ψ(SO2-NH) transition state isosteres of peptides. Synthesis of the glutathione disulfide analogue

An efficient and facile synthesis of N-Cbz-β-aminoalkanesulfonamides

“…After further oxidation and aminolysis, the duplicated peaks disappeared (vide post product 4g), revealing that the steric hindrance between Cbz and methanesulfonamide groups is less than that between Cbz and acetylthiomethyl groups. The crucial step is the preparation of N-Cbz--aminoalkanesulfonyl chlorides, which were mainly prepared previously via chlorination of the corresponding sulfonic acid with thionyl chloride [9,24,25], or oxalyl chloride [9,26], or oxidation of thioacetates or disulfides via phosgene [16,17], triphosgene [18,19], or chlorine in an aqueous solution [15,20]. Recently, Nishiguchi and his coworkers described a new and very useful reaction for the conversion of thiols, disulfides, thioacetates, and thiocarbamates to the corresponding sulfonyl chlorides in good yields via N-chlorosuccinimide (NCS) oxidation in dilute hydrochloric acid [37,38].…”

“…Aminoalkanesulfinyl chlorides were generally prepared from naturally occurring amino acids or amino alcohols via conversion of them into the corresponding thiolacetates and subsequent treatment with sulfuryl chloride in the presence of acetic anhydride [4,11] or chlorine in an aqueous solution [12,13], or prepared from cysteamine hydrochloride via the oxidation reaction with iodine to the corresponding disulfide, followed by treatment with chlorine in an aqueous solution [1315]. Aminoalkanesulfonyl chlorides can be prepared via oxidation of thiols, thioacetates, or disulfides with phosgene [16,17], triphosgene [18,19], or chlorine in an aqueous solution [15,20], or via reaction of -aminoalkanesulfonic acids or -aminoalkanesulfonates with phosgene [21,22] or triphosgene [23], thionyl chloride [9,24,25], or oxalyl chloride [9,26]. Although aminoalkanesulfinyl chlorides show higher reactivity than aminoalkanesulfonyl chlorides, the oxidation step did not always result in high yields and was difficult to optimize for use in solid phase synthesis.…”

Nitrobenzoxadiazole-based GSTP1-1 inhibitors containing the full peptidyl moiety of (pseudo)glutathione

“…Of necessity we considered some structural modifications of the GSH peptide moiety to achieve stability toward g-GT and possibly ameliorate bioavailability. Over the years we designed a variety of GSH mimics and derivatives characterized by amino acid substitution and/or bioisosteric replacements of the g-glutamyl linkage, addressed to enhance both metabolic resistance and affinity to GST binding sites, through the attribution of specific chemical and conformational properties to the modified GSH backbone [27][28][29][30][31][32][33][34] . Among these, the g-oxa-glutamyl (Glo) analog of GSH, H-Glo[Cys-Gly-OH]-OH, deserves particular attention for more than one reason: (1) as expected, the replacement of the scissile g-glutamyl-cysteinyl peptide bond with the OCONH unit assures resistance to g-GTmediated hydrolysis 29,35 ; (2) the substitution does not sensibly alter the physico-chemical properties of the tripeptide; (3) groups crucial for binding to the G-site resemble those of the natural ligand, with the H-bond donor/acceptor potential of the GSH backbone fairly maintained and (4) more importantly, S-conjugates of this urethane mimic of glutathione have been shown to inhibit MRP1 36 .…”

Novel glutathione analogues containing the dithiol and disulfide form of the Cys-Cys dyad

“…In the context of our studies on the synthesis of glutathione (GSH) analogues (Luisi et al, 1993;Calcagni et al, 1995;Calcagni et al, 1996) we are investigating structures containing cyclic frameworks centered at the Cterminal moiety. Although a number of chemical modifications have been performed on this molecule (Chen et al, 1986;Douglas, 1989;Xie et al, 1991;Embrey et al, 1994;GrOger et al, 1996), literature examination revealed that no data are available on GSH analogues containing a Cys residue replacing the C-terminal Gly and giving rise to a -Cys-Cys sequence.…”