Study On Synthesis Of Octreotide Acetate

As a kind of important chemical substances, bioactive peptides act as anunsubstitutional role in life activities. Presently, the research of bioactivepeptides is very vigorous, which in particularly focuses on the aspect ofpharmaceutical. The research and development of peptide drugs have been thenew focus of pharmaceutical because of the technological maturation ofchemistry peptide synthesis and the progress of solid-phase peptide synthesisespecially. Comparing with the enzymatic and gene engineering method on thesynthesis of peptide, chemistry peptide synthesis has more advantages aboutthe syntheses of short and middle peptide chains, and which attracts moreinterests. Many new drugs with more advantages than native analogues have beensynthesized by using the technique of chemistry peptide synthesis, such asoctreotide. Octreotide, an analogue of synthetic hormone somatostatin, hasbeen used as a clinical therapeutic agent to treat VI-Pomasyndrome,carcinoid syndrome,glucagonoma,gastrinoma/Zollinger Ellison,insulinoma , GRFoma and esophagus-varicosity bleeding.Somatostatin, a cyclic peptide consisting of 14 amino acids, plays aninhibitory role in the hormonal regulation of at least three organ systems inhumans: (i) the central nervous system, the hypothalamus, and pituitary gland,(ii) the gastrointestinal tract, and (iii) the exocrine and endocrine pancreas.Because of the "growth inhibitory" effect obtained in most tissues by thestimulation of somatostatin receptors, a large number of human tumors arealso somatostatin receptor positive. The pharmacological properties ofsomatostatin have generated an interest in the use of this peptide fortherapeutic purposes. Somatostatin is unsuitable for in vivo used due to its veryshort biological half-life, however an eight-amino acid peptide analogue ofsomatostatin , octreotide, has a longer half-life as well as inhibitory propertiesmore potent than the native somatostatin. Because of its growth hormone 68吉林大学硕士学位论文inhibitory effects, octreotide has been used as a clinical therapeutic agent totreat a wide variety of tumors which contain somatostatin receptors. It wasfirstly approved by USA FDA as an agent to treat tumors of gastrointestinaltract endocrine and hypophysis and acromegaly in 1988, then approved byUSA FDA to treat acromegaly in 1998 again. Octreotide consisting of two D-amino acids (D-Phe1, D-Trp4), aminoalcohol (Threoninol), and a disulfide bond (Cys2-S-S-Cys7), which is noteasily destroyed by enzyme because these amino acids in these places of 1, 4and 8 are not native amino acids existing in nature, exhibits a prolongedhalf-life in vivo (60 to 90 min in human), and is functionally 2000 times moreeffective than somatostatin. Octreotide containing D-amino acid andC-terminal alcohol is not freely formed in human, so it only can besynthesized using chemistry peptide synthesis. Generally, there are twostrategies about chemistry synthesis of polypeptide drugs: (i) solid-phasepeptide synthesis, (ii) solution-phase peptide synthesis. Owing to C-terminal alcohol, the problems resolved chiefly arepreparation of alcohol and selection of holders. Although many methods havebeen reported for solid-phase synthesis of octreotide, they were complicatedand harsh (anhydrous HF) and low yield. Large-scale synthesis of productionwas difficult because the existing methods of synthesis were inefficient andcomplex. In this paper, the method reported by using BH3/THF to reducecarboxyl has been studied and improved. Simultaneously, the method usingNaBH4 to reduce Fmoc-carboxyl producing amino alcohol with high yield(93%) is also described. Fmoc-threoninol was anchored onto amino-resin forthe synthesis of peptide alcohol (ol-peptide). In the process of elongatingpeptide chain, dosages reduced of amino acids provided high coupling yield(97%), and reduced the cost of material drug. Cl...