含尿嘧啶结构单元二肽衍生物的设计、合成及生物活性研究
收稿日期: 2018-11-30
修回日期: 2019-01-26
网络出版日期: 2019-02-19
基金资助
国家自然科学基金（No.21542003）和重庆市自然科学基金（No.cstc2016jcyjA0421）资助项目.
Design, Synthesis and Biological Activity of Dipeptide Derivatives Bearing Uracil Unit
Received date: 2018-11-30
Revised date: 2019-01-26
Online published: 2019-02-19
Supported by
Project supported by the National Natural Science Foundation of China (No. 21542003) and the Natural Science Foundation of Chongqing City (No. cstc2016jcyjA0421).
为探索新型抗糖尿病分子，设计了含有尿嘧啶结构单元的二肽衍生物.以尿嘧啶、多聚甲醛和半胱氨酸为原料，经过两步反应获得关键中间体S-胸腺嘧啶-L-半胱氨酸（IM-2），再经氨基保护、羧基酯化和氨基酸偶联，顺利合成了16个二肽衍生物.所得目标化合物均经1H NMR、13C NMR和HRMS进行结构确认，并开展了过氧化物酶体增殖物受体反应元件（PPRE）激动活性、α-葡萄糖苷酶-rat抑制活性、二肽基肽酶-4（DPP-4）抑制活性筛选.生物活性结果显示，这些二肽衍生物的PPRE相对激动活性、α-葡萄糖苷酶和DPP-4抑制活性都很弱；同时发现，该类分子的α-葡萄糖苷酶抑制活性变化趋势与PPRE激动活性、DPP-4抑制活性变化趋势相反，这为新型多肽多靶点药物的设计提供了新思路.
关键词： 糖尿病; 尿嘧啶; 二肽衍生物; 过氧化物酶体增殖物激活受体反应元件(PPRE); α-葡萄糖苷酶抑制活性; 二肽基肽酶-4抑制活性
唐雪梅 , 范莉 , 张泽朝 , 杨大成 . 含尿嘧啶结构单元二肽衍生物的设计、合成及生物活性研究[J]. 有机化学, 2019 , 39(5) : 1460 -1468 . DOI: 10.6023/cjoc201811040
In order to explore a new type of anti-diabetic molecules, dipeptide derivatives containing uracil structural units were designed. The key intermediate S-thymine-L-cysteine (IM-2) was obtained from uracil, paraformaldehyde and cysteine through two step reactions, and then 16 dipeptide derivatives were successfully synthesized through amino protection, carboxylation and amino acid coupling. All new compounds have been characterized by 1H NMR, 13C NMR and HRMS, and the peroxisome proliferator response element (PPRE) activated activity, α-glucosidase-rat inhibitory activity and dipeptidyl peptidase-4 (DPP-4) inhibitory activity were screened for all target molecules. The results showed that these molecules had weak above-mentioned activities, meanwhile the change trend of α-glucosidase-rat inhibitory activity of these molecules is opposite to that of PPRE agonistic activity and DPP-4 inhibitory activity. It maybe provides an idea for the research of designing novel polypeptide multi-target drugs.
[1] Deshpande, A. D.; Harris-Hayes, M.; Schootman, M. Phys. Ther. 2008, 88, 1254.
[2] American Diabetes Association Diabetes Care, 2014, 37 (suppl. 1), S81.
[3] Karuranga, S.; Fernandes, J. R.; Huang, Y.; Malanda, B. International Diabetes Federation (IDF) Diabetes Atlas 8th, 2017, p. 10, www.diabetesatlas.org.
[4] Hemmingsen, B.; Sonne, D. P.; Metzendorf, M. I.; Richter, B. Cochrane Database Syst. Rev. 2017, 5, CD012204.
[5] Nathan, K. T.; Ahmed-Sarwar, N.; Werner, P. Consult Pharm. 2016, 31, 251.
[6] Turner, N.; Zeng, X. Y.; Osborne, B.; Rogers, S.; Ye, J. M. Trends Pharmacol. Sci. 2016, 37, 379.
[7] Nissen, S. E.; Wolski, K. N. Engl. J. Med. 2007, 356, 2457.
[8] Faich, G. A.; Moseley, R. H. Drug Saf. 2001, 10, 537.
[9] Riddle, M. C. Diabetes Care 2017, 40, 629.
[10] Leonard, C. E.; Hennessy, S.; Han, X.; Siscovick, D. S.; Flory, J. H.; Deo, R. Trends Endocrinol. Metab. 2017, 28, 561.
[11] Kajbaf, F.; Lalau, J. D. Pharmacoepidemiol. Drug Saf. 2014, 23, 1123.
[12] Richter, B.; Bandeira-Echtler, E.; Bergerhoff, K.; Lerch, C. L. Cochrane Database Syst. Rev. 2008, 16, CD006739.
[13] Nathan, D. M.; Buse, J. B.; Davidson, M. B.; Ferrannini, E.; Holman, R. R.; Sherwin, R.; Zinman, B. Diabetes Care 2009, 32, 193.
[14] Chen, Y. Technol. Econom. Guide 2016, 32, 100(in Chinese). (陈俣, 科技经济导刊, 2016, 32, 100.)
[15] Zhang, W.; Song, J. Q.; Zhang, B. Z.; Yang, W. L.; Wang, R. Sci. Sin.: Chim. 2013, 43, 941(in Chinese). (张伟, 宋竟婧, 张邦治, 杨雯乐, 王锐, 中国科学:化学, 2013, 43, 941.)
[16] Lee, K.; Boovanahalli, S. K.; Nam, K. Y.; Kang, S. U.; Lee, M.; Phan, J.; Wu, L.; Waugh, D. S.; Zhang, Z. Y.; No, K. T.; Lee, J. J.; Burke, T. R. Jr. Bioorg. Med. Chem. 2005, 15, 4037.
[17] Fu, H.; Park, J.; Pei, D. Biochemistry 2002, 41, 10700.
[18] Larsen, S. D.; Stevens, F. C.; Lindberg, T. J.; Bodnar, P. M.; O'Sullivan, T. J.; Schostarez, H. J.; Palazuk, B. J.; Bleasdale, J. E. Bioorg. Med. Chem. Lett. 2003, 13, 971.
[19] Zhang, D. Y.; Shao, W. F.; Liu, Z. H.; Liu, Y. L.; Huang, Y. W. J. Tea Sci. 2009, 29, 41(in Chinese). (张冬英, 邵宛芳, 刘仲华, 刘亚林, 黄业伟, 茶叶科学, 2009, 29, 41.)
[20] Lee, B.; Shi, L.; Kassel, D. B.; Asakawa, T.; Takeuchi, K.; Christopher, R. J. Eur. J. Pharmacol. 2008, 589, 306.
[21] Deng, X. Y.; Han, L.; Zhou, J. P.; Zhang, H. B.; Li, Q. Bioorg. Chem. 2017, 75, 357.
[22] Ma, L. J.; Zhang, G. L.; Chen, S. Y.; Wu, B.; You, J. S.; Xia, C. Q.; Yu, X. Q. J. Pept. Sci. 2005, 11, 812.
[23] Tang, X. M.; Tang, G. X.; Wang, H.; Luo, L. F.; Yang, D. C. Bull. Chem. Soc. Ethiop. 2012, 26, 415.
[24] Kong, L. Q.; Zhao, J.; Fan, L.; Yang, D. C. Chin. Chem. Lett. 2009, 20, 314.
[25] Zhao, J.; Kong, L. Q.; Fan, L.; Yang, D. C. J. Southwest Univ. (Nat. Sci.) 2008, 30, 54(in Chinese). (赵晋, 孔令强, 范莉, 杨大成, 西南大学学报(自然科学版), 2008, 30, 54.)
[26] Yang, D. C.; Fan, L. Chem. Res. Appl. 2003, 15, 498(in Chinese). (杨大成, 范莉, 化学研究与应用, 2003, 15, 498.)
[27] Yang, D. C.; Fan, L.; Zhong, Y. G. Chin. J. Org. Chem. 2003, 23, 493(in Chinese). (杨大成, 范莉, 钟裕国, 有机化学, 2003, 23, 493.)
[28] Sun, X. L.; Fan, L.; Tang, X. M.; Yang, D. C. J. Org. Chem. Res. 2016, 4, 23(in Chinese). (孙晓丽, 范莉, 唐雪梅, 杨大成, 有机化学研究, 2016, 4, 23.)
[29] Wang, G. B.; Wang, L. F.; Li, C. Z.; Sun, J.; Zhou, G. M.; Yang, D. C. Res. Chem. Intermed. 2012, 38, 77.
[30] Yang, L.; Yan, J. F.; Fan, L.; Chen, X.; Shangguan, R. Y.; Wang, L. F.; Yang, D. C. Chin. J. Org. Chem. 2012, 32, 1908(in Chinese). (杨龙, 晏菊芳, 范莉, 陈欣, 上官瑞燕, 汪林发, 杨大成, 有机化学, 2012, 32, 1908.)
[31] Yang, Y.; Yan, J. F.; Fan, L.; Chen, X.; Jiang, L.; Yang, D. C. Acta Pharm. Sin. 2012, 47, 1630(in Chinese). (杨艳, 晏菊芳, 范莉, 陈欣, 蒋理, 杨大成, 药学学报, 2012, 47, 1630.)
[32] Tang, X. M.; Fan, L.; Yu, H. X.; Liao, Y. H.; Yang, D. C. Chin. J. Org. Chem. 2009, 29, 595(in Chinese). (唐雪梅, 范莉, 于红霞, 廖玉华, 杨大成, 有机化学, 2009, 29, 595.)
[33] Tang, G. X.; Yan, J. F.; Fan, L.; Song, X. L.; Jiang, L.; Luo, L. F.; Yang, D. C. Sci. China, Chem. 2013, 56, 490.
[34] Zhang, X. H.; Yan, J. F.; Fan, L.; Wang, G. B.; Yang, D. C. Acta Pharm. Sin. B 2011, 1, 100.
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