丹参脂溶性成分结构优化研究进展

doi:10.6023/cjoc202206054

摘要/Abstract

丹参作为一种传统中药在临床上广泛应用于心脑血管疾病的治疗, 对其有效成分及衍生物的研究一直是国内外的研究热点. 丹参的有效成分主要分为脂溶性成分和水溶性成分, 其脂溶性成分具有多种药理活性, 但因其水溶性不足、生物利用度低的缺点限制了临床应用. 为了能够推进丹参脂溶性成分的临床应用, 研究人员以丹参脂溶性成分为先导化合物进行结构优化, 以期能够提高其类药性. 综述了近年来丹参主要脂溶性成分的结构优化及相关药理活性的研究进展, 总结了主要脂溶性成分的成药性结构优化策略以及该类衍生物的合成方法, 阐述了不同位置结构优化对药理活性的影响, 旨在为丹参脂溶性成分创新药物的研发提供新的研究思路.

关键词: 丹参, 脂溶性成分, 结构优化

As a traditional Chinese medicine, Salvia miltiorrhiza has been widely applied in the treatment of cardiovascular diseases in clinical. Research on its active components and derivatives has become an issue of great focus both domestically and internationally. The active ingredients of Salvia miltiorrhiza are mainly divided into lipid-soluble and water-soluble ingredients with the lipid-soluble ones performing various pharmacological properties. However, their poor solubility and bioavailability have limited their clinical applications. In order to promote the clinical application of lipid-soluble ingredients of Salvia miltiorrhiza, these components are used as lead compounds to perform structural optimization to improve drug-like properties. In order to generate novel research ideas for the development of novel drugs based on lipid-soluble ingredients of Salvia miltiorrhiza, the research progress of structural optimization and related biological activities of the major lipid-soluble ingredients of Salvia miltiorrhiza in recent years is reviewed, the structural optimization strategy of the drug-like properties of these compounds and the synthetic approaches of their derivatives are summarized, and the effects of different structure modifications on pharmacological activities are described.

Key words: Salvia miltiorrhiza, lipid-soluble ingredients, structural optimization

引用此文

李兴军, 王江, 柳红. 丹参脂溶性成分结构优化研究进展[J]. 有机化学, 2023, 43(2): 471-490.

Xingjun Li, Jiang Wang, Hong Liu. Research Progress on Structural Optimization on the Lipid-Soluble Ingredients of Salvia miltiorrhiza[J]. Chinese Journal of Organic Chemistry, 2023, 43(2): 471-490.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

图/表 44

图1. 丹参主要水溶性成分

Figure 1. Main water-soluble ingredients of Salvia miltiorrhiza

图2. 丹参主要脂溶性成分

Figure 2. Main lipid-soluble ingredients of Salvia miltiorrhiza

图3. 丹参酮IIA的结构优化

Figure 3. Structural optimization of tanshinone IIA

图4. A环骨架改造

Figure 4. Modification of A ring skeleton

Compd.	Structure	LNCaP IC₅₀/(μmol•L^-1)
TS-IIA		0.5
1		0.7
Compd.	Structure	LNCaP IC₅₀/(μmol•L^-1)
2		3.2
3		0.6
4		1.0
5		1.2
6		3.5
7		1.7
8		2.4
9		3.6

表1. 丹参酮IIA的A环骨架优化对其体外前列腺癌细胞增殖抑制活性的影响

Table 1. Effect of A ring skeleton optimization of tanshinone IIA on its inhibitory activity of prostate cancer cell proliferation in vitro

图5. 运用孪药原理在A环引入水溶性基团

Figure 5. According to twin-principle to introduce hydrophilic groups at the A-ring

图6. 丹参酮IIA的C环结构修饰

Figure 6. C-ring structural modification of tanshinone IIA

化合物	IC₅₀/(μmol•L^-1)
化合物	K562	Hela	MCF-7	PC3	CNE
丹参酮IIA	6.9	7.1	6.1	21.1	5.8
11	3.9	17.1	13.6	20.6	23.8

表2. 丹参酮IIA和化合物11的抗肿瘤活性

Table 2. Antitumor activity of tanshinone IIA and compound 11

图7. 2'-苯基苯并咪唑类丹参酮IIA衍生物的合成

Figure 7. Synthesis of 2'-phenyl benzimidazoles tanshinone IIA derivatives

图8. 丹参酮IIA的C环氨基酸酯前药修饰

Figure 8. C-ring amino acid ester prodrug modification of tanshinone IIA

图9. 化合物15和16的合成

Figure 9. Synthesis of compounds 15 and 16

图10. 化合物17的合成

Figure 10. Synthesis of compound 17

Bacterial species		LNCaP IC₅₀/(μmol•L^-1)
Bacterial species		Tanshinone IIA	17
Gram-negative bacteria	E. coli	>128.0	>64.0
	P. aeruginosa	>128.0	>64.0
	S. typhimurium	>128.0	>64.0
Gram-positive bacteria	L. monocytogenes	>128.0	16.0
Gram-positive bacteria	S. aureus	>128.0	16.0

表3. 丹参酮IIA和化合物17对多种革兰氏阴性菌(G-)及革兰氏阳性菌(G＋)的最小抑菌浓度(MIC)

Table 3. Minimum inhibitory concentration (MIC) of tan- shinone IIA and compound 17 against Gram-negative bacteria (G-) and Gram-positive bacteria (G＋)

图11. 丹参酮IIA磺酰胺类衍生物的合成

Figure 11. Synthesis of sulfonamide derivatives of tanshinone IIA

图12. 丹参酮IIA D环水溶性改造

Figure 12. Water-solubility structural optimization of D ring of tanshinone IIA

图13. 丹参酮IIA D环结构修饰

Figure 13. Structural optimization of D ring of tanshinone IIA

图14. 丹参酮IIA D环引入磷酸酯基团

Figure 14. Phosphate ester group is added to the D ring of tanshinone IIA

图15. 化合物23的设计原理

Figure 15. Design principle of compound 23

图16. 化合物24的设计原理

Figure 16. Design principle of compound 24

图17. 丹参酮IIA A/D环同时改造

Figure 17. A/D ring of tanshinone IIA was modified simultaneously

图18. 丹参酮IIA去环衍生物

Figure 18. Decycled derivatives of tanshinone IIA

Compd.	IC₅₀/(μmol•L^-1)
Compd.	HepG2	Hela	MCF-7	MGC	A549	U937
26	2.0	0.3	3.2	0.8	0.3	2.8
Tanshinone IIA	4.9	3.5	>5.0	>5.0	2.2	>5.0

表4. 丹参酮IIA和化合物26的抗癌活性

Table 4. Antitumor activity of tanshinone IIA and compound 26

图19. 丹参酮I的结构优化

Figure 19. Structural optimization of tanshinone I

图20. 丹参酮I的A环结构修饰

Figure 20. Structural modification of A ring of tanshinone I

图21. 丹参酮I的C环单羰基双取代衍生物

Figure 21. Monocarbonyl disubstituted derivatives of the C ring of tanshinone I

图22. 化合物28/29的合成

Figure 22. Synthesis of compounds 28 and 29

图23. 化合物30的合成

Figure 23. Synthesis of compound 30

Bacterial species		LNCaP IC₅₀/(μmol•L^-1)
Bacterial species		Tanshinone I	30
Gram-negative bacteria	E. coli	>128.0	84.0
	P. aeruginosa	>128.0	42.0
	S. typhimurium	>128.0	42.0
Gram-positive bacteria	L. monocytogenes	>128.0	42.0
	S. aureus 29213	>128.0	21.0
	S. aureus 25923	>128.0	32.0

表5. 丹参酮IIA和化合物30的抗菌活性

Table 5. Antibacterial activity of tanshinone IIA and compound 30

图24. 丹参酮I的多环修饰策略

Figure 24. Polycyclic modification strategy of tanshinone I

图25. 隐丹参酮结构优化

Figure 25. Structural optimization of cryptotanshinone

图26. 隐丹参酮B环选择性硝基化修饰

Figure 26. Selective nitrylation of the B ring of cryptotanshi- none

图27. 2'-苯基苯并咪唑类隐丹参酮衍生物的合成

Figure 27. Synthesis of 2'-phenyl benzimidazole derivatives of cryptotanshinone

图28. 隐丹参酮的碱解与氨解

Figure 28. Alkali-hydrolysis and ammonolysis of cryptotan- shinone

图29. 隐丹参酮D环氨解衍生物

Figure 29. Aminolysis derivatives of cryptotanshinone D ring

图30. 新丹参内酯的结构优化

Figure 30. Structural optimization of neo-tanshinlactone

图31. 化合物39的合成

Figure 31. Synthesis of compound 39

图32. 新丹参内酯A环的简化

Figure 32. Simplification of A ring of neo-tanshinlactone

图33. 化合物41的合成

Figure 33. Synthesis of compound 41

图34. 新丹参内酯B环内酰胺衍生物

Figure 34. B-ring lactam derivatives of neo-tanshinlactone

图35. 新丹参内酯C环杂原子的替代

Figure 35. Substitution of heteroatoms in C ring of neo- tanshinlactone

图36. 新丹参内酯C环开环衍生物

Figure 36. Ring-opening derivatives of C ring of neo-tanshin- lactone

图37. 新丹参内酯烷氨基侧链替代D环类衍生物

Figure 37. Alkane amino side-chain replacement derivatives of the D ring of neo-tanshinlactone

图38. 新丹参内酯烷氧基侧链替代D环类衍生物

Figure 38. Alkoxy side-chain replacement derivatives of the D ring of neo-tanshinlactone

图39. 新丹参内酯与查尔酮的杂合衍生物

Figure 39. Heterozygous derivatives of neosalvianolide and chalcone

参考文献 37

[1]	Wu, Y.-B.; Ni, Z.-Y.; Shi, Q.-W.; Dong, M.; Kiyota, H.; Gu, Y.-C.; Cong, B. Chem. Rev. 2012, 112, 5967 doi: 10.1021/cr200058f
[2]	(a) Yan, S.-C.; Liang, M.-Q; Khalid, R.; Ting, H.; Ping, Q.-L. Chin. J. Nat. Med. 2015, 13, 0163.
	(b) Guo, Y.-B.; Li, Y.; Xue, L.-M.; Severino, P. R.; Gao, S.-H.; Niu, J.-Z.; Qin, L.-P.; Zhang, D.-W.; Bromme, D. J. Ethnopharmacol. 2014, 155, 1401. doi: 10.1016/j.jep.2014.07.058
[3]	Li, Z.-M.; Xu, S.-W; Liu, P.-Q. Acta Pharmacol. Sin. 2018, 39, 802. doi: 10.1038/aps.2017.193
[4]	(a) Fang, J.; Little, P. J.; Xu, S.-W. Med. Res. Rev. 2018, 38, 201. doi: 10.1002/med.21438
	(b) Chen, X.-P.; Guo, J.-J.; Bao, J.-L.; Lu, J.-J.; Wang, Y.-T. Med. Res. Rev. 2014, 34, 768. doi: 10.1002/med.21304
[5]	(a) Wang, X.-H.; Bastow, K.F.; Sun, C.-M.; Lin, Y.-L.; Yu, H.-J.; Don, M.-J.; Wu, T.-S.; Nakamura, S.; Lee, K.-H. J. Med. Chem. 2004, 47, 5816. doi: 10.1021/jm040112r
	(b) Lin, W.-J.; Huang, J.-J.; Liao, X.-L.; Yuan, Z.-W.; Feng, S.-L.; Xie, Y.; Ma, W.-Z. Pharmacol. Res. 2016, 111, 849. doi: 10.1016/j.phrs.2016.07.044
[6]	Zhou, L.-M.; Zuo, Z.; Chow, M. S. S. J. Clin. Pharmacol. 2005, 45, 1345. doi: 10.1177/0091270005282630
[7]	(a) Yuan, L.-M.; Li, Q.-H.; Zhang, Z.-G.; Liu, Q.-L.; Wang, X.-C.; Fan, L.-H. J. Cell. Biochem. 2019, 121, 1400. doi: 10.1002/jcb.29375 pmid: 21774934
	(b) Shang, Q.-H.; Xu, H.; Huang, L. Evidence-Based Complementary Altern. Med. 2012, 2012, 716459. pmid: 21774934
	(c) Gao, S.; Liu, Z.-P.; Li, H.; Little, P.-J.; Liu, P.-Q.; Xu, S.-W. Atherosclerosis 2012, 220, 3. doi: 10.1016/j.atherosclerosis.2011.06.041 pmid: 21774934
[8]	Liu, W.-G.; Zhou, J.-M.; Geng, G.-Y.; Shi, Q.-W.; Sauriol, F.; Wu, J.-H. J. Med. Chem. 2012, 55, 971. doi: 10.1021/jm2015292
[9]	Bi, Y.-F.; Wang, Y.-Y.; Wu, Z.; Yang, X.-M. CN 106800582, 2017.
[10]	Li, M.-M.; Xia, F.; Li, C.-J.; Xu, G.; Qin, H.-B. Tetrahedron Lett. 2018, 59, 46. doi: 10.1016/j.tetlet.2017.11.046
[11]	Xu, D.-F.; Hu, H.; Guan, J.; Da, J.; Xie, Y.-P.; Liu, Y.-L.; Kong, R.; Song, G.-Q. Zhou, H. Chem. Biol. Drug Des. 2019, 94, 1656. doi: 10.1111/cbdd.13567
[12]	(a) Bianchini, G.; Balko, J.-M.; Mayer, I.-A.; Sanders, M.-E.; Gianni, L. Nat. Rev. Clin. Oncol. 2016, 13, 674.
	(b) Biffi, G.; Tannahill, D.; Mccafferty, J.; Balasubramanian, S. Nat. Chem. 2013, 5, 182. doi: 10.1038/nchem.1548
	(c) Reed, J.-E.; Arnal, A.-A.; Neidle, S.; Vilar, R. J. Am. Chem. Soc. 2006, 128, 5992. doi: 10.1021/ja058509n
	(d) Wang, T.; Zou, J.; Wu, Q.; Wang, R.; Yuan, C.-L.; Shun, J.; Zhai, B.-B.; Huang, X.-T.; Liu, N.-Z.; Hua, F.-Y.; Wang, X.-C.; Mei, W.-J. Eur. J. Pharmacol. 2021, 912, 174586. doi: 10.1016/j.ejphar.2021.174586
	(e) Wu, Q.; Zheng, K.-D.; Huang, X.-T.; Li, L.; Mei, W.-J. J. Med. Chem. 2018, 61, 10488. doi: 10.1021/acs.jmedchem.8b01018
	(f) Zeng, L.; Wu, Q.; Wang, T.; Li, L.-P.; Zhao, X.-H.; Chen, K.; Qian, J.-Y.; Yuan, L.; Xu, H.; Mei, W.-J. Bioorg. Chem. 2021, 106, 104433. doi: 10.1016/j.bioorg.2020.104433
[13]	Zhou, C.-X.; Gan, L.-D.; Zeng, L.-W.; Zhu, Z.-B. CN 103980341, 2014.
[14]	(a) Kusumi, T.; Kishi, T.; Kakisawa, H. J. Chem. Soc., Perkin Trans. 1 1976, 1716.
	(b) Li, X.-B.; Cheng, X.; Zhang, D.-L.; Wu, H.-Q.; Ye, J.-T.; Du, J.; Huang, Z.-S.; Gu, L.-Q.; An, L.-K. Pharmazie 2014, 69, 163. doi: 10.1002/ardp.18390690210
[15]	(a) Domagala, J.-M. J. Antimicrob. Chemother. 1994, 33, 685. doi: 10.1093/jac/33.4.685 pmid: 11428933
	(b) Chen, Y.-L.; Fang, K.-C.; Sheu, J.-Y.; Hsu, S.-L.; Tzeng, C.-C. J. Med. Chem. 2001, 44, 2374. pmid: 11428933
	(c) Wang, D.-D.; Zhang, W.-X.; Wang, T.-T.; Li, N. Mu, H.-B.; Zhang, J.-W.; Duan, J.-Y. Int. J. Mol. Sci. 2015, 16, 17668. doi: 10.3390/ijms160817668 pmid: 11428933
[16]	Qin, Y.-L.; Jin, Q.; Wu, X.-Z.; Wang, W. CN 106905408, 2017.
[17]	Su, M.; Wang, W. CN 107663224, 201.
[18]	(a) Li, Q.-N.; Huang, Z.-P.; Gu, Q.-L.; Zhi, Z.-E.; Yang, Y.-H.; He, L.; Chen, K.-L.; Wang, J.-X. Chin. J. Nat. Med. 2018, 16, 113.
	(b) Wang, J.-X.; Huang, Z.-P.; He, L.; He, L.; You, Q.-D.; Li, X.-N. CN 107118254, 2017.
[19]	Sun, Q.-Y.; Zhang, W.-D.; Yuan, H. CN 107540725, 2018.
[20]	Zhang, K.-J.; Wang, K.-Z.; Zhang, X.-Y.; Qian, Z.-L.; Zhang, W.-B.; Zheng, X.; Wang, J.-Y.; Jiang, Y.; Zhang, W.-H.; Lu, Z.-Y.; Hao, H.-P.; Jiang, S. J. Med. Chem. 2022, 65, 7746. doi: 10.1021/acs.jmedchem.2c00077
[21]	Ding, C.-Y; Chen, H.-J.; Liang, B.; Jiao, M.-K.; Liang, G.; Zhang, A. Chem. Sci. 2019, 10, 4667. doi: 10.1039/C9SC00086K
[22]	Liu, J.-X.; Ren, J.; Yang, K.; Chen, S.; Yang, X.-N.; Zhao, Q.-S. Eur. J. Med. Chem. 2022, 235, 114294. doi: 10.1016/j.ejmech.2022.114294
[23]	Huang, H.; Yao, Y.-F; Hou, G.-D.; Zhao, C.; Qin, J.-L.; Zhang, Y.-X.; Duan, Y.-T.; Song, C.-J.; Chang, J.-B. Eur. J. Med. Chem. 2021, 224, 113708. doi: 10.1016/j.ejmech.2021.113708
[24]	Zheng, L.-H.; Zhang, Y.; Liu, G.-J.; Cheng, S.; Zhang, G.; An, C.; Sun, S.-P.; Wang, J.; Pang, B.; Li, S.-H. Anticancer Drugs 2020, 31, 601. doi: 10.1097/CAD.0000000000000908
[25]	Jin, H.; Li, H.; Mao, S.-J.; Ma, W.-C.; Chen, Y.-T.; Liu, S.-Y. CN 102702302, 2012.
[26]	Liu, X.-W.; Chen, Z.-Y.; Wang, G.-L.; Ma, X.-T.; Gong, Y.; Liu, X.-L; Feng, T.-T.; Zhou, Y. Synth. Commun. 2017, 47, 2378. doi: 10.1080/00397911.2017.1378359
[27]	(a) Ding, C.-Y.; Song, S.-S.; Jiao, M.-K.; Wang, Y.-Q.; Liao, Z.-H.; Zhang, A. CN 105622709, 2016,
	(b) Xu, W.-Q.; Jiang, C.-F.; Yang, F.-J.; Shen, X.; Li, R.-F.; Xue, D. CN 103288916, 2013.
[28]	Wang, D.-D.; Lu, C.-B; Sun, F.-F.; Cui, M.-X.; Mu, H.-B.; Duan, J.-Y.; Geng, H.-L. Res. Microbiol. 2017, 168, 46. doi: 10.1016/j.resmic.2016.08.002
[29]	Ding, C.-Y.; Tian, Q.-T.; Li, J.; Jiao, M.-K.; Song, S.-S.; Wang, Y.-Q.; Miao, Z.-M.; Zhang, A. J. Med. Chem. 2018, 61, 760. doi: 10.1021/acs.jmedchem.7b01259
[30]	Zhao, Q.-S.; Leng, Y.; Deng, X.; Zhao, Y.; Shen, Y.; Luo, X.-X. CN 102603861, 2012.
[31]	(a) Xu, D.-F.; Zhang, C.-X.; Ji, Y.-J. CN 102127037, 2011.
	(b) Xu, D.-F. CN 106699771, 2017.
[32]	(a) Dong, Y.-Z.; Shi, Q.; Pai, H.-C.; Peng, C.-Y.; Pan, S.-L.; Teng, C.-M.; Nakagawa-Goto, N.; Yu, D.-L.; Liu, Y.-N.; Wu, P.-C.; Bastow, K.-F.; Morris-Natschke, S. L.; Brossi, A.; Lang, J.-Y.; Hsu, J. L.; Huang, M.-C.; Lee, E. Y. H. P.; Lee, K.-H. J. Med. Chem. 2010, 53, 2299. doi: 10.1021/jm1000858
	(b) Wang, X.; Bastow, K.-F.; Sun, C.-M.; Lin, Y.-L.; Yu, H.-J.; Don, M.-J.; Wu, T.-S.; Nakamura, S.; Lee, K.-H. J. Med. Chem. 2004, 47, 5816. doi: 10.1021/jm040112r
[33]	Dong, Y.-Z.; Shi, Q.; Liu, Y.-N.; Wang, X.; Bastow, K.-F.; Lee, K.-H. J. Med. Chem. 2009, 52, 3586. doi: 10.1021/jm9001567
[34]	Dong, Y.-Z.; Shi, Q.; Nakagawa-Goto, K.; Wu, P.-C.; Morris-Natschke, S. L.; Brossi, A.; Bastow, K.-F.; Lang, J.-Y.; Huang, M.-C.; Lee, K.-H. Bioorg. Med. Chem. 2010, 18, 803. doi: 10.1016/j.bmc.2009.11.049
[35]	Dong, Y.-Z.; Shi, Q.; Nakagawa-Goto, K.; Lai, C.-Y.; Morris-Natschke, S. L.; Bastow, K.-F.; Lee, K.-H. Bioorg. Med. Chem. Lett. 2010, 20, 4085. doi: 10.1016/j.bmcl.2010.05.079
[36]	Banerji, B.; Killi, S. K.; Katarkar, A.; Chatterjee, S.; Tangella, Y.; Prodhan, C.; Chaudhuri, K. Bioorg. Med. Chem. 2017, 25, 202. doi: 10.1016/j.bmc.2016.10.026
[37]	Saquib, M.; Baig, M. H.; Khan, M. F.; Azmi, S.; Khatoon, S.; Rawat, A. K.; Dong, J. J.; Asad, M.; Arshad, M.; Hussain, M. K. ChemistrySelect 2021, 6, 8754. doi: 10.1002/slct.202101853