簡(jiǎn)介

我國(guó)目前由于對(duì)Fmoc-O-叔丁基-D-酪氨酸應(yīng)用研究不多,酪氨酸尚未得到充分開(kāi)發(fā)利用,在18種氨基酸中可以說(shuō)酪氨酸類(lèi)衍生物是應(yīng)用最少的種類(lèi)。因此,國(guó)內(nèi)市場(chǎng)上Fmoc-O-叔丁基-D-酪氨酸幾乎不占什么份額,供大于求[1]。雖然一些大型氨基酸生產(chǎn)企業(yè)有每月數(shù)十噸的生產(chǎn)能力,可能實(shí)際上也沒(méi)有生產(chǎn)那么多Fmoc-O-叔丁基-D-酪氨酸產(chǎn)品上市。盡管我國(guó)Fmoc-O-叔丁基-D-酪氨酸市場(chǎng)供大于求,但仍有一些生化制品公司出于商業(yè)利益考慮,仍從國(guó)外進(jìn)口Fmoc-O-叔丁基-D-酪氨酸經(jīng)分裝后作為生化試劑銷(xiāo)售,但就總量而言也是微不足道的。中國(guó)林科院亞林所經(jīng)過(guò)多年研究,己經(jīng)將竹副產(chǎn)品Fmoc-O-叔丁基-D-酪氨酸用酶促化學(xué)方法合成,不僅提高了酪氨酸產(chǎn)品的附加值,而且推動(dòng)了竹產(chǎn)業(yè)的發(fā)展,開(kāi)拓了與Fmoc-O-叔丁基-D-酪氨酸相關(guān)產(chǎn)品應(yīng)用的新領(lǐng)域[2-4]。其結(jié)構(gòu)式如圖所示。

圖1 Fmoc-O-叔丁基-D-酪氨酸的結(jié)構(gòu)式。

應(yīng)用

Fmoc-O-叔丁基-D-酪氨酸在醫(yī)藥上是合成甲狀腺素、多巴、腎上腺素的前體,直接參與合成多巴胺、去甲腎上腺素和腎上腺素等神經(jīng)遞質(zhì),控制神經(jīng)遞質(zhì)水平,參與甲狀腺、腦垂體等腺體激素的合成[5]。臨床上用于生殖避孕療效研究。同時(shí)。Fmoc-O-叔丁基-D-酪氨酸可以促進(jìn)蛋白質(zhì)的合成和骨的鈣化,對(duì)生長(zhǎng)發(fā)育有很大的影響。它可通過(guò)血腦屏障,在腦中經(jīng)多巴胺酶作用生成供機(jī)體維持能量的物質(zhì)[6]。在臨床上Fmoc-O-叔丁基-D-酪氨酸用于治療肝昏迷、帕金森氏綜合癥、潰瘍病、心力衰竭、癡呆癥及精神病等證。國(guó)外已將Fmoc-O-叔丁基-D-酪氨酸用于腎臟病患者。例如：英國(guó)科學(xué)家將Fmoc-O-叔丁基-D-酪氨酸開(kāi)發(fā)成一種制劑,服用這種制劑減肥時(shí)沒(méi)有饑餓感而有幸福感,它能使人在身體和精神上產(chǎn)生興奮[7]。隨著我國(guó)醫(yī)療保健水平的提高，F(xiàn)moc-O-叔丁基-D-酪氨酸的需求量將會(huì)迅速增加。

事實(shí)上，F(xiàn)moc-O-叔丁基-D-酪氨酸主要供作合成神經(jīng)遞質(zhì)(如多巴胺、去甲腎上腺素和腎上腺素等),這些物質(zhì)關(guān)系到體力和精神狀態(tài)[8]。科學(xué)家認(rèn)為,抑郁癥或精神消沉產(chǎn)生的直接原因是腦中多巴胺、去甲腎上腺素和其他神經(jīng)遞質(zhì)含量水平降低,服用酪氨酸能夠延長(zhǎng)這些化合物的半衰期,也就自然能解脫精神和機(jī)體萎靡癥狀,從而能更好的工作而富于創(chuàng)造性[9]。大量的研究和試驗(yàn)都證明,服用Fmoc-O-叔丁基-D-酪氨酸增加了神經(jīng)遞質(zhì)的合成,而且實(shí)際上也減輕了抑郁癥癥狀,變得機(jī)敏和注意力集中[10]。

此外，在飼料工業(yè)中，F(xiàn)moc-O-叔丁基-D-酪氨酸可作為飼料添加劑,添加于雛禽的飼料中。一方面，盡量減少苯丙氨酸轉(zhuǎn)化為酪氨酸的數(shù)量，以維護(hù)畜、禽生長(zhǎng)中氨基酸的平衡。另一方面是避免雛雞、仔豬因體內(nèi)酪氨酸不足,甲狀腺、腎上腺激素受到破壞而引起體重降低[11]。

治療作用

服用Fmoc-O-叔丁基-D-酪氨酸實(shí)際表現(xiàn)出來(lái)的對(duì)精神、體能、代謝速率、皮膚、生長(zhǎng)速率和心理的調(diào)節(jié)作用,表明Fmoc-O-叔丁基-D-酪氨酸在臨床應(yīng)用和保健功能是多方面的[12]。主要對(duì)長(zhǎng)期疲勞、嗜睡癥、煩悶、抑郁癥、性冷淡、變態(tài)反應(yīng)(過(guò)敏癥)、頭疼、抗饑餓、抗紫外輻射、減肥、血壓、帕金森氏癥、增強(qiáng)記憶、注意力缺陷混亂、癡呆癥、苯酮服癥、解酒、精神振奮等人群有很好的改善效果[13]。而且國(guó)外己將Fmoc-O-叔丁基-D-酪氨酸研制成藥品和保健品,其中有Fmoc-O-叔丁基-D-酪氨酸粉劑、片劑、膠囊、維生素復(fù)合劑、Fmoc-O-叔丁基-D-酪氨酸-微量元素復(fù)合劑、和Fmoc-O-叔丁基-D-酪氨酸-多腺體復(fù)合劑[14-15]。

參考文獻(xiàn)

[1] Y. Al-Abed, Synthesis and uses of peptidomimetics including azapeptides, The Feinstein Institutes for Medical Research, USA . 2020, p. 222pp.

[2] J. Bojarska, M. Remko, I.D. Madura, K. Kaczmarek, J. Zabrocki, W.M. Wolf, Synthesis, experimental and in silico studies of N-fluorenylmethoxycarbonyl-O-tert-butyl-N-methyltyrosine, coupled with CSD data: a survey of interactions in the crystal structures of Fmoc-amino acids, Acta Crystallogr., Sect. C: Struct. Chem. 76(4) (2020) 328-345.

[3] J.R. Courter, J.Z. Hamilton, N.R. Hendrick, M. Zaval, A.B. Waight, R.P. Lyon, P.D. Senter, S.C. Jeffrey, P.J. Burke, Structure-activity relationships of tubulysin analogues, Bioorg. Med. Chem. Lett. 30(14) (2020) 127241.

[4] T. Ishizawa, Preparation of O-alkyl serine derivatives by reacting serine cyclic sulfamidate derivatives with alcohols, Chugai Seiyaku Kabushiki Kaisha, Japan . 2020, p. 96pp.

[5] A. Jamieson, A. Mahindra, I. Black, Fmoc protected (2S)-2-amino-8-[(1,1-dimethylethoxy)amino]-8-oxo-octanoic acid, (S)-2-amino-8-oxononanoic acid and (S)-2-amino-8-oxodecanoic acid for peptide synthesis, The University Court of the University of Glasgow, UK . 2019, p. 58pp.

[6] S. Jiang, H. Hao, T. Wang, X. Wu, M. Wang, K. Zhang, Preparation method of oxadiazoles and thiadiazoles and their application, China Pharmaceutical University, Peop. Rep. China . 2019, p. 31pp.

[7] V. Kshtriya, B. Koshti, H. Narode, S. Naskar, N. Gour, Controlled self-assembly of modified aromatic amino acids, ChemRxiv  (2021) 1-15.

[8] W. Li, X. Feng, J. Wang, M. Tian, L. Wen, S. Liang, B. Wang, Method for preparing N-(9-fluorenylmethyloxycarbonyl)-O-tert-butyl-L-serine, Sichuan Shifang Sangao Biochemical Industry Co., Ltd., Peop. Rep. China . 2019, p. 8pp.

[9] K. Nomura, R. Takeyama, Method for producing peptides, and method for deactivating bases used for deprotecting Fmoc group, Chugai Seiyaku Kabushiki Kaisha, Japan . 2019, p. 84pp.

[10] J. Park, S.-M. Jin, A.K. Mishra, J.A. Lim, E. Lee, Photo-Curable Lacquer Sap Resin Based on Urushiol-Mimicking, Tyrosine-Containing Additive, Langmuir 38(32) (2022) 10010-10021.

[11] M. Skoczylas, S. Bocian, B. Buszewski, Quantitative structure - retention relationships of amino acids on the amino acid- and peptide-silica stationary phases for liquid chromatography, J. Chromatogr. A 1609 (2020) 460514.

[12] H. Takeuchi, Y. Asaka, A. Nagaya, M. Handa, K. Masuya, T. Taguri, Y. Nemoto, Y. Kobayashi, A. Matsuda, H. Kurasaki, D.R. Cary, Method for producing peptide compounds containing N-alkyl amino acids by coupling of amino acid mixed anhydrides with silylated amino acids, Nissan Chemical Corporation, Japan; PeptiDream Inc. . 2020, p. 145pp.

[13] A. Temperini, D. Aiello, F. Mazzotti, C.M. Athanassopoulos, P. De Luca, C. Siciliano, 2,3-diaminopropanols obtained from D-serine as intermediates in the synthesis of protected 2,3-L-diaminopropanoic acid (L-Dap) methyl esters, Molecules 25(6) (2020) 1313.

[14] X. Xie, X. Suo, Y. Li, Q. Wang, Y. Jiang, Y. Cui, Oligopeptide two-dimensional nanomaterial and application as drug carriers, Xinzhou Teachers University, Peop. Rep. China . 2022, p. 16pp.

[15] J. Zhang, X. Pan, L. Liang, W. Lu, S. Wang, L. He, R. Si, J. Wang, Preparation of peptoid compounds containing tert-butyl substituted serine useful as Abl kinase inhibitors for the treatment of chronic myelocytic leukemia, Xi'an Jiaotong University, Peop. Rep. China . 2019, p. 15pp.