Synthesis of Limonin Derivatives with Improved Anti-inflammatory and Analgesic Properties

Author(s): Chengshu Jia, Bin Hu, Yingying Ji, Yourui Su, Guoqing Gong, Qihua Zhu, Yungen Xu*

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 3 , 2020

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Graphical Abstract:


Background: Limonoids represent an important class of natural products which possess a broad range of biological activities. Albeit their enormous potentials as therapeutic candidates, they usually suffer from low bioavailability, poor aqueous solubility and relatively weak biological activities which result in significant challenges in the clinic applications. Therefore, the exploration and development of novel limonin derivatives with improved drug-like properties through the structural modifications recently have attracted great attention in the biological and medicinal chemistry field.

Methods: Based on the structural modifications of C17-furan ring in limonin, a series of limonin derivatives was designed, synthesized and screened for their anti-inflammatory and analgesic activities in vivo.

Results and Conclusion: Preliminary pharmacological studies revealed that most tested compounds exhibited more potent anti-inflammatory and analgesic efficacies than lead molecule limonin. Especially, for compound 3f, it exhibited a stronger anti-inflammatory effect than that of naproxen and comparable analgesic potency with aspirin. In the formalin test, 3f showed an obviously attenuated phase-II pain response which indicated that it may produce an anti-inflammatory effect in the periphery. Furthermore, the significantly low hERG inhibition (IC50 >100 μM) and high LD50 value of target molecule 3f further demonstrated it as a promising analgesic/anti-inflammatory candidate with excellent drug-like profiles.

Keywords: Limonin derivatives, anti-inflammatory effect, analgesic activity, drug-like properties, C17-furan, hERG.

Roy, A.; Saraf, S. Limonoids: Overview of significant bioactive triterpenes distributed in plants kingdom. Biol. Pharm. Bull., 2006, 29(2), 191-201.
[] [PMID: 16462017]
Zhang, Y.; Xu, H. Recent progress in the chemistry and biology of limonoids. RSC Advances, 2017, 7(56), 35191-35220.
Ruberto, G.; Renda, A.; Tringali, C.; Napoli, E.M.; Simmonds, M.S.J. Citrus limonoids and their semisynthetic derivatives as antifeedant agents against Spodoptera frugiperda larvae. A structure-activity relationship study. J. Agric. Food Chem., 2002, 50(23), 6766-6774.
[] [PMID: 12405773]
Carpinella, M.C.; Defago, M.T.; Valladares, G.; Palacios, S.M. Antifeedant and insecticide properties of a limonoid from Melia azedarach (Meliaceae) with potential use for pest management. J. Agric. Food Chem., 2003, 51(2), 369-374.
[] [PMID: 12517097]
Cai, J-Y.; Zhang, Y.; Luo, S-H.; Chen, D-Z.; Tang, G-H.; Yuan, C-M.; Di, Y-T.; Li, S-H.; Hao, X-J.; He, H-P.; Aphanamixoid, A. Aphanamixoid A, a potent defensive limonoid, with a new carbon skeleton from Aphanamixis polystachya. Org. Lett., 2012, 14(10), 2524-2527.
[ ] [PMID: 22540189]
Sarigaputi, C.; Sangpech, N.; Palaga, T.; Pudhom, K. Suppression of inducible nitric oxide synthase pathway by 7-deacetylgedunin, a limonoid from Xylocarpus sp. Planta Med., 2015, 81(4), 312-319.
[] [PMID: 25714725]
Akihisa, T.; Noto, T.; Takahashi, A.; Fujita, Y.; Banno, N.; Tokuda, H.; Koike, K.; Suzuki, T.; Yasukawa, K.; Kimura, Y. Melanogenesis inhibitory, anti-inflammatory, and chemopreventive effects of limonoids from the seeds of Azadirachta indicia A. Juss. (neem). J. Oleo Sci., 2009, 58(11), 581-594.
[] [PMID: 19844073]
Xie, F.; Zhang, M.; Zhang, C-F.; Wang, Z-T.; Yu, B-Y.; Kou, J-P. Anti-inflammatory and analgesic activities of ethanolic extract and two limonoids from Melia toosendan fruit. J. Ethnopharmacol., 2008, 117(3), 463-466.
[] [PMID: 18384989]
Chi, G.; Wei, M.; Xie, X.; Soromou, L.W.; Liu, F.; Zhao, S. Suppression of MAPK and NF-κB pathways by limonene contributes to attenuation of lipopolysaccharide-induced inflammatory responses in acute lung injury. Inflammation, 2013, 36(2), 501-511.
[] [PMID: 23180366]
Matsuda, H.; Yoshikawa, M.; Iinuma, M.; Kubo, M. Antinociceptive and anti-inflammatory activities of limonin isolated from the fruits of Evodia rutaecarpa var. bodinieri. Planta Med., 1998, 64(4), 339-342.
[] [PMID: 9619117]
Sanna, G.; Madeddu, S.; Giliberti, G.; Ntalli, N.G.; Cottiglia, F.; De Logu, A.; Agus, E.; Caboni, P. Limonoids from Melia azedarach fruits as inhibitors of Flaviviruses and Mycobacterium tubercolosis. PLoS One, 2015, 10(10), e0141272
[] [PMID: 26485025]
Maneerat, W.; Laphookhieo, S.; Koysomboon, S.; Chantrapromma, K. Antimalarial, antimycobacterial and cytotoxic limonoids from Chisocheton siamensis. Phytomedicine, 2008, 15(12), 1130-1134.
[] [PMID: 18617378]
Balestrieri, E.; Pizzimenti, F.; Ferlazzo, A.; Giofrè, S.V.; Iannazzo, D.; Piperno, A.; Romeo, R.; Chiacchio, M.A.; Mastino, A.; Macchi, B. Antiviral activity of seed extract from Citrus bergamia towards human retroviruses. Bioorg. Med. Chem., 2011, 19(6), 2084-2089.
[] [PMID: 21334901]
Ono, E.; Inoue, J.; Hashidume, T.; Shimizu, M.; Sato, R. Anti-obesity and anti-hyperglycemic effects of the dietary citrus limonoid nomilin in mice fed a high-fat diet. Biochem. Biophys. Res. Commun., 2011, 410(3), 677-681.
[] [PMID: 21693102]
Chidambara Murthy, K.N.; Jayaprakasha, G.K.; Kumar, V.; Rathore, K.S.; Patil, B.S. Citrus limonin and its glucoside inhibit colon adenocarcinoma cell proliferation through apoptosis. J. Agric. Food Chem., 2011, 59(6), 2314-2323.
[] [PMID: 21338095]
Kim, J.; Jayaprakasha, G.K.; Patil, B.S. Limonoids and their anti-proliferative and anti-aromatase properties in human breast cancer cells. Food Funct., 2013, 4(2), 258-265.
[] [PMID: 23117440]
Chidambara Murthy, K.N.; Jayaprakasha, G.K.; Patil, B.S. Citrus limonoids and curcumin additively inhibit human colon cancer cells. Food Funct., 2013, 4(5), 803-810.
[] [PMID: 23584140]
Tundis, R.; Loizzo, M.R.; Menichini, F. An overview on chemical aspects and potential health benefits of limonoids and their derivatives. Crit. Rev. Food Sci. Nutr., 2014, 54(2), 225-250.
[] [PMID: 24188270]
Yoon, J.S.; Yang, H.; Kim, S.H.; Sung, S.H.; Kim, Y.C. Limonoids from Dictamnus dasycarpus protect against glutamate-induced toxicity in primary cultured rat cortical cells. J. Mol. Neurosci., 2010, 42(1), 9-16.
[] [PMID: 20155333]
Aliero, B.L. Larvaecidal effects of aqueous extracts of Azadirachta indica (neem) on the larvae of Anopheles mosquito. Afr. J. Biotechnol., 2003, 2(9), 325-327.
Yang, Y.; Wang, X.; Zhu, Q.; Gong, G.; Luo, D.; Jiang, A.; Yang, L.; Xu, Y. Synthesis and pharmacological evaluation of novel limonin derivatives as anti-inflammatory and analgesic agents with high water solubility. Bioorg. Med. Chem. Lett., 2014, 24(7), 1851-1855.
[] [PMID: 24569111]
Manners, G.D.; Jacob, R.A.; Breksa, A.P., III; Schoch, T.K.; Hasegawa, S. Bioavailability of citrus limonoids in humans. J. Agric. Food Chem., 2003, 51(14), 4156-4161.
[] [PMID: 12822961]
Hosseinzadeh, H.; Ramezani, M.; Salmani, G. Antinociceptive, anti-inflammatory and acute toxicity effects of Zataria multiflora Boiss extracts in mice and rats. J. Ethnopharmacol., 2000, 73(3), 379-385.
[] [PMID: 11090990]
Singh, P.P.; Junnarkar, A.Y.; Rao, C.S.; Varma, R.K.; Shridhar, D.R. Acetic acid and phenylquinone writhing test: A critical study in mice. Methods Find. Exp. Clin. Pharmacol., 1983, 5(9), 601-606.
[PMID: 6668969]
Ramabadran, K.; Bansinath, M.; Turndorf, H.; Puig, M.M. Tail immersion test for the evaluation of a nociceptive reaction in mice. Methodological considerations. J. Pharmacol. Methods, 1989, 21(1), 21-31.
[] [PMID: 2704245]
Sewell, R.D.E.; Spencer, P.S.J. Antinociceptive activitiy of narcotic agonist and partial agonist analgesics and other agents in the tail-immersion test in mice and rats. Neuropharmacology, 1976, 15(11), 683-688.
[] [PMID: 12485]
Kotlinska, J.H.; Gibula-Bruzda, E.; Witkowska, E.; Chung, N.N.; Schiller, P.W.; Izdebski, J. Antinociceptive effects of two deltorphins analogs in the tail-immersion test in rats. Peptides, 2013, 39, 103-110.
[] [PMID: 23183627]
Yin, Z-Y.; Li, L.; Chu, S-S.; Sun, Q.; Ma, Z-L.; Gu, X-P. Antinociceptive effects of dehydrocorydaline in mouse models of inflammatory pain involve the opioid receptor and inflammatory cytokines. Sci. Rep., 2016, 6, 27129.
[] [PMID: 27272194]
Hunskaar, S.; Fasmer, O.B.; Hole, K. Formalin test in mice, a useful technique for evaluating mild analgesics. J. Neurosci. Methods, 1985, 14(1), 69-76.
[] [PMID: 4033190]
Roche, O.; Trube, G.; Zuegge, J.; Pflimlin, P.; Alanine, A.; Schneider, G. A virtual screening method for prediction of the HERG potassium channel liability of compound libraries. ChemBioChem, 2002, 3(5), 455-459.
[<455:AID-CBIC455>3.0.CO;2-L] [PMID: 12007180]
Wang, S-C.; Yang, Y.; Liu, J.; Jiang, A-D.; Chu, Z-X.; Chen, S-Y.; Gong, G-Q.; He, G-W.; Xu, Y-G.; Zhu, Q-H. Discovery of novel limonin derivatives as potent anti-inflammatory and analgesic agents. Chin. J. Nat. Med., 2018, 16(3), 231-240.
[] [PMID: 29576060]
Jin, S.; Wang, J.; Chen, S.; Jiang, A.; Jiang, M.; Su, Y.; Yan, W.; Xu, Y.; Gong, G. A novel limonin derivate modulates inflammatory response by suppressing the TLR4/NF-κB signalling pathway. Biomed. Pharmacother., 2018, 100, 501-508.
[] [PMID: 29477914]
Kim, J.; Jayaprakasha, G.K.; Muthuchamy, M.; Patil, B.S. Structure-function relationships of citrus limonoids on p38 MAP kinase activity in human aortic smooth muscle cells. Eur. J. Pharmacol., 2011, 670(1), 44-49.
[] [PMID: 21924259]
Perez, J.L.; Jayaprakasha, G.K.; Valdivia, V.; Munoz, D.; Dandekar, D.V.; Ahmad, H.; Patil, B.S. Limonin methoxylation influences the induction of glutathione S-transferase and quinone reductase. J. Agric. Food Chem., 2009, 57(12), 5279-5286.
[] [PMID: 19480426]
Yan, Y.; Yuan, C-M.; Di, Y-T.; Huang, T.; Fan, Y-M.; Ma, Y.; Zhang, J-X.; Hao, X-J. Limonoids from Munronia henryi and their anti-tobacco mosaic virus activity. Fitoterapia, 2015, 107, 29-35.
[] [PMID: 26388557]
Hu, B.; Song, Q.; Xu, Y. Scale-up synthesis of antidepressant drug vilazodone. Org. Process Res. Dev., 2012, 16(9), 1552-1557.
Gan, Z.; Hu, B.; Song, Q.; Xu, Y. Convenient chlorination of some special aromatic compounds using N-chlorosuccinimide. Synthesis, 2012, 44(07), 1074-1078.
Hu, B.; Deng, L. Catalytic asymmetric synthesis of trifluoromethylated γ-amino acids through umpolung addition of trifluoromethyl imines to carboxylic acid derivatives. Angew. Chem. Int. Ed. Engl., 2018, 57(8), 2233-2237.
[] [PMID: 29232488]
Hu, B.; Deng, L. Deng, Li, Direct catalytic asymmetric synthesis of trifluoromethylated r-amino esters/lactones via umpolung strategy. J. Org. Chem., 2019, 84(2), 994-1005.
[] [PMID: 30543752]
Hu, B.; Bezpalko, M.W.; Fei, C.; Dickie, D.A.; Foxman, B.M.; Deng, L. Origin of and a solution for uneven efficiency by cinchona alkaloid-derived, pseudoenantiomeric catalysts for asymmetric reactions. J. Am. Chem. Soc., 2018, 140(42), 13913-13920.
[] [PMID: 30252465]
Geissman, T.A.; Tulagin, V. Some observations on the structure of limonin. J. Org. Chem., 1946, 11(6), 760-770.
[] [PMID: 20282500]
Hunskaar, S.; Hole, K. The formalin test in mice: Dissociation between inflammatory and non-inflammatory pain. Pain, 1987, 30(1), 103-114.
[] [PMID: 3614974]
Sanguinetti, M.C.; Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature, 2006, 440(7083), 463-469.
[] [PMID: 16554806]

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Year: 2020
Page: [285 - 299]
Pages: 15
DOI: 10.2174/1570180816666181113102359

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