Spacers, hydrolyzable

The mesogenic units with methylenic spacers were prepared by reacting the sodium salt of either 4-methoxy-4 -hydroxybiphenyl or 4-phenylphenol with a bromoester in DMF at 82° C for at least 4 hours in the presence of tetrabutylammonium hydrogen sulfate (TBAH) as phase transfer catalyst. In this way, ethyl 4-(4-oxybi-phenyl)butyrate, ethyl 4-(4-methoxy-4 -oxybiphenyl)butyrate, ethyl 4-(4-oxybiphenyl)valerate, ethyl 4-(4-methoxy-4 -oxybiphenyl)-valerate, n-propyl 4-(4-oxybiphenyl)undecanoate and n-propyl 4-(4-methoxy-4 -oxybiphenyl)undecanoate were obtained. These esters were hydrolyzed with base and acidified to obtain the carboxylic acids. The corresponding potassium carboxylates were obtained by reaction with approximately stoichiometric amounts of potassium hydroxide. Experimental details of these syntheses were described elsewhere (27). 

One of the most successful conjugate polymer systems was developed by Duncan and Kopecek (25). The polymer carrier used in their system is poly [N(2-hydroxypropyl) methacrylamide] a biocompatible polymer that was originally developed as a plasma extender. They have evaluated a number of polymer conjugated drugs for cancer chemotherapy with interesting results. The attachment of the drug is through a peptidyl spacer pendent to the polymer backbone. These peptides links are stable in aqueous media but are readily hydrolyzed intracellularly... 

A novel polymerized vesicular system for controlled release, which contains a cyclic a-alkoxyacrylate as the polymerizable group on the amphiphilic structure, has been developed. These lipids can be easily polymerized through a free radical process. It has been shown that polymerization improves the stabilities of the synthetic vesicles. In the aqueous system the cyclic acrylate group, which connects the polymerized chain and the amphiphilic structure, can be slowly hydrolyzed to separate the polymer chain and the vesicular system and generate a water-soluble biodegradable polymer. Furthermore, in order to retain the fluidity and to prepare the polymerized vesicles directly from prev lymerized lipids, a hydrophilic spacer has been introduced. 

If a NHS-PEG-maleimide compound is used for this type of activation and coupling, the intermediate maleimide-activated dendrimer should be quickly purified of excess crosslinker and reaction by-products and immediately used to couple ligand. This is due to the fact that the maleimide hydrolyzes in aqueous solution at a higher rate than an SMCC-type crosslinker, because of the extreme hydrophilicity of the PEG spacer arm compared to the cyclohexane spacer of SMCC. 

The synthesis of some multiblock copolymers was attempted by successive polymerization using this iniferter technique. However, pure tri- or tetrablock copolymers free from homopolymers were not isolated by solvent extraction because no suitable solvent was found for the separation. In 1963, Merrifield reported a brilliant solid-phase peptide synthesis using a reagent attached to the polymer support. If a similar idea can be applied to the iniferter technique, pure block copolymer could be synthesized by radical polymerization. The DC group attached to a polystyrene gel (PSG) through a hydrolyzable ester spacer was prepared and used as a PSG photoiniferter (Eq. 53) [186] ... 

In Czamik s model compound 6 both cobalt(III) ions are presented in the same molecule [33]. Two (cyclen)Co(IH) units are covalently linked by a 1,4-dibutylbenzene spacer. By 6 the activated phosphodiester BNPP at pH 7.0 and 25 °C is hydrolyzed 3.2 times faster than by 2 equiv of (cyclen)Co(III) (7) under the same conditions. A more than 107-fold rate enhancement over the spontaneous hydrolysis of BNPP is observed. The reaction mechanism may be similar to that proposed for compound 2. 

Route A utilizes Boc/Bzl chemistry for the synthesis of the main peptide with Fmoc/OFm at the side-chain functions where additional chemistry is performed. For synthesis of extended cyclic peptides, the /V "-Fmoc group is removed and the extension is synthesized with Fmoc/ Bzl chemistry, whereas for reverse-extended cyclic peptides, the to-Fm ester is hydrolyzed and the peptide spacer is built up in the N-to-C direction with fluorenylmethyl esters with all the risk of epimerization or more correctly, it is incorporated by fragment condensation. 

Fig. 26. The preparation of well-defined peptidic surfaces [65,66]. A Using a thiol spacer, homopolypeptides (poly-A in this case) that adopt an a-helical conformation are synthesized on a gold surface. B Using an aminopeptidase, the longer peptidic chains are hydrolyzed to yield a more homogeneous surface. (Reproduced with the permission of Ref. 65,66)...

Shinkai et al/73,74 have reported the construction of crowned arborols that incorporated diaza crown ethers as spacers, and three-directional, aromatic branching centers (Scheme 5.24). In this case, the convergent construction was found to be more effective than the divergent approach. Tetraoxadiazacrown monomer 93 was prepared from N-benzyloxycarbonyldiazacrown ether (94) and a monoacyl chloride 95, affording the diprotected intermediate 96, which was catalytically debenzylated (Pd/C, H2) to give diester 93 or hydrolyzed (aq.base) to afford diacid 97. Monomer 97 was then transformed to tetraester 98, by means of the mixed anhydride method, with two equivalents of the... 

Method D. The polysaccharide was hydrolyzed with acetic acid to fragments having between 5 and 15 repeating units. After purification, ethylendiamine reacts at the terminal reducing end introducing a terminal amino function. Similarly to method A, the reaction with ADH introduced a spacer having terminally a very reactive hydrazide function [104]. 

Figure 5 Starting from natural mRNA, a cDNA library (A blue) is produced and like ribosomal display, the cDNA is transcribed into mRNA (B) with no stop codons. The 3 -end of each mRNA molecule is ligated to a short synthetic DNA linker (C) and sometimes a polyethyleneglycol spacer, which terminates with a puramycin molecule (small red sphere). The ligation is stabilized by the addition of psoralen (green clamp), which is photoactivated to covalently join both strands. Addition of crude polysomes or purified ribosomes (D) results in translation of the mRNA into protein, but the ribosome stalls at the mRNA-DNA junction. Since there are no stop codons, release factors cannot function and instead the puromycin enters the A-site of the ribosome (A). Because puramycin is an analog of tyrosyl-tRNA, the peptidyl transferase subunit catalyzes amide bond formation between the puromycin amine and the peptide carboxyl terminus, but is unable to hydrolyze the amide link (which should be an ester in tyrosyl-tRNA) to release the dimethyladenosine. The ribosome is dissociated to release the mRNA-protein fusion (E), which is protected with complementary cDNA using RT-PCR (F). The mRNA library can then be selected against an immobilized natural product probe (G), nonbinding library members washed away and the bound mRNA (H) released with SDS. PCR amplification of the cDNA provides a sublibrary (A) for another round of selection or for analysis/ sequencing.

In contrast, only partial hydrolysis was observed under the same conditions for / ara-substituted prodrugs 94 and 96. The kinetics of hydrolysis of the para-fluoro substituted prodrug 95 was more favorable but, in that case, only a relatively slow self-elimination of the spacer was observed. From these data, it clearly appeared that ort/io-activated prodrugs 71, 72, and 73 were more conveniently hydrolyzed than their corresponding para-substituted isomers. 

Binuclear Zn complexes compared to mononuclear species were also shown to be more efficient by a factor of about 3 for hydrolyzing phosphate mono- and diesters (308). These complexes are based on dimers derived from 1,4,7-triazacyclododecane and 1,5,9-triazacyclo-tetradecane ligands (14 and 15, Fig. 16). A 10 rate enhancement over the noncatalyzed reaction was obtained. The distance between the metal binding sites influenced the reagent reactivity. Short spacers... 

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