TY - JOUR
T1 - Synthesis and pharmacology of novel analogues of oxytocin and deaminooxytocin
T2 - Directed methods for the construction of disulfide and trisulfide bridges in peptides
AU - Chen, Lin
AU - Zoulíková, Ivana
AU - Slaninová, Jiřina
AU - Barany, George
PY - 1997/3/14
Y1 - 1997/3/14
N2 - Using as models the neurohypophyseal nonapeptide hormone oxytocin and its analogue deaminooxytocin, several directed routes to formation of sulfur- sulfur bridges have been developed and evaluated. The linear sequences (through common octapeptide-resin intermediates) were assembled smoothly on tris(alkoxy)benzylamide (PAL) poly(ethylene glycol)polystyrene (PEG-PS) graft supports, using stepwise Fmoc solid-phase chemistry. Side-chain protection of β-mercaptopropionic acid (Mpa) and/or cysteine (Cys) was provided by S- 2,4,6-trimethoxybenzyl (Tmob), S-acetamidomethyl (Acm), and/or a series of sulfenyl thiocarbonate and carbamoylsulfenyl protecting/activating groups: S- (methoxycarbonyl)sulfenyl (Scm), S(methoxycarbonyl)disulfanyl (Sscm), S-(N- methyl-N-phenylcarbamoyl)sulfenyl (Snm), and S-(N-methyl-N- phenylcarbamoyl)disulfanyl (Ssnm). Thiolytic displacement of S-Snm (preferred) or S-Scm provided intramolecular cyclized peptide disulfides, and homologation of the chemistry with S-Ssnm (again preferred) and S-Sscm provided the corresponding trisulfides along with smaller amounts of disulfides and tetrasulfides. These chemistries could be implemented both in solution and in solid-phase modes. Various parameters were studied systematically and optimized, and the novel trisulfides of oxytocin and deaminooxytocin were synthesized and purified to homogeneity. The trisulfide compounds were evaluated in three assays: uterotonic in vitro, uterotonic in vivo, and pressor tests, and they showed substantial potencies, ranging from 5% to 40% of the parent (disulfide) activities, as well as protracted actions. The affinities of the peptide trisulfides to uterine membrane receptors were only 3.3-3.6-fold lower than those of the parent disulfides. Possible explanations of the biological results are discussed.
AB - Using as models the neurohypophyseal nonapeptide hormone oxytocin and its analogue deaminooxytocin, several directed routes to formation of sulfur- sulfur bridges have been developed and evaluated. The linear sequences (through common octapeptide-resin intermediates) were assembled smoothly on tris(alkoxy)benzylamide (PAL) poly(ethylene glycol)polystyrene (PEG-PS) graft supports, using stepwise Fmoc solid-phase chemistry. Side-chain protection of β-mercaptopropionic acid (Mpa) and/or cysteine (Cys) was provided by S- 2,4,6-trimethoxybenzyl (Tmob), S-acetamidomethyl (Acm), and/or a series of sulfenyl thiocarbonate and carbamoylsulfenyl protecting/activating groups: S- (methoxycarbonyl)sulfenyl (Scm), S(methoxycarbonyl)disulfanyl (Sscm), S-(N- methyl-N-phenylcarbamoyl)sulfenyl (Snm), and S-(N-methyl-N- phenylcarbamoyl)disulfanyl (Ssnm). Thiolytic displacement of S-Snm (preferred) or S-Scm provided intramolecular cyclized peptide disulfides, and homologation of the chemistry with S-Ssnm (again preferred) and S-Sscm provided the corresponding trisulfides along with smaller amounts of disulfides and tetrasulfides. These chemistries could be implemented both in solution and in solid-phase modes. Various parameters were studied systematically and optimized, and the novel trisulfides of oxytocin and deaminooxytocin were synthesized and purified to homogeneity. The trisulfide compounds were evaluated in three assays: uterotonic in vitro, uterotonic in vivo, and pressor tests, and they showed substantial potencies, ranging from 5% to 40% of the parent (disulfide) activities, as well as protracted actions. The affinities of the peptide trisulfides to uterine membrane receptors were only 3.3-3.6-fold lower than those of the parent disulfides. Possible explanations of the biological results are discussed.
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U2 - 10.1021/jm9607156
DO - 10.1021/jm9607156
M3 - Article
C2 - 9083475
AN - SCOPUS:0030939626
SN - 0022-2623
VL - 40
SP - 864
EP - 876
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 6
ER -