Modification of the Sugar Moiety

Substitution at the 2 -position of the sugar moiety has become one of the most widely used modifications. Above all, 2 -alkylation of riboses have been studied by several groups during the late 1980s. It seems worth mentioning that formally, 2 -substituted oligomers may be considered on the one hand to be alkylated ORNs, and on the other hand to be alkoxylated ODNs. Thus, prompted particularly by the discovery of the catalytic effect of ribozymes, the 

Different synthetic routes have been described for synthesis of 2 -modified nucleosides [152]. 2 -Fluoro nucleosides are usually prepared starting from arabinofuranosylnucleosides. 2,2 -Anhydroarabinofuranosyluracil 61 has been reported to yield 2 -deoxy-2 fluorouridine upon treatment with hydrogen fluoride. 2 -Amino-2-deoxyuridine may be easily prepared by similar rearrangements in large scale synthesis [153]. Synthesis of 2 -deoxy-2 -fluoropurine 

Direct methylation with diazomethane [154] or alkylation of organotin derivatives of uridine 64 lead to non 2 -0-selective alkylations. The organotin approach using alkyl halides and temperatures up to 130 °C leads to the formation of equal amounts of 2 - and 3 -0-alky-luridines, which may be separated by chromatography after dimethoxytritylation. Alkylation of the uracil moiety does not occur with this method. Purification of the isomeric mixture may be achieved after further derivatization [155]. 

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Except for this particular example, quantitative deprotections were observed for other sugar nitrates without modification of the sugar moiety. Some other Al-deriva-tives such as diphenyl hydrazino substituents introduced by triflate displacement at the C-6 position of galactose residues were photolyzed but in low yields [112]. This group remains of limited interest for any further use in synthesis. 

S. Ogawa and D. Aso, Chemical modification of the sugar moiety of methyl acarviosin synthesis and inhibitory activity of eight analogues containing a 1,6-anhydro bridge,... 

The syntheses of the 6 -0-(bromopentyl)-substituted allofuranosyl-purine and -pyrimidine phosphoramidite (40a-c) and the 2 -0-[(3-bromopropoxy)methyl] substituted allofuranosyl-purine and -pyrimidine phosphoramidite (41a-c) have been reported. Such modifications of the sugar moiety presented opportunities for the functionalisation of oligonucleotides with a variety of soft nucleophiles while the fully protected sequence was still on the solid support. ... 

It would seem reasonable that, with proper protection of the phosphoric group, sulfonylation of nucleotides will gain wider utility as a method for the modification of the sugar moieties in these compounds. 

Unlike dehydrogenases, enzymes cleaving the glycosyl bond are extremely sensitive to modifications of the sugar moiety. The arabino analogs, arabino-NAD+ and 2 -fluoro-araW/K>-NAD (12) are both potent, slow-binding competitive inhibitors of calf spleen NADase with ATj values of 170 nAf and 2 fiM,... 

Most of the work on the derivatization of podophyllotoxin has targeted the C4 position. These studies can be classified according to the fate of the carbon-oxygen bond, which may be either retained or replaced by a carbon-nitrogen or a carbon-carbon bond. When retaining the C-0 bond, derivatization has involved either the modification of the sugar moiety or its replacement with groups of different chemical nature. 

Exemplary Chemical Transformations of Daunomycin-Type Antibiotics Resulting in Modifications of the Sugar Moiety... 

The above-described acylation of the sugar moiety of the nucleotide adenosine (3) [2] has been followed by a series of papers reporting on the chemoselec-tive enzymatic modification of natural compounds carrying both hydroxyl and amino groups. In addition to the extensive work on nucleosides developed by Gotor and coworkers [8], the biocatalyzed esterification of the hydroxylated alkaloids castanospermine (4) and 1-deoxynojirimidn (5) should be mentioned. Both compounds were selectively acylated at their C-6 and/or C-2 OH by the protease subtilisin, despite the presence of a potentially more reactive amino functions [9]. 

In all cases, 2,6-dideoxy sugars of the d- or L-series are common and important parts of these various molecules. In general, the specific therapeutic effect is thought to be caused by the aglycone, and the sugar residue to be responsible mainly for regulating the pharmacokinetics. Thus, parameters like bioavailability, resorption, distribution, or therapeutic width are influenced by the carbohydrate moieties. By modification of the carbohydrate moiety it is, e.g., possible to enhance the efficacy of unspecific aglycones like anthracyclines or aureolic acids, or also to reduce possible side effects. Such as approach is followed in the field of class-I and -II anthracyclines in order to decrease their considerable cardiotoxicity. 

From an additional study, modification or removal of the sugar moiety also has a substantial influence on the cytotoxic potency of eleutherobin and its cross-resistance in Taxol-resistant cells [14]. These structure/activity profiles should be usable for future design of more potent eleutherobin derivatives. 

Since the beginning of the 1990s studies have been concentrated on the synthesis of more functionalized lumazine nucleosides <90Mi 718-06,93MI718-17) with further modifications at the sugar moiety <94MI 718-03). 

Introduction of a fluoride at the 3-position of neuraminic acid yielded a compound (57) that was a competitive inhibitor of the a-(2,6)-sialyl-trans-ferase. Base and sugar-modified analogues of CMP-Neu5Ac have also been prepared to investigate the tolerance of oc-(2,6)-sialyl-transferase to base exchange (58) and modification of the 5-, 8- or 9-position of neuraminic acid (59), (60). While base-exchange was not tolerated, modifications of the acid moiety yielded compounds that were substrates for the enzyme. 

To confirm this, it would be interesting to study some other PPG that have modifications on the sugar moieties, or feruloyl radicals in stead of caffeoyl ones. 

Methyl transfer reactions play a significant part in the modifications of aromatic polyketides, both of the polyketide core [61,62] as well as of several of the sugar moieties [44,53]. In Streptomyces, more than 20 amino acid sequences have been found that may represent enzymes involved in methyl transfer reactions in the biosynthesis of aromatic polyketides [149]. One of these enzymes, the S-adenosyl-L-methionine-dependent DnrK, is involved in the methylation of the C-4 hydroxyl group in daunorubicin/doxorubicin biosynthesis (Scheme 10, step 12). The subunit of the homo-dimeric enzyme displays a fold typical for small-molecule methyltransferases. The structure of the ternary complex with bound products S-adenosyl-L-homocysteine and 4-methoxy-8-rhodomycin provided insights into the structural basis of substrate recognition and catalysis [149]. The position and orientation of the substrates suggest an Sn2 mechanism for methyl transfer, and mutagenesis experiments show that there is no catalytic base in the vicinity of the substrate. Rate enhancement is thus most likely due to orientational and proximity effects [149]. 

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