黑皮素类似物和瑞林类寡肽药物的合成研究
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摘要
布雷默浪丹(PT-141)和美拉诺坦(MT-II)是α-促黑素细胞激素(α-MSH)的衍生物,均为环七肽结构。大量研究已证实它们的受体分子在性唤起、降低食欲以及催化黑色素的合成中起着重要的作用,由此可以治疗性功能障碍、肥胖以及刺激皮肤产生黑皮素抵抗紫外线灼伤等疾病。PT-141是美国Palatin公司开发的一种治疗性功能障碍的药物,目前已完成III期临床,是针对女性性冷淡患者唯一有效的候选药物,耐受性好,号称代表了当今性医学的最高研究水平。
本论文设计了PT-141和MT-II的固相合成路线,以wang树脂为载体,采用Fmoc保护策略。实验考查了第一个氨基酸与载体的键合、氨基酸缩合、环合、环肽的切割等关键步骤的反应条件,优化了合成工艺,收率达到33.7%。与文献方法比,此合成工艺操作简单、合成效率高且成本低,适合于规模化生产。本论文的另一个研究方向是瑞林类寡肽抗癌药物的合成。该类药物在治疗前列腺癌、乳腺癌、子宫肌瘤、青春性早熟、子宫内膜异位症和功能性子宫出血等疾病时疗效显著。在我国,受合成技术的限制,此类药品几乎完全依靠进口,价格昂贵,多数患者难以承受。
本文采用液相和固相逐步缩合两种方法对瑞林类药物前四肽的合成进行了研究。首先以Ser(Bzl)-OMe·HCl为起始原料,采用Fmoc保护策略,液相逐步缩合的方法合成出保护的前四肽酯,最后在NaOH中水解得到保护的前四肽,产品的总收率为15.5%。而固相法以Fmoc-Ser(But)-wang resin为起始原料,采用Fmoc保护策略、固相逐步缩合的方法合成出前四肽,对其切割条件进行了优化,最高收率为31.5%。另外,本文还创新性的采用水合肼切割wang树脂的方法合成出保护的四肽肼,总收率为39.6%。
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%.
本论文设计了PT-141和MT-II的固相合成路线,以wang树脂为载体,采用Fmoc保护策略。实验考查了第一个氨基酸与载体的键合、氨基酸缩合、环合、环肽的切割等关键步骤的反应条件,优化了合成工艺,收率达到33.7%。与文献方法比,此合成工艺操作简单、合成效率高且成本低,适合于规模化生产。本论文的另一个研究方向是瑞林类寡肽抗癌药物的合成。该类药物在治疗前列腺癌、乳腺癌、子宫肌瘤、青春性早熟、子宫内膜异位症和功能性子宫出血等疾病时疗效显著。在我国,受合成技术的限制,此类药品几乎完全依靠进口,价格昂贵,多数患者难以承受。
本文采用液相和固相逐步缩合两种方法对瑞林类药物前四肽的合成进行了研究。首先以Ser(Bzl)-OMe·HCl为起始原料,采用Fmoc保护策略,液相逐步缩合的方法合成出保护的前四肽酯,最后在NaOH中水解得到保护的前四肽,产品的总收率为15.5%。而固相法以Fmoc-Ser(But)-wang resin为起始原料,采用Fmoc保护策略、固相逐步缩合的方法合成出前四肽,对其切割条件进行了优化,最高收率为31.5%。另外,本文还创新性的采用水合肼切割wang树脂的方法合成出保护的四肽肼,总收率为39.6%。
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%.
引文
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[3] Merrifield R. B., Solid phase peptide synthesis. I. The Synthesis of a tetrapeptide, J. Am. Chem. Soc., 1963, 85(14): 2149~2154
[4] Wang S. S., p-Alkoxybenzyl alcohol resin and p-Alkoxybenzyloxycarbonylh-ydrazide resin for solid phase synthesis of protected peptide fragments p- Alkoxybenzyl alcohol resin and p-Alkoxybenzyloxycar bonylhydrazide resin forsolid phase synthesis of protected peptide fragments, J. Am. Chem. Soc., 1973, 95(4): 1328~1333
[5] Mitchill A. R., Kent S. B., Merrifield R. B., A new synthetic route to tert-butyloxycarbonylaminoacyl-4-(oxymethyl)phenylacetamidomethyl-resin, an im-proved support for solid-phase peptide synthesis, J. Org. Chem., 1978, 43(14): 2845~2852
[6] Leznoff C.C., The use of insoluble polymer supports in general organic synthesis, Acc. Chem. Res., 1978, 11(9):327~333
[7] McNally J. J., Youngman M. A., Dax S. L., Mannich reactions of resin-bound substrates: 2. A versatile three-component solid-phase organic synthesis methodology, Tetrahedron Lett., 1998, 39(9): 967~970
[8] Hruby V. J., Muscio F., Grogisky C. M., et al., Solid-phase synthesis of [2-isoleucine, 4-leucine]oxytocin and [2-phenylalanine, 4-leucine]oxytocin and some of their pharmacological properties, J. Med. Chem., 1973, 16 (6): 624~629
[9] Flouret G., Arnold W. H., Cole J. W., et al., Synthesis and biological activity of the hypothalamic LH- and FSH-releasing decapeptide, J. Med. Chem., 1973, 16(4): 369~373
[10] Coy D. H., Coy E. J., Schally A. V., et al., Synthesis and biological activity of LH-RH analogs modified at the carboxyl terminus, J. Med. Chem., 1975, 18(3): 275~277
[11] Carpino L. A., Han G. Y., 9-Fluorenylmethoxycarbonyl amino-protecting group, J. Org. Chem., 1972, 37(22): 3404~3409
[12] Bodanszky M., Deshmane S. S., Martinez J., Side reactions in peptide synthesis. 11. Possible removal of the 9-fluorenylmethyloxycarbonyl group by the amino components during coupling, J. Org. Chem. 1979, 44(10): 1622~1625
[13] Wenschuh H., Beyermann M., Krause E, et al., Fmoc amino acid fluorides: convenient reagents for the solid-phase assembly of peptides incorporating sterically hindered residues, J. Org. Chem. 1994, 59(12): 3275~3280
[14] Collingwood S. P., Conversion of alcohols into alkyl bromides and iodides via o-alkylisoureas , Tetrahedron Lett., 1987, 28(38): 4445~4448
[15] Sheehan J. C., Ledis S. L., Total synthesis of a monocyclic peptide lactone antibiotic, etamycin, J. Am. Chem. Soc., 1973, 95 (3): 875~879
[16] Carpino L. A., 1-Hydroxy-7-azabenzotriazole. An efficient peptide coupling additive, J. Am. Chem. Soc., 1993, 115 (10):4397~4398
[17] Knorr R., Trzeciak A., Bannwarth W., et al., New coupling reagents in peptide chemistry, Tetrahedron Lett., 1989, 30(15): 1279~1230
[18] Danishefsky S. A., mannich-like approach to naphthyridinomycin. Tetrahedron Lett., 1984, 25(38): 4203~4206
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