Research Progress on Structural Optimization on the Lipid-Soluble Ingredients of Salvia miltiorrhiza

doi:10.6023/cjoc202206054

Abstract

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

Cite this article

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.

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Fig. & Tab. 44

Figure 1. Main water-soluble ingredients of Salvia miltiorrhiza

Figure 2. Main lipid-soluble ingredients of Salvia miltiorrhiza

Figure 3. Structural optimization of tanshinone IIA

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

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

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

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

Table 2. Antitumor activity of tanshinone IIA and compound 11

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

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

Figure 9. Synthesis of compounds 15 and 16

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

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

Figure 11. Synthesis of sulfonamide derivatives of tanshinone IIA

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

Figure 13. Structural optimization of D ring of tanshinone IIA

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

Figure 15. Design principle of compound 23

Figure 16. Design principle of compound 24

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

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

Table 4. Antitumor activity of tanshinone IIA and compound 26

Figure 19. Structural optimization of tanshinone I

Figure 20. Structural modification of A ring of tanshinone I

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

Figure 22. Synthesis of compounds 28 and 29

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

Table 5. Antibacterial activity of tanshinone IIA and compound 30

Figure 24. Polycyclic modification strategy of tanshinone I

Figure 25. Structural optimization of cryptotanshinone

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

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

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

Figure 29. Aminolysis derivatives of cryptotanshinone D ring

Figure 30. Structural optimization of neo-tanshinlactone

Figure 31. Synthesis of compound 39

Figure 32. Simplification of A ring of neo-tanshinlactone

Figure 33. Synthesis of compound 41

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

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

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

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

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

Figure 39. Heterozygous derivatives of neosalvianolide and chalcone

References 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

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