild conditions in organic solvents was studied for the first time. A regular PUA (η_red = 1,53 dL/g) was obtained by PC of 3 with hexamethylenediamine. A dipeptide (Phe-Phe) containing regular poly(ester urethane amide) (η_red = 0,58 dL/g) was synthesized by PC of 3 with p-toluenesulfonic acid salt of bis(L-phenylalanine) 1,4-butylene diester. A tripeptide (Phe-Lys-Phe) containing PUA (η_red = 0,38 dL/g) with pendent ester groups was prepared via PC of 3 with N,N-bis(trimethylsilyl)-L-lysine methyl ester. These novel AABBPs which may be considered as structural analogs of AB type bioanalogous polymers — conventional poly(amino acids) are of interest in enzymology, immunology, pharmacology, and biotechnology (as materials for biomedical applications).     

Reactivities of substituted acyclic and cyclic enolethers in photoinduced cationic polymerization

The reactivities of different acyclic and cyclic enolethers in photoinduced cationic polymerization are investigated. While an β-methyl moiety leads to an increase of reactivity of the enolether in cationic polymerization, methyl substituents in β-positions decrease it. Two β-subtituents prevent homopolymerization completely. Ring strain in cyclic enolethers leads to a higher reactivity but is overruled by effects of sterical hindrance. It is shown that the type of photoinitiator affects the reaction rate of photoinduced cationic polymerization. In this respect different pyridinium salts were investigated. The difference in reactivities of these photoinitiators is due to the correspondence of their absorption spectrum with the emission spectrum of the source of UV irradiation used. Inefficient molar masses of polymers from β-substituted enolethers are explained by side reactions which can be suppressed by lowering the reaction temperature.     

Growth mechanism of crystals of glycine-L-alanine copolymer in the course of polymerization

In order to examine the growth mechanism of copolymer crystals formed during polymerization, the heterogeneous copolymerization of glycine N-carboxy anhydride (NCA) and L -alanine NCA has been studied in acetonitrile. In the polymerization systems with higher contents of glycine, the crystal growth occurs through formation of the cross-β type structure as proposed previously for poly(S-methyl-L -cysteine), giving rise to chain-folded crystals and rather high conversions. The high conversion is accounted for by the widening of the cross-section of the β-chains in the backbone crystal, due to the introduction of L -alanine residues into the polyglycine chain. Copolymerization at higher contents of L -alanine leads to conversions over 90% and extended chain crystals, due to the formation of α-helices on the ribbon-like crystals composed of the β-structure just as in the case of L -alanine NCA homopolymerization, indicating the occlusion of the glycine residues into the helices.     

Poly[(4‐hydroxybutyric acid)‐alt‐(glycolic acid)]: Synthesis by Thermal Polycondensation of Metal Salts of 4‐Chlorobutyric Acid Carboxymethyl Ester

Summary: A new sequential copolyester consisting of glycolic acid and 4‐hydroxybutyric acid units was prepared by a thermal polycondensation method that uses the formation of metal chloride salts as a driving force. The polymerization conditions (time, temperature) were studied in order to obtain appropriate molecular weights and high yields. Thermal properties and thermal stability were also determined. The polymerization kinetics of sodium, potassium and cesium monomer derivatives were studied by differential scanning calorimetry and the results compared. Non‐isothermal data and an isoconversional procedure (free model) were applied to determine the Arrhenius parameters (activation energy and pre‐exponential factor). The kinetic model was selected according to both the Coats‐Redfern method and the evaluation of isokinetic parameters.

DSC heating runs of sodium, potassium and cesium salts of 4‐chlorobutyric acid carboxymethyl ester after preheating at 100 °C.     

Polymerization of β-aminopropionitrile

The polymerization of β-aminopropionitrile (β-APN) was carried out by using basic catalysts such as sodium sec-butoxide in organic solvents and gave polyamidine which was converted to poly-β-alanine by hydrolysis. Poly-β-alanine was identified by IR and ¹H -NMR spectra and elemental analysis. The degree of polymerization was determined to 9,1 by vapor pressure osmometry. Free β-alanine was obtained by hydrolysis of the poly-β-alanine. From a kinetic study of this polymerization, it was found that the rate of polymerization was The polymerization mechanism of β-APN is discussed.