Hydrolytically labile

In order to become useful dmg delivery devices, biodegradable polymers must be formable into desired shapes of appropriate size, have adequate dimensional stability and appropriate strength-loss characteristics, be completely biodegradable, and be sterilizahle (70). The polymers most often studied for biodegradable dmg delivery applications are carboxylic acid derivatives such as polyamides poly(a-hydroxy acids) such as poly(lactic acid) [26100-51-6] and poly(glycolic acid) [26124-68-5], cross-linked polyesters poly(orthoesters) poly anhydrides and poly(alkyl 2-cyanoacrylates). The relative stabiUty of hydrolytically labile linkages ia these polymers (70) is as follows ... 

Even though poly(ortho esters) contain hydrolytically labile Linkages, they are highly hydrophobic materiads and for this reason are very stable and can be stored without careful exclusion of moisture. However, the ortho ester linkage in the polymer is inherently thermally unstable and at elevated temperatures is believed to dissociate into an alcohol and a ketene acetal (33). A possible mechanism for the thermal degradation is shown below. This thermal degradation is similar to that observed with polyurethanes (34). 

Poly (iminocarbonates) are little known polymers that, in a formal sense, are derived from polycarbonates by the replacement of the carbonyl oxygen by an imino group (Fig. 5). This backbone modification dramatically increases the hydrolytic lability of the backbone, without appreciably affecting the physicomechanical properties of the polymer the mechanical strength and toughness of thin,... 

Synthesis and Characterization of Hydrolytically Labile Poly(phosphoester—urethanes)... 

The past two decades have produced a revival of interest in the synthesis of polyanhydrides for biomedical applications. These materials offer a unique combination of properties that includes hydrolytically labile backbone, hydrophobic bulk, and very flexible chemistry that can be combined with other functional groups to develop polymers with novel physical and chemical properties. This combination of properties leads to erosion kinetics that is primarily surface eroding and offers the potential to stabilize macromolecular drugs and extend release profiles from days to years. The microstructural characteristics and inhomogeneities of multi-component systems offer an additional dimension of drug release kinetics that can be exploited to tailor drug release profiles. 

Rosenthal, A.F., Vargas, L.A., Isaacson, Y.A., and Bittman, R., A simple synthesis of phosphonate-containing lipids. Introduction of the phosphonic acid moiety into hydrolytically labile compounds, Tetrahedron Lett., 977,1975. 

Convertible isocyanide reagent 66 allows a mild and chemoselective in situ post-Ugi activation of the isonitrile bom amide with simultaneous deprotection of the nucleophilic amine, that is, liberation and activation of two Ugi-reactive groups, if desired also under subsequent lactam formation [33]. Another recently introduced convertible isocyanide, l-isocyano-2-(2,2-dimethoxyethyl)-benzene 73, was shown effective by Rhoden et al. In the course of this short sequence, a hydrolytically labile W-acylindole 78 is formed, which is displaced intramolecularly by the amine portion of the former Boc-protected amino acid 75 (Scheme 13). 

The greater hydrolytic lability of O-formyl than of O-benzoyl groups has been used in the preparation of ribonucleoside 2 -acetal 5 -esters.153 Acid-catalyzed reaction between 5,6-dihydro-4-methoxy-2//-pyran and N2-benzoyl-5 -0-benzoyl-3 -0-formylguanosine, followed by selective deformylation of the product with dilute methano-lic ammonia, gave N2-benzoyl-5 -0-benzoyl-2 -0-(4-methoxytetrahy-dropyran-4-yl)guanosine. 

In the author s own laboratory the Cu(II)-catalyzed hydrolysis of the phosphate ester derived from 2-[4(5)-imidazolyl] phenol recently has been investigated146. The pertinent results are (a) the pre-equilibrium formation of a hydrolytically labile Cu(II)-substrate complex (1 1), (b) the occurrence of catalysis with the free-base form of the imidazolyl and phosphate moieties and (c) the extraordinary rate acceleration at pH 6 (104) relative to the uncatalyzed hydrolysis146. The latter recalls the unusual rate enhancement encountered above with five-membered cyclic phosphates and suggests a mechanism in which the metal ion, at the center of a square planar complex or a distorted tetrahedral complex, might induce strain in the P-O ester bonds (60). viz. 

The principle upon which this approach is based is an enzyme-substrate reaction that produces a change in pH and a hydrolytically labile, pH-sensitive polymer containing dispersed therapeutic agent that can vary the erosion rate and concomitant drug release in response to that pH change. Figure 1 shows two types of drug... 

Kirby (1983, pp. 91 94) has discussed possible ways of reconciling the hydrolytic lability of 1,3-dioxolanes with ALPH, and has come to the conclusion that whereas one anticlinal sp3 lone pair may not expel a leaving group, two might. This explanation of the ready opening of 1,3-dioxolanes cannot of course be applied to the opening of oxazolidines [14], where there is only one lone pair available. 

Brook, M.A., Balduzzi, S., Mohamed, M. and Gottardo, C. (1999) The photolytic and hydrolytic lability of sisyl (Si(SiMe3)3) ethers, an alcohol protecting group. Tetrahedron, 55, 10027—10040. 

Polyanhydrides Polyanhydrides have a hydrophobic backbone with a hydrolytically labile anhydride linkage. These polymers widely vary in chemical composition and include aliphatic, aromatic, and fatty acid-based polyanhydrides. The rate of degradation depends on the chemical composition of the polymer. In general, aliphatic polyanhydrides degrade more rapidly than the aromatic polymer. Hence, copolymer blends with varying ratios of aliphatic-to-aromatic polyanhydrides can be synthesized to suit specific applications. 

Trialkylsilyl protection of carboxylic acids and amines is rare owing to hydrolytic lability. Nevertheless, synthetically useful silicon protecting groups have been developed for these functional groups in which the requisite stability is achieved by incorporating the silicon atom into a 2-(trimethylsilyl)ethyl substituent. The principle is illustrated [Scheme 1.9] by the reaction of 2-(trimethylsilyl)ethyl esters with tetrabutylammonium fluoride the pentavalent siliconate intermediate fragments with loss of ethylene and fluorotrimethylsilane14-15 to liberate a carboxylic arid as its tetrabutylammonium salt. 

The three classes of relay deprotection strategies cited above are the most common but there are many other possibilities as in the rhodium(l)-catalysed isomerisation of a robust ally] ether to a hydrolytically labile enol ether discussed in section 1.2.11. 

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