Synthesis of 9-Substituted Berberine Derivatives with Microwave Irradiation

doi:10.1007/s40242-018-7425-6

Abstract

Abstract: Hyperglycemia is frequently accompanying with hyperlipidemia. To explore the potent drugs with dual-activity and dual-site effects that could reduce blood glucose and blood lipid at the same time, fibrate group with lipid-lowering effect on the 9th position of berberine(BBR) was introduced using the drug design combination principle and the multi-target collaborative treatment method. Moreover, the molecular structure of BBR was modified, and six 9-substituted derivatives of BBR were designed and synthesized, among which, five compounds have never been reported before. In addition, the molecular structures of these derivatives were identified using liquid chromatography-mass spectrometry(LC-MS), ¹H nuclear magnetic resonance(¹H NMR) and ¹³C NMR, respectively. Furthermore, the microwave irradiation experimental technique was applied in the synthesis reaction using the novel microwave synthesizer, which accelerated the reaction rate, enhanced the reaction yield, reduced the reaction by-products, and simplified the post-processing steps. In the meantime, the 9-position regioselective demethylation of BBR was explored through quantum chemical calculation during the synthesis of berberrubine. The computations were consistent with the experimental results, which contributed to deducing the mechanism of its selective methylation.

Key words: Berberine derivative, Microwave irradiation, Quantum chemistry, Regioselectivity

HAN Xie, SHAO Kaiyuan, HU Wenxiang. Synthesis of 9-Substituted Berberine Derivatives with Microwave Irradiation[J]. Chemical Research in Chinese Universities, 2018, 34(4): 571-577.

References

[1] Li B., Zhu W. L., Cheng K. X., Acta Pharm. Sin., 2008, 43, 773
[2] Yin J., Hu R., Chen M., Tang J., Li F., Yang Y., Chen J., Metabolism, 2002, 51, 1439
[3] Kong W., Wei J., Abidi P., Lin M., Inaba S., Li C., Wang Y., Wang Z., Si S., Pan H., Wang Y., Li Z., Liu J., Jiang J. D., Nat. Med., 2004, 10, 1344
[4] Hu W. X., Xu L. L., Wang Z., Jing J., Zhang Z. Y., Antidiabetics and Antiatheroscloresis Medicine Compounds and Preparing Method Thereof, ZL200710179390.3, 2011
[5] Ma L. J., Modern J. Integrated Tradi. Chin. Western Med., 2013, 22, 3453
[6] Frisch M. J., Trucks G. W., Schlegel H. B., Scuseria G. E., Robb M. A., Cheeseman J. R., Scalmani G., Barone V., Mennucci B., Peters-son G. A., Nakatsuji H., Caricato M., Li X., Hratchian H. P., Izmay-lov A. F., Bloino J., Zheng G., Sonnenberg J. L., Hada M., Ehara M., Toyota K., Fukuda R., Hasegawa J., Ishida M., Nakajima T., Honda Y., Kitao O., Nakai H., Vreven T., Montgomery J. A. Jr., Peralta J. E., Ogliaro F., Bearpark M., Heyd J. J., Brothers E., Kudin K. N., Staro-verov V. N., Kobayashi R., Normand J., Raghavachari K., Rendell A., Burant J. C., Iyengar S. S., Tomasi J., Cossi M., Rega N., Millam N. J., Klene M., Knox J. E., Cross J. B., Bakken V., Adamo C., Jaramillo J., Gomperts R., Stratmann R. E., Yazyev O., Austin A. J., Cammi R., Pomelli C., Ochterski J. W., Martin R. L., Morokuma K., Zakrzewski V. G., Voth G. A., Salvador P., Dannenberg J. J., Dapprich S., Daniels A. D., Farkas Ö., Foresman J. B., Ortiz J. V., Cioslowski J., Fox D. J., Gaussian 09, Revision A. 1, Gaussian Inc., Wallingford CT, 2009
[7] Lv D. X., ChemicaI Constituents and Their Biological Activities from Berberisagricolaahrendt, Southwest University, Chongqing, 2007
[8] BodiwalaH. S., Sabde S., Mitra D., BhutaniK. K., Singh I. P., J. Eur. J. Med. Chem., 2011, 46, 1045
[9] Biswanath D., Srinivas K. V. N. S., Syn. Commun., 2002, 32, 3027
[10] Zhang M. X., Li C., Zheng J., Li X. G., The Third National Conference on Organic Synthetic Chemistry and Process, Chongqing, 2010
[11] Liu L. X., Yuan X., Gao Y., Zhou D. B., Nat. Prod. Res. Dev., 2014, 26, 427
[12] Jiang Y. R., Polyaminomodified Berberine Derivatives as New and Strong DNA-binders, Sun Yat-sen University, Guangzhou, 2006
[13] Hong J., Study on the Synthesis and Anti Inflammatory Activity of Four Hydrogen Berberine Derivatives, Jinan University, Guangzhou, 2013
[14] Chen J., Wang T., Xu S., Lin A., Yao H., Xie W., Zhu Z., Xu J., Eur. J. Med. Chem., 2017, 132, 173
[15] Huang L., Luo Z., He F., Lu J., Li X., Bioorgan. Med. Chem., 2010, 18, 4475
[16] Jiang H. L., Wang X., Huang L., Luo Z. H., Su T., Ding K., Li X. S., Bioorgan. Med. Chem., 2011, 19, 7228
[17] Zhang W. J., Ou T. M., Lu Y. J., Huang Y. Y., Wu W. B., Huang Z. S., Zhou J. L., Wong K. Y., Gu L. Q., Bioorgan. Med. Chem., 2007, 15, 5493
[18] Qiu Z. B., The Structure Modification Study on Componenet of Coptis and Magnolia Herb Pairs, Guangzhou University of Chinese Medicine, Guangzhou, 2012
[19] He Y., Gao Y. H., Wu Z. H., Preparation Method and Application of 9-Substituted Double-Functional Group Berberine Derivative, CN 106045989A, 2016
[20] Lu M. W., Hu W. X., Chin. J. Org. Chem., 1995, 6, 561
[21] Hu W. X., Hu W. H., Wang J. Y., Ding J. F., Yu L. H., Chin. J. Med. Chem., 1999, 9(1), 70
[22] Liu M., Hu W. X., Adv. Mater Res., 2013, 22, 1711
[23] Han X., Shao K. Y., Hu W. X., J. Microwave Chem., 2017, 1(1), 15
[24] Shen X. Z., He H. J., Yang B. W., Zhao Z. G., Shao K. Y., Hu W. X., Chem. Res. Chinese Universities, 2017, 33(5), 773