Synthesis of a new dicarba-analogue of the drug octreotide~R

摘要

Somatostatin is a cyclic tetradecapeptide originally isolated from bovine hypothalamus,Among its biological activities,this cyclopeptide inhibits the release of growth hormone mainly through the binding with two of the five somatostatin receptors subtypes known,hsst_2 and hsst_5.As these receptors are expressed in approximately 90% of carcinoid tumors,somatostatin was thought to be a good candidate for tumor therapy.However,the short half-life of in vivo hampered the use of somatostatin for medical treatments.Consequently,many linear and cyclic synthetic analogs of somatostatin have been prepared and tested in the past years.Among them,the cyclic octapeptide octreotide(SMS 201-995,sandostatin~R)strongly binds hsst_2 receptor subtype in vitro and it is still used in clinical protocols though with alternate results.The amino acid sequence of octreotide,D-Phe-c[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-ol,shows the same disulphide bridge of the parent somatostatin.However,the disulfide linkage is known to be easily broken by chemical reactants as well as by endogenous enzymes.This prompted us to search a more stable tether bridging the active motif of sandostatin identified into the sequence Phe-D-Trp-Lys-Thr.At the same time the new side-chain-to-side-chain bridge has to preserve the octreotide conformation:a type II' beta-turn spanning residues D-Trp and Lys.A way to change the disulphide bridge in a more stable structure is to substitute sulphurs atoms with methylene groups,so giving origin to the so called "dicarba-analogues".Ring closing metathesis(RCM)of two olefinic residues by Grubbs Ruthenium catalysts disclosed the way for preparing cyclopeptides with an all-hydrocarbon bridge.RCM can be achieved in solid phase synthesis of peptide containing unsaturated glycine residues at positions i and i + n(n = 3,4,5,7),followed by the double bond reduction.Following this methodology,we previously report the synthesis of the unsaturated and saturated octreotide analogues with the(2S,7S)-4,5-dehydro-2,7-diaminosuberic acid structure bridging Phe and Thr residues.In this paper we report the synthesis of the corresponding saturated analogue containing the(2S,7S)-2,7-diaminosuberic acid residue in the ring motif.