Synthesis and in vitro Anti-proliferative Activities on LNCaP, LS180 and MKN45 of Novel 20(R)-Panaxadiol Derivatives

  • Авторы: Deng J.1, Yang X.2, Luan M.2, Liu S.2, Zhang J.2, Jiang S.3, Wang W.4, Hou G.5, Meng Q.2, Wang H.2
  • Учреждения:
    1. School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai Universit
    2. School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University
    3. , Shandong Shenxiangchuanqi Biotechnology Co., Ltd
    4. , Shandong Shenxiangchuanqi Biotechnology Co., Ltd.
    5. School of Basic Medical Sciences, Binzhou Medical University
  • Выпуск: Том 23, № 15 (2023)
  • Страницы: 1731-1739
  • Раздел: Oncology
  • URL: https://kld-journal.fedlab.ru/1871-5206/article/view/694346
  • DOI: https://doi.org/10.2174/1871520623666230412095428
  • ID: 694346

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Аннотация

Background: 20(R)-PD, a tetracyclic triterpenoid, is a non-natural saponin present in the form of protopanaxadiol. Because of its essential biological activities, especially anti-tumor activity, structural modification of 20(R)-PD and the development of innovative and novel 20(R)-PD derivatives with better anti-tumor activity are increasingly relevant.

Aims:20(R)-Panaxadiol (20(R)-PD) can inhibit tumor proliferation. Three series of novel 20(R)-PD derivatives were synthesized by modifying the A-ring.

Objective: The objective of this work was to synthesize and evaluate the in vitro anti-proliferative activities of 20(R)- PD derivatives in LNCaP, LS180, and MKN45 cancer cells. Structural modifications were performed at the C-3 position and A-ring.

Methods: The in vitro anti-proliferative activities of novel derivatives in LNCaP, LS180, and MKN45 cells were evaluated by the MTT assay. The effects of compounds 5 and C9 on apoptosis were determined by flow cytometry.

Results: Compounds 5, B2, C2, C4, C7, C8, C9, C10, and C11 exhibited good anti-proliferative activities in LNCaP, LS180, and MKN45 cells in vitro. The best anti-proliferative activity was observed for the C-series derivatives with the introduction of amino acids at the C-3 position. C9 exhibited good potent activity with an IC50 of 2.89 µM.

Conclusion: Compound C9 is a potential candidate with potent anti-proliferative activity.

Об авторах

Jianqiang Deng

School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai Universit

Email: info@benthamscience.net

Xinyu Yang

School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University

Email: info@benthamscience.net

Mingzhu Luan

School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University

Email: info@benthamscience.net

Shuqi Liu

School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University

Email: info@benthamscience.net

Juan Zhang

School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University

Email: info@benthamscience.net

Sheng Jiang

, Shandong Shenxiangchuanqi Biotechnology Co., Ltd

Email: info@benthamscience.net

Wenshui Wang

, Shandong Shenxiangchuanqi Biotechnology Co., Ltd.

Email: info@benthamscience.net

Guige Hou

School of Basic Medical Sciences, Binzhou Medical University

Email: info@benthamscience.net

Qingguo Meng

School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University

Автор, ответственный за переписку.
Email: info@benthamscience.net

Hongbo Wang

School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University

Автор, ответственный за переписку.
Email: info@benthamscience.net

Список литературы

  1. Shibata, S.; Tanaka, O.; Nagai, M.; Ishii, T. Studies on the constituents of japanese and chinese crude drugs. XII. Panaxadiol, a sapogenin of ginseng roots. (2). Chem. Pharm. Bull., 1963, 11(6), 762-765. doi: 10.1248/cpb.11.762 PMID: 14068711
  2. Karikura, M.; Miyase, T.; Tanizawa, H.; Takino, Y.; Taniyama, T.; Hayashi, T. Studies on absorption, distribution, excretion and metabolism of ginseng saponins. V. The decomposition products of ginsenoside Rb2 in the large intestine of rats. Chem. Pharm. Bull. , 1990, 38(10), 2859-2861. doi: 10.1248/cpb.38.2859 PMID: 2076572
  3. Li, G.; Cui, Y.; Wang, H.; Kwon, W.S.; Yang, D.C. Molecular differentiation of Russian wild ginseng using mitochondrial nad 7 intron 3 region. J. Ginseng Res., 2017, 41(3), 326-329. doi: 10.1016/j.jgr.2016.06.003 PMID: 28701873
  4. Wang, C.; Liu, J.; Deng, J.; Wang, J.; Weng, W.; Chu, H.; Meng, Q. Advances in the chemistry, pharmacological diversity, and metabolism of 20(R)-ginseng saponins. J. Ginseng Res., 2020, 44(1), 14-23. doi: 10.1016/j.jgr.2019.01.005 PMID: 32095093
  5. Liu, J.; Xu, Y.; Yang, J.; Wang, W.; Zhang, J.; Zhang, R.; Meng, Q. Discovery, semisynthesis, biological activities, and metabolism of ocotillol-type saponins. J. Ginseng Res., 2017, 41(3), 373-378. doi: 10.1016/j.jgr.2017.01.001 PMID: 28701880
  6. Yang, Q.; Wang, N.; Zhang, J.; Chen, G.; Xu, H.; Meng, Q.; Du, Y.; Yang, X.; Fan, H. In vitro and in silico evaluation of stereoselective effect of ginsenoside isomers on platelet P2Y12 receptor. Phytomedicine, 2019, 64152899 doi: 10.1016/j.phymed.2019.152899 PMID: 31454649
  7. Chen, G.; Ge, H.; Li, J.; Li, J.; Zhai, X.; Wu, J.; Song, Y. Microbial transformation of 20(R)-panaxadiol by Absidia corymbifera AS 3.3387. J. Mol. Catal., B Enzym., 2016, 123, 154-159. doi: 10.1016/j.molcatb.2015.11.015
  8. Song, Y.; Yan, S.S.; Lin, H.J.; Li, J.L.; Zhai, X.G.; Ren, J.; Chen, G.T. ( R )-panaxadiol by whole cells of filamentous fungus Absidia coerulea AS 3.3382. J. Asian Nat. Prod. Res., 2018, 20(8), 719-726. doi: 10.1080/10286020.2017.1358267 PMID: 28944684
  9. Wei, Y.; Ma, C.M.; Hattori, M. Synthesis of dammarane-type triterpene derivatives and their ability to inhibit HIV and HCV proteases. Bioorg. Med. Chem., 2009, 17(8), 3003-3010. doi: 10.1016/j.bmc.2009.03.019 PMID: 19339186
  10. Bi, Y.; Ma, C.; Zhou, Z.; Zhang, T.; Zhang, H.; Zhang, X.; Lu, J.; Meng, Q.; Lewis, P.J.; Xu, J. Synthesis and antibacterial evaluation of novel hydrophilic ocotillol-type triterpenoid derivatives from 20 (S)-protopanaxadiol. Rec. Nat. Prod., 2015, 9(3), 356.
  11. Zhang, J.; Zhang, Q.; Xu, Y.; Li, H.; Zhao, F.; Wang, C.; Liu, Z.; Liu, P.; Liu, Y.; Meng, Q.; Zhao, F. Synthesis and in vitro anti-inflammatory activity of C20 epimeric ocotillol-type triterpenes and protopanaxadiol. Planta Med., 2019, 85(4), 292-301. doi: 10.1055/a-0770-0994 PMID: 30380571
  12. Wang, M.; Li, H.; Liu, W.; Cao, H.; Hu, X.; Gao, X.; Xu, F.; Li, Z.; Hua, H.; Li, D. Dammarane-type leads panaxadiol and protopanaxadiol for drug discovery: Biological activity and structural modification. Eur. J. Med. Chem., 2020, 189112087 doi: 10.1016/j.ejmech.2020.112087 PMID: 32007667
  13. Wang, Z.; Li, M.Y.; Zhang, Z.H.; Zuo, H.X.; Wang, J.Y.; Xing, Y.; Ri, M.; Jin, H.L.; Jin, C.H.; Xu, G.H.; Piao, L.X.; Jiang, C.G.; Ma, J.; Jin, X. Panaxadiol inhibits programmed cell death-ligand 1 expression and tumour proliferation via hypoxia-inducible factor (HIF)-1α and STAT3 in human colon cancer cells. Pharmacol. Res., 2020, 155104727 doi: 10.1016/j.phrs.2020.104727 PMID: 32113874
  14. Xiao, S.; Wang, X.; Xu, L.; Li, T.; Cao, J.; Zhao, Y. Novel panaxadiol triazole derivatives induce apoptosis in HepG-2 cells through the mitochondrial pathway. Bioorg. Chem., 2020, 102104078 doi: 10.1016/j.bioorg.2020.104078 PMID: 32702511
  15. Yan, B.; Chen, Z.; Zhai, X.; Yin, G.; Ai, Y.; Chen, G. Microbial carbonylation and hydroxylation of 20(R)-panaxadiol by Aspergillus niger. Nat. Prod. Res., 2018, 32(7), 782-787. doi: 10.1080/14786419.2017.1360887 PMID: 28768436
  16. Lin, X.H.; Cao, M.N.; He, W.N.; Yu, S.W.; Guo, D.A.; Ye, M. Biotransformation of 20(R)-panaxadiol by the fungus Rhizopus chinensis. Phytochemistry, 2014, 105, 129-134. doi: 10.1016/j.phytochem.2014.06.001 PMID: 24994672
  17. Shibata, S.; Fujita, M.; Itokawa, H.; Tanaka, O.; Ishii, T. Studies on the constituents of japanese and chinese crude drugs. XI. Panaxadiol, a sapogenin of ginseng roots. (1). Chem. Pharm. Bull. , 1963, 11(6), 759-761. doi: 10.1248/cpb.11.759 PMID: 14068710
  18. Nagai, M.; Tanaka, O.; Shibata, S. Chemical studies on the oriental plant drugs. XXVI. Saponins and sapogenins of ginseng. The absolute configurations of Cinenic Acid and Panaxadiol. Chem. Pharm. Bull. , 1971, 19(11), 2349-2353. doi: 10.1248/cpb.19.2349
  19. Wang, J.Z.; Weng, W.Z.; Ma, Y.; He, X.T.; Meng, Q.G. Crystal structure of (1 S, 3a R, 3b R, 10a R, 10b R, 12a R)-8-amino-3a,3b,6,6,10a-pentamethyl-1-(( S )-2,6,6-trimethyltetrahydro-2 H -pyran-2-yl)-2,3,3a,3b,4,5,5a,6,10,10a,10b,11,12,12a-tetradecahydro-1 H -cyclopenta7,8phenanthro2,3- dthiazol-12-ol - a panaxadiol dervative, C 31 H 50 N 2 O 2 S. Z. Kristallogr. New Cryst. Struct., 2019, 234(3), 397-400. doi: 10.1515/ncrs-2018-0238
  20. Zhang, C.; Li, X.; Gao, Y.; Zhang, L.; Fu, X. Synthesis and primary research on antitumor activity of three new panaxadiol fatty acid esters. Chem. Res. Chin. Univ., 2007, 23(2), 176-182. doi: 10.1016/S1005-9040(07)60037-3
  21. Wu, Y.; Chen, W.Q.; Zhao, Y.Q.; Piao, H.R. Efficient synthesis of panaxadiol derivatives using continuous-flow microreactor and evaluation of anti-tumor activity. Chin. Chem. Lett., 2015, 26(3), 334-338. doi: 10.1016/j.cclet.2014.11.013
  22. Xiao, S.; Chen, S.; Sun, Y.; Zhou, W.; Piao, H.; Zhao, Y. Synthesis and anti-tumor evaluation of panaxadiol halogen-derivatives. Bioorg. Med. Chem. Lett., 2017, 27(17), 4204-4211. doi: 10.1016/j.bmcl.2017.06.061 PMID: 28757064
  23. Li, X.L.; Wang, C.Z.; Mehendale, S.R.; Sun, S.; Wang, Q.; Yuan, C.S. Panaxadiol, a purified ginseng component, enhances the anti-cancer effects of 5-fluorouracil in human colorectal cancer cells. Cancer Chemother. Pharmacol., 2009, 64(6), 1097-1104. doi: 10.1007/s00280-009-0966-0 PMID: 19277659
  24. Deng, J.Q.; Mu, X.D.; Zhao, R.L.; Liu, Z.; Tang, H.J.; He, M.; Meng, Q.G. Crystal structure of (20 R)-20,25-epoxy-dammaran-3,12-dione, C 30 H 48 O 3. Z. Kristallogr. New Cryst. Struct., 2018, 234(1), 145-147. doi: 10.1515/ncrs-2018-0237
  25. Baek, N.I.; Kim, D.S.; Lee, Y.H.; Park, J.D.; Lee, C.B.; Kim, S.I. Cytotoxicities of ginseng saponins and their degradation products against some cancer cell lines. Arch. Pharm. Res., 1995, 18(3), 164-168. doi: 10.1007/BF02979189
  26. Jin, Y.H.; Choi, J.; Shin, S.; Lee, K.Y.; Park, J.H.; Lee, S.K. Panaxadiol selectively inhibits cyclin A-associated Cdk2 activity by elevating p21WAF1/CIP1 protein levels in mammalian cells. Carcinogenesis, 2003, 24(11), 1767-1772. doi: 10.1093/carcin/bgg097 PMID: 12819186
  27. Liu, X.K.; Ye, B.J.; Wu, Y.; Lin, Z.H.; Zhao, Y.Q.; Piao, H.R. Synthesis and anti-tumor evaluation of panaxadiol derivatives. Eur. J. Med. Chem., 2011, 46(6), 1997-2002. doi: 10.1016/j.ejmech.2011.02.022 PMID: 21439693
  28. Abu-Dief, A.M.; El-Khatib, R.M.; Aljohani, F.S.; Al-Abdulkarim, H.A.; Alzahrani, S.; El-Sarrag, G.; Ismael, M. Synthesis, structural elucidation, DFT calculation, biological studies and DNA interaction of some aryl hydrazone Cr3+, Fe3+, and Cu2+ chelates. Comput. Biol. Chem., 2022, 97107643 doi: 10.1016/j.compbiolchem.2022.107643 PMID: 35189479
  29. El-Remaily, M.A.E.A.A.A.; Soliman, A.M.M.; Khalifa, M.E.; El-Metwaly, N.M.; Alsoliemy, A.; El-Dabea, T.; Abu-Dief, A.M. Rapidly, highly yielded and green synthesis of dihydrotetrazolo1,5‐ apyrimidine derivatives in aqueous media using recoverable Pd (II) thiazole catalyst accelerated by ultrasonic: Computational studies. Appl. Organomet. Chem., 2022, 36(2)e6320 doi: 10.1002/aoc.6320
  30. Abu-Dief, A.M.; El-khatib, R.M.; Aljohani, F.S.; Alzahrani, S.O.; Mahran, A.; Khalifa, M.E.; El-Metwaly, N.M. Synthesis and intensive characterization for novel Zn(II), Pd(II), Cr(III) and VO(II)-Schiff base complexes; DNA-interaction, DFT, drug-likeness and molecular docking studies. J. Mol. Struct., 2021, 1242130693 doi: 10.1016/j.molstruc.2021.130693
  31. Abu-Dief, A.M.; Abdel-Rahman, L.H.; Abdelhamid, A.A.; Marzouk, A.A.; Shehata, M.R.; Bakheet, M.A.; Almaghrabi, O.A.; Nafady, A. Synthesis and characterization of new Cr(III), Fe(III) and Cu(II) complexes incorporating multi-substituted aryl imidazole ligand: Structural, DFT, DNA binding, and biological implications. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2020, 228117700 doi: 10.1016/j.saa.2019.117700 PMID: 31748163
  32. Li, F.; Liu, Z.; Sun, H.; Li, C.; Wang, W.; Ye, L.; Yan, C.; Tian, J.; Wang, H. PCC0208017, a novel small-molecule inhibitor of MARK3/MARK4, suppresses glioma progression in vitro and in vivo. Acta Pharm. Sin. B, 2020, 10(2), 289-300. doi: 10.1016/j.apsb.2019.09.004 PMID: 32082974
  33. Yang, Y.; Guan, D.; Lei, L.; Lu, J.; Liu, J.Q.; Yang, G.; Yan, C.; Zhai, R.; Tian, J.; Bi, Y.; Fu, F.; Wang, H. H6, a novel hederagenin derivative, reverses multidrug resistance in vitro and in vivo. Toxicol. Appl. Pharmacol., 2018, 341, 98-105. doi: 10.1016/j.taap.2018.01.015 PMID: 29408042

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