Syntheses and biological activities of parallel and antiparallel homo and hetero bis-cystine dimers of oxytocin and deamino-oxytocin

New methods have been developed for the synthesis of disulfide-bridged homo and hetero peptide dimers (both parallel and antiparallel), as exemplified in the oxytocin and deamino-oxytocin families. The linear sequences were assembled by 9-fluorenyl-methyloxycarbonyl (Fmoc) solid-phase synthesis techniques, with orthogonal protection for the two beta-thiols by appropriate combinations of S-[(N'-methyl-N'-phenylcarbamoyl)sulfernyl] (Snm), S-acetamido-methyl (Acm) and S-2, 4, 6-trimethoxybenzyl (Tmob) groups. Two octapeptide-resins gave rise to four different nonapeptide amides, which were brought together in defined ways to provide access to four of the six possible dimeric products. For each dimer, the first disulfide bond was formed in solution by a directed method, and then the second disulfide bond was formed, without purification of the intermediates, by iodine oxidation. Final isolated yields of the desired pure dimers were in the 20% to 40% range. Biological activities ranged from 0.2% to 6% that of oxytocin, depending on the assay, and were in some cases considerably protracted. These data are consistent with the hypothesis that dimers revert slowly to monomers under the testing conditions.