Isostere, sulfur-methylene

The simplest approach to isosteric replacement of one or both sulfur atoms of the cystine disulfide with a methylene or ethylene moiety is given for natural bioactive peptides when one cysteine residue is located in the N-terminal sequence position and the related amino group or peptide extension is not involved in the bioactivity. This allows for direct side chain to backbone (N-terminus) cyclization via amide bonds with suitable 5-carboxyalkyl derivatives of the second cysteine residue, or with the oo-carboxy group of aminodicarboxylic adds containing an alkyl side chain that mimics the Ca to Ca spacer in cystine. Thereby, the length and degree of branching of the sulfide or alkyl spacer can additionally be varied. 

The isostere in which sulfur replaces the methylene group at the 4 position in the furan ring of customary sugars also shows good activity as an inhibitor of HIV reverse transcriptase. The initial step consists of formation of the thioacetal (53-3) from glyoxal benzoate (53-1) and the methyl acetal of thioglyoxal (53-2). Reaction of... 

Representatives of all kinds have been explored for synthetic applications while mechanistic investigations were mainly focussed on the distinct FruA enzymes isolated from rabbit muscle [196] and yeast [197,198]. For mechanistic reasons, all DHAP aldolases appear to be highly specific for the donor component DHAP [199], and only a few isosteric replacements of the ester oxygen for sulfur (46), nitrogen (47), or methylene carbon (48) were found to be tolerable in preparative experiments (Fig. 7) [200,201], Earlier assay results [202] that had indicated activity also for a racemic methyl-branched DHAP analog 53 are now considered to be artefactual [203]. Dihydroxyacetone sulfate 50 has been shown to be covalently bound via Schiff base formation, but apparently no a-deprotonation occurred as neither H/D-exchange nor C-C... 

In Table XII is shown the effect of isosteric replacement of the 3-methylene moiety by oxygen or sulfur. Only a limited number of examples were studied so that a definitive assessment as to the effect of these substitutions is not really possible. The one 3-oxa analog (entry 2) possessed about 1-3% the activity of the parent compound. Results with the 3-thia derivatives (entries 3, 17) were variable, but the lla-hydroxy-lS, 16-... 

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