Acylation nucleic acids

This is a sedative drug with low adult toxicity, which proved to be a very potent human teratogen, causing phocomelia (shortening of the limbs) and other defects when taken between the third and eighth week. In some cases, only a few doses were taken, but on the critical days (e.g., days 24-27 for phocomelia of arms). It is not readily reproducible in laboratory animals (e.g., rats). Mechanism is unknown, but a metabolite suspected, possibly produced by cytochrome P-450. A number of metabolites are produced and some chemical breakdown occurs. Phthalylglutamic acid metabolite is teratogenic in mice. Thalidomide may acylate nucleic acids and polyamines. The S-enantiomer is more embryotoxic than the R-enantiomer. 

Amides, like esters, are abundant in all living organisms—proteins, nucleic acids, and many pharmaceuticals have amide functional groups. The reason for this abundance of amides, of course, is that they are stable to the conditions found in living organisms. Amides are the least reactive of the common acid derivatives and undergo relatively few nucleophilic acyl substitution reactions. 

A combinatorial approach for biocatalytic production of polyesters was demonstrated. A library of polyesters were synthesized in 96 deep-well plates from a combination of divinyl esters and glycols with lipases of different origin. In this screening, lipase CA was confirmed to be the most active biocatalyst for the polyester production. As acyl acceptor, 2,2,2-trifluoroethyl esters and vinyl esters were examined and the former produced the polymer of higher molecular weight. Various monomers such as carbohydrates, nucleic acids, and a natural steroid diol were used as acyl acceptor. 

Potentially tautomeric pyrimidines and purines are /V-alkylated under two-phase conditions, using tetra-n-butylammonium bromide or Aliquat as the catalyst [75-77], Alkylation of, for example, uracil, thiamine, and cytosine yield the 1-mono-and 1,3-dialkylated derivatives [77-81]. Theobromine and other xanthines are alkylated at N1 and/or at N3, but adenine is preferentially alkylated at N9 (70-80%), with smaller amounts of the N3-alkylated derivative (20-25%), under the basic two-phase conditions [76]. These observations should be compared with the preferential alkylation at N3 under neutral conditions. The procedure is of importance in the derivatization of nucleic acids and it has been developed for the /V-alkylation of nucleosides and nucleotides using haloalkanes or trialkyl phosphates in the presence of tetra-n-butylammonium fluoride [80], Under analogous conditions, pyrimidine nucleosides are O-acylated [79]. The catalysed alkylation reactions have been extended to the glycosidation of pyrrolo[2,3-r/]pyrimidines, pyrrolo[3,2-c]pyridines, and pyrazolo[3,4-r/]pyrimidines (e.g. Scheme 5.20) [e.g. 82-88] as a route to potentially biologically active azapurine analogues. 

Many examples of catalytic nucleic acids obtained by in vitro selection demonstrate that reactions catalyzed by ribozymes are not restricted to phosphodiester chemistry. Some of these ribozymes have activities that are highly relevant for theories of the origin of life. Hager et al. have outlined five roles for RNA to be verified experimentally to show that this transition could have occurred during evolution [127]. Four of these RNA functionalities have already been proven Its ability to specifically complex amino acids [128-132], its ability to catalyze RNA aminoacylation [106, 123, 133], acyl-transfer reactions [76, 86], amide-bond formation [76,77], and peptidyl transfer [65,66]. The remaining reaction, amino acid activation has not been demonstrated so far. 

N,0-Acyltransferase. The /V-acyl transferase enzyme is believed to be involved in the carcinogenicity of arylamines. These compounds are first V-oxidized, and then, in species capable of their A-acetylation, acetylated to arylhydroxamic acids. The effect of N, O-transacetylation is shown in Figure 7.22. The A/-acyl group of the hydroxamic acid is first removed and is then transferred, either to an amine to yield a stable amide or to the oxygen of the hydroxylamine to yield a reactive N-acyloxyarylaminc. These compounds are highly reactive in the formation of adducts with both proteins and nucleic acids, and N, O -acy I Iransfcrasc, added to the medium in the Ames test, increases the mutagenicity of compounds such as A-hydroxy-2-acetylaminofluorine. 

Another group of cyclene-based molecules interacting with nucleic acids was described by us. [12] In this case, cyclene nitrogen atoms were substituted with carbamoyl groups which irreversibly reduced the basicity and binding abilities but were useful for the synthesis of more complex molecules (Scheme 14). Simple carbamoyl-substituted cyclenes were obtained by standard protection - acylation - deprotection... 

Finally, novel nucleic acid catalysts have also been selected from random sequence pools (reviewed in Ref. 19). Joyce and co-workers have manipulated the function of the Group I self-splicing ribozyme, selecting variants that can utilize calcium or cleave DNA from partially randomized pools [20,21], Lorsch and Szostak [22] selected a polynucleotide kinase ribozyme from a completely random sequence pool that flanked a previously selected ATP binding site. Many of the novel ribozymes can catalyze reactions that are relevant to protein biosynthesis, bolstering arguments that translation may have arisen in a putative RNA world. For example, Lohse and Szostak [23] have selected ribozymes that can carry out an acyl transfer reaction, while Illangasekare et al. [24] have isolated a... 

Actually it is doubtful that the antiviral properties of polyanions are based only on the interferon induction (46), since several groups have also demonstrated other activities of polyanions. Thus, e.g. poly(vinylsulfonate) has been found to interact with nucleic acids, thus inhibiting their acylation or methylation (47). Tempel (48) has shown that in mice phosphatases can be activated with poly(vinylsulfonate). 

Parallel kinetic resolution (PKR), a concept that has been introduced for reactions where starting from a racemic mixture can allow the preparation of two different compounds at the same reaction rate [31], has been appHed for the separation of a mixture of P-D/L-deoxynucleosides. A practical synthesis of P-t-3 - and P-L-5 -0-levuHnyl-2 -deoxynucleosides has been described for the first time [32] through enzymatic acylation and/or hydrolysis processes. It is remarkable that the different behavior exhibited by PSL in the acylation of D- and L-nucleosides allows the parallel kinetic resolution of D/L nucleoside racemic mixtures. Scheme 10.12 shows a PKR of a 1 1 mixture of D and L nucleosides via an acylation reaction for furnishing easily separable compounds. This methodology would have tremendous potential for both research and industrial applications in the nucleic acid field. 

Figure 13.5. Stractme of mitotane, its acyl chloride conversion product formed by the enzyme cytochrome P450 1 IB (CYPl IB), and the reaction products of the latter with amino groups in proteins or nucleic acids. CYP1 IB occurs in the mitochondria within the adrenal cortex, rendering this tissne (and its derived tissues) selectively susceptible to mitotane.

Reactive sites of enzymes and nucleic acids in the zinc finger of the chromosome are better modeled if all of the atoms are considered because so many small interactions contribute to the overall behavior of these systems making it more essential to use all atom force fields. Unlike phospholipids in the membrane, phospholipids (as second messengers) in the cytosol may interact specifically with certain proteins and the exact nature of their acyl chain may play a role in those interactions, so it would be better modeled using that all atom force fields. 

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