The Solide Phase Synthesis Of Peptides By The Tyr Side Chain Anchoring Approach And The Synthesis Of Paclitaxel-Peptide Conjugates

The peptide drugs are characterized with high efficacy, good bioavailability, low toxicity and many other advantages. The solid phase peptide synthesis (SPPS) is widely used in peptide synthesis. However, the traditional SPPS usually extends the peptide chains either from the C terminal or the N terminal. It would be convenient to develop novel solid phase synthesis of peptides from both the C terminal and the N terminal. We design a novel SPPS method by anchoring the side chain of Tyr to the Wang resin through Mitsunobu reaction, the N terminal is protected with Fmoc which could be deprotected with 20% piperidine/DMF, the C terminal is protected with methyl ester which could be deprotected with 0.1 M LiOH in aqueous THF solution. By applying PyBOP as coupling reagent, eight tripeptide derivatives and a pentapeptide were prepared.Paclitaxel is a microtubule-targeting anticancer drug. It has been approved for the treatment of lung cancer, gastric cancer and many other solid cancers. Octreotide, Tyr3-octreotide and vapreotide are synthetic analogues of somatostatin, they are selective somatostatin receptor subtype II (SSTR 2) inhibitors. Since SSTR 2 is widely overexpressed in the tumor tissues, we use them as tumor-targeting molecules and design three paclitaxel-peptide conjugates to enhance the selectivity and bioavailability of paclitaxel as well as to reduce its adverse effects. The selective reaction of succinic anhydride with the 2’-hydroxyl of paclitaxel produces 2’-O-succinyl-paclitaxel. It is coupled with octreotide, Tyr3-octreotide and vapreotide respectively to give the (PTX)2-octreotide, (PTX)2-Tyr3-octreotide and (PTX)2-vapreotide conjugates. They are evaluated for their growth inhibitory activities against HeLa, A549, MCF-7 and K562 tumor cells by the MTT assay. (PTX)2-octreotide and (PTX)2-Tyr3-octreotide exhibit potent inhibitory activity on HeLa (IC50= 4.23 nM,4.17 nM, respectively), A549 (IC50= 30.11 nM,26.79 nM, respectively) and K562 cells (IC50= 3.06 nM,6.32 nM, respectively). In pharmacokinetic study, (PTX)2-Tyr3-octreotide shows improvements in the pharmacokinetic properties.