Study On The Synthesis Of Melanocortin Analogues And Relin Drugs

Bremelanotide (PT-141) and Melanotan II (MT-II) are artificial synthesized cyclic heptapeptide, which derived fromα-melanocyte-stimulating hormone (α-MSH). Numerous studies have demonstrated that their receptors have played important roles in the sexual arousal, appetite decreasing and melanin synthesizing. So, they can be used in the treatment of sexual dysfunction, obesity, as well as melanin deficiency and so on. PT-141 has been developed by the company of Palatin Technologies for the treatment of sexual dysfunction. The results of Phase III clinical trial proved that it is well tolerated and will be the only candidate drug for female sexual dysfunction disease. Thus, PT-141 has been claimed to be the representative of the highest level in the current sexual medicine.Our experiments were focused on the loading of the first amino acid to the resin, condensation, cyclization as well as the cleavage of the peptide from the resin. After optimization of these key steps, the total yield can be reached 33.7%. Compared with the reported methods, our approach is simple, convenient, and low cost, so that it can be suit for scale production.Furthermore, the synthesis of relin drugs was also studied in this thesis. These drugs have been used in the treatment of prostate and breast cancer, hysteromyoma and so on. However, in domestic, crude drugs still can not be synthesized due to the technical reasons. And the high import price of which also restricts their application. The tetrapeptide pGlu-His-Trp-Ser-OH was synthesized in both liquid and solid phase in this paper. In the liquid phase, Ser(Bzl)-OMe was used as the starting material and it was coupled with Fmoc-Trp-OH, then the Fmoc protecting group was removed and coupled with Fmoc-His(Trt)-OH. Then, the operations were repeated until coupled with pGlu-OH. Finally, protected tetrapeptide ester was hydrolyzed using NaOH to give protected tetrapeptide, and the total yield is 15.5%. Whereas on the solid-phase procedure, with Fmoc-Ser(But)-wang resin as starting material, thetetrapeptide was synthesized by Fmoc protection strategy. The yield was raised to 37.1%. Moreover, we have also successfully got tetrapeptide hydrazide, which cleaved from Wang-resin using hydrazine hydrate in the yield of 39.6%.