Alpha-hydroxy Esters Research Articles

Bioinspired growth of crystalline carbonate apatite on biodegradable polymer substrata.

Mineralization in biological systems is a widespread, yet incompletely understood phenomenon involving complex interactions at the biomacromolecule-mineral nucleus interface. This study was aimed at understanding and controlling mineral formation in a poly(alpha-hydroxy ester) model system, to gain insight into biological mineralization processes and to develop biomaterials for orthopaedic tissue regeneration. We specifically hypothesized that providing a high surface density of anionic functional groups would enhance nucleation and growth of bonelike mineral following exposure to simulated body fluids (SBF). Polymer surface functionalization was achieved via hydrolysis of 85:15 poly(lactide-co-glycolide) (PLG) films. This treatment led to an increase in surface carboxylic acid and hydroxyl groups, resulting in a substantial increase in polymer surface energy from 42 to 49 dynes/cm2. Treated polymers exhibited a 3-fold increase in heterogeneous mineral grown and growth of a continuous mineral film on the polymer surface. The mineral grown on PLG surfaces is a carbonate apatite, the major mineral component of vertebrate bone tissue. Mineral crystal size and morphology were dependent on the solution characteristics but unaffected by the degree of surface prehydrolysis. The mechanism of heterogeneous carbonate apatite growth was examined via ion binding assays, which indicated that calcium binding is mediated independently by the presence of soluble phosphate counterions and surface functional groups. These findings indicate that poly(alpha-hydroxy ester) materials can be readily mineralized using a biomimetic process, and that the impetus for mineral nucleation in this system appears more complicated than the simple electrostatic interactions proposed in previous biomineralization theory.

Peptide acylation by poly(alpha-hydroxy esters).

Poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) microspheres were investigated concerning the possible acylation of incorporated peptides. Atrial natriuretic peptide (ANP) and salmon calcitonin (sCT) were encapsulated into PLA and PLGA microspheres. Peptide integrity was monitored by HPLC-MS analysis during microsphere degradation for four weeks. sCT fragmentation with endoproteinase Glu-C was used for identifying modified amino acids. Peptide stability in lactic acid solutions was investigated to elucidate possible mechanisms for preventing peptide acylation. Both peptides were acylated by lactic and glycolic acid units inside degrading microspheres in a time-dependent manner. After 21 days, 60% ANP and 7% sCT inside PLA microspheres were acylated. Fragmentation of sCT with endoproteinase Glu-C revealed that besides the N-terminal amine group, lysine, tyrosine or serine are further possible targets to acylation. Stability studies of the peptides in lactic acid solutions suggest that oligomers are the major acylation source and that lower oligomer concentration and higher pH substantially decreased the reaction velocity. The use of PLA and PLGA for drug delivery needs substantially more circumspection. As, according to FDA standards. the potential hazards of peptide acylation products need to be assessed, our findings may have significant implications for products already on the market. Techniques to minimize the acylation reaction are suggested.

Chain extension of sugar delta-lactones with the enolate of tert-butyl bromoacetate and elaboration into functionalized C-ketosides, C-glycosides, and C-glucosyl glycines.

[structure: see text] We describe the synthesis of a series of exocyclic sugar epoxides 1 prepared in a one-step procedure from sugar delta-lactones with the enolate of tert-butyl bromoacetate. Ring opening of the sugar oxiranes provides C-ketosides while reduction affords functionalized C-glycosides bearing an alpha-hydroxy ester moiety. The alpha-hydroxy ester can be converted into C-glucosyl glycine analogues 2.

Chiral recognition by CD-sensitive dimeric zinc porphyrin host. 1. Chiroptical protocol for absolute configurational assignments of monoalcohols and primary monoamines.

A general microscale protocol for the determination of absolute configurations of primary amino groups or secondary hydroxyl groups linked to a single stereogenic center is described. The chiral substrates are linked to the achiral trifunctional bidentate carrier molecule (3-aminopropylamino)acetic acid (1, H(2)NCH(2)CH(2)CH(2)NHCH(2)COOH) and the resultant conjugates are then complexed with dimeric zinc porphyrin host 2 giving rise to 1:1 host/guest sandwiched complexes. These complexes exhibit exciton-coupled bisignate CD spectra due to stereodifferentiation leading to preferred porphyrin helicity. Since the chiral sense of twist between the two porphyrins in the complex is dictated by the stereogenic center of the substrate, the sign of the couplet determines the absolute configuration at this center. The twist of the porphyrin tweezer in the complex can be predicted from the relative steric sizes of the groups flanking the stereogenic center, such that the bulkier group protrudes from the complex sandwich. In certain alpha-hydroxy esters and alpha-amino esters, electronic factors and hydrogen bonding govern the preferred conformation of the complex, and hence the CD spectra.

Chiral Palladium(II)-catalyzed asymmetric glyoxylate-Ene reaction: alternative approach to the enantioselective synthesis of alpha-hydroxy esters

An effective chiral palladium catalyst [Pd(CH(3)CN)(2)(S)-Tol-BINAP](SbF(6))(2) (2b) is developed for asymmetric glyoxylate-ene reactions. This palladium dicationic catalyst provides a simple but efficient approach to the asymmetric synthesis of alpha-hydroxy esters in excellent yields with high enantioselectivities at relatively higher reaction temperature (60 degrees C).

Oxidation of methyl trimethylsilyl ketene acetals to alpha-hydroxyesters with urea hydrogen peroxide catalyzed by methyltrioxorhenium

In the presence of catalytic amounts of MTO, methyltrioxorhenium, methyl trimethylsilyl ketene acetals are oxidized with urea hydrogen peroxide to afford alpha-hydroxy and alpha-siloxy esters. On treatment with potassium fluoride, the alpha-hydroxy esters are obtained in high yields.

Dynamic kinetic resolution of alpha-hydroxy acid esters

[formula: see text] Enzymatic resolution in combination with ruthenium-catalyzed racemization of the substrate led to dynamic kinetic resolution of alpha-hydroxy esters in good yields and excellent ee's. Studies of different parameters showed that the best results were obtained using Pseudomonas cepacia lipase, ruthenium catalyst 3, and 4-chlorophenyl acetate as acyl donor in cyclohexane.

Osteoblast migration on poly(α-hydroxy esters)

We investigated the migration of rat calvaria osteoblast populations on poly(alpha-hydroxy ester) films for up to 14 days to determine effects of substrate composition and culture conditions on the migratory characteristics of osteoblasts. Initial osteoblast culture conditions included cell colonies formed by seeding a high (84,000 cells/cm(2)) or low (42,000 cells/cm(2)) density of isolated osteoblasts on the polymer films, and bone tissue cultures formed by plating bone chips directly on the substrates. High density osteoblast colonies cultured and allowed to migrate and proliferate radially on 85:15 poly(DL-lactic-co-glycolic acid) (PLGA) films, 75:25 PLGA films, and tissue culture polystyrene controls demonstrated that the copolymer ratio in the polymer films did not affect the rate of increase in substrate surface area (or culture area) covered by the growing cell colony. However, the rate of increase in culture area was dependent on the initial osteoblast seeding density. Initial cell colonies formed with a lower osteoblast seeding density on 75:25 PLGA resulted in a lower rate of increase in culture area, specifically 4.9 +/- 0.3 mm(2)/day, versus 14.1 +/- 0.7 mm(2)/day for colonies seeded with a higher density of cells on the same polymer films. The proliferation rate for osteoblasts in the high and low density seeded osteoblast colonies did not differ, whereas the proliferation rate for the osteoblasts arising from the bone chips was lower than either of these isolated cell colonies. Confocal and light microscopy revealed that the osteoblast migration occurred as a monolayer of individual osteoblasts and not a calcified tissue front. These results demonstrated that cell seeding conditions strongly affect the rates of osteoblast migration and proliferation on biodegradable poly(alpha-hydroxy esters). (c) 1996 John Wiley & Sons, Inc.

Enhanced selectivities for the hydroxyl-directed methanolysis of esters using the 2-acyl-4-aminopyridine class of acyl transfer catalysts: ketones as binding sites.

In this paper we describe the preparation of a series of 2-acyl-4-aminopyridines, and their use as catalysts for the hydroxyl-directed methanolysis of alpha-hydroxy esters in preference to alpha-methoxy esters. Hydroxyl-direction with these catalysts, which contain ketones at the 2-position of the pyridine, is achieved by reversible addition of the alcohol of the hydroxy ester to the ketone to provide the corresponding hemiketal. Their activity is compared to that of the previously described catalyst 2-formyl-4-pyrrolidinopyridine (FPP), which contains an aldehyde at the 2-position of the pyridine. The catalysts which contain ketones at the 2-position range in reactivity from 10 times slower to slightly faster than FPP, and certain of these are much more selective for the methanolysis of hydroxy esters than FPP. This increase in selectivity is ascribed to a decrease in the rate of the nondirected methanolysis reaction with the ketone-derived catalysts. The evidence suggests that the nondirected reaction does not proceed by an intermolecular general base mechanism, but rather via a nucleophilic catalysis mechanism in which the hydroxyl group of the hemiacetal formed upon addition of methanol to the aldehyde of FPP acts as the nucleophile. Since the hydroxyl group derived from a hemiketal is more hindered and less nucleophilic than that derived from a hemiacetal, the nondirected reaction is much slower for the catalysts containing ketones as binding sites.

Polymer-supported silyl cyanide and silyl azide: Useful reagents for solid-phase applications

The support of a delicate reagent on a solid matrix allows for better and safer handling of the reagent itself. Because we had an interest in silicon-based supported reagents(1) we turned our attention to a polymer-supported trialkylsilyl cyanide and trialkylsilyl azide starting from a commercially available trialkylsilane resin. The supported cyanide was obtained with excellent yield and proved to be shelf-stable. This supported reagent was reacted with a series of aldehydes and ketones yielding the corresponding polymer-supported cyanohydrins in good-to-excellent yields. A stability study on a model cyanohydrin demonstrated that these supported intermediates also can be stored for a prolonged time. For the last step, a cleavage strategy that could release either cyanohydrins or alpha-hydroxy esters was adopted. Finally, we prepared a polymer-supported trialkylsilyl azide, which also proved to be shelf-stable.

Synthetic biodegradable polymers for orthopaedic applications.

Synthetic biodegradable polymers offer an alternative to the use of autografts, allografts, and nondegradable materials for bone replacement. They can be synthesized with tailored mechanical and degradative properties. They also can be processed to porous scaffolds with desired pore morphologic features conducive to tissue ingrowth. Moreover, functionalized polymers can modulate cellular function and induce tissue ingrowth. This review focuses on four classes of polymers that hold promise for orthopaedic applications: poly alpha-hydroxy esters, polyphosphazenes, polyanhydrides, and polypropylene fumarate crosslinked networks.

Studies on the Mechanism of Action of 2-Formyl-4-pyrrolidinopyridine: Isolation and Characterization of a Reactive Intermediate.

This paper describes the mechanism of action of 2-formyl-4-pyrrolidinopyridine (FPP, 1a) which is a catalyst for the hydroxyl-directed methanolysis of alpha-hydroxy esters. This species was initially designed to act as a nucleophilic catalyst; however, we have ruled out a nucleophilic mechanism by examining the activity of 6-substituted-FPP derivatives. These compounds are more hindered in the vicinity of the pyridine nitrogen than FPP itself but are also more active catalysts. Furthermore, the presence of p-nitrophenol, a mild acid, was found to accelerate the catalytic reaction. These results are inconsistent with a nucleophilic catalysis mechanism. We provide evidence that the reaction instead proceeds via dioxolanone intermediate 10. Dioxolanone 10 can be obtained by treating either the p-nitrophenyl ester or the pentafluorophenyl ester of glycolic acid with FPP in chloroform in the absence of methanol. It has been isolated, characterized, and shown to be kinetically competent when subjected to the conditions of the catalytic reaction.

Osteoblast function on synthetic biodegradable polymers.

Rat osteoblasts were cultured on films of biodegradable poly(L-lactic acid) (PLLA), 75:25 poly(DL-lactic-co-glycolic acid) (PLGA), 50:50 PLGA, and poly(glycolic acid) (PGA) for up to 14 days. Osteoblasts attached equally well to all the polymer substrates after 8 h in culture. By day 4 in culture, osteoblasts had exceeded confluency numbers, and their proliferation leveled off by day 7. An increase in alkaline phosphatase (ALP) activity from 1.92 (+/- 0.47) x 10(-7) for day 7 to 5.75 (+/- 0.12) x 10(-7) mumol/cell per min for day 14 was reported for osteoblasts cultured on 75:25 PLGA, which was comparable to that observed for tissue culture polystyrene (TCPS) controls. The ALP activities expressed by osteoblasts cultured on PLLA, 50:50 PLGA, and PGA films did not significantly increase over time. Collagen synthesis for osteoblasts cultured on all polymer substrates was similar to that of TCPS and did not vary with time. The morphology of cultured osteoblasts was not affected by the continuous degradation of the polymer substrates. These results demonstrate that poly(alpha-hydroxy esters) can provide a suitable substrate for osteoblast culture and hold promise in bone regeneration by osteoblast transplantation.

Analysis of conjugated bile acids in human biological fluids. Synthesis of hyodeoxycholic acid 3- and 6-glycosides and related compounds.

The glucuronide, glucoside and N-acetylglucosaminide conjugates of hyodeoxycholic acid were synthesized. In addition, murideoxycholic acid 3-glycosides and some of their C-5 epimeric analogs were also prepared. The principal reactions used are 1) the Koenigs-Knorr condensation reaction of 3-oxo-6 alpha-hydroxy and 6-oxo-3 alpha-hydroxy esters with an appropriate alpha-acetohalosugar catalyzed by cadmium carbonate in benzene under reflux, 2) reduction of the resulting bile acid glycoside methyl ester-acetates with tert-butylamine-borane complex, and 3) subsequent hydrolysis with aqueous lithium hydroxide.

Mixed metal vinyl stabilizer synergism. V: Dehydrochlorinations reactions of model compounds

AbstractThe capture of HCl from cumyl chloride, a model compound for degrading PVC, by epoxidized soybean oil, yielding the related chlorohydrin, is relatively inefficient. The reaction is much accelerated by the presence of metal salts that are primary stabilizers, in particular by zinc carboxylates. In such instances, the initial reaction product is not the chlorohydrin, but the corresponding alphahydroxy ester and metal chloride. Such metal salts, however, also strongly catalyze the rate of loss of HCl from the model compound. Mixed metal blends are found to accelerate the reaction of liberated HCl with epoxy compounds with, on the other hand, only slight catalysis of the dehydrochlorination reaction, and with formation of the secondary metal chloride.

Isolation and identification of cerebrosides from the marine sponge Chondrilla nucula

A cerebroside mixture has been isolated from the marine sponge Chondrilla nucula. Acid-catalyzed methanolysis of this cerebroside mixture afforded methyl glucosides, three long-chain bases, and a mixture of alpha-hydroxy fatty acid methyl esters. The bases were identified as saturated C(17), C(18), and C(19) trihydroxy bases (1,3,4-trihydroxy-2-aminoalkanes) by gas-liquid chromatographic-mass spectrometric analysis of their corresponding trimethylsilyl derivatives. The methyl ester fraction consisted of a mixture of homologous C(16) to C(26) saturated straight-chain alpha-hydroxy esters plus a trace of saturated C(25) iso alpha-hydroxy ester.