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The Chemistry and Pharmacology of Citrus Limonoids

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Gualdani, Roberta [UCL] Cavalluzzi, Maria Lentini, Giovanni Habtemariam, Solomon

Citrus limonoids (CLs) are a group of highly oxygenated terpenoid secondary metabolites found mostly in the seeds, fruits and peel tissues of citrus fruits such as lemons, limes, oranges, pumellos, grapefruits, bergamots, and mandarins. Represented by limonin, the aglycones and glycosides of CLs have shown to display numerous pharmacological activities including anticancer, antimicrobial, antioxidant, antidiabetic and insecticidal among others. In this review, the chemistry and pharmacology of CLs are systematically scrutinised through the use of medicinal chemistry tools and structure-activity relationship approach. Synthetic derivatives and other structurally-related limonoids from other sources are include in the analysis. With the focus on literature in the past decade, the chemical classification of CLs, their physico-chemical properties as drugs, their biosynthesis and enzymatic modifications, possible ways of enhancing their biological activities through structural modifications, their ligand efficiency metrics and systematic graphical radar plot analysis to assess their developability as drugs are among those discussed in detail.

Document type Article de périodique (Journal article)
Publication date 2016
Language Anglais
Journal information "Molecules" - Vol. 21, no.11, p. 1530 (2016)
Peer reviewed yes
Publisher MDPI AG
issn 1420-3049
e-issn 1420-3049
Publication status Publié
Affiliation UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire
Links
  1. Manners Gary D., Citrus Limonoids: Analysis, Bioactivity, and Biomedical Prospects, 10.1021/jf071797h
  2. Wang Shouchuang, Tu Hong, Wan Jian, Chen Wei, Liu Xianqing, Luo Jie, Xu Juan, Zhang Hongyan, Spatio-temporal distribution and natural variation of metabolites in citrus fruits, 10.1016/j.foodchem.2015.11.113
  3. Hamdan D., El-Readi M. Z., Tahrani A., Herrmann F., Kaufmann D., Farrag N., El-Shazly A., Wink M., Secondary Metabolites of Ponderosa Lemon (Citrus pyriformis) and their Antioxidant, Anti-Infl ammatory, and Cytotoxic Activities, 10.5560/znc.2011.66c0385
  4. Hamdan Dalia, El-Readi Mahmoud Zaki, Tahrani Ahmad, Herrmann Florian, Kaufmann Dorothea, Farrag Nawal, El-Shazly Assem, Wink Michael, Chemical composition and biological activity of Citrus jambhiri Lush, 10.1016/j.foodchem.2010.12.129
  5. Russo Marina, Arigò Adriana, Calabrò Maria Luisa, Farnetti Sara, Mondello Luigi, Dugo Paola, Bergamot ( Citrus bergamia Risso ) as a source of nutraceuticals: Limonoids and flavonoids, 10.1016/j.jff.2015.10.005
  6. Nakagawa Hiroyuki, Takaishi Yoshihisa, Tanaka Naonobu, Tsuchiya Koichiro, Shibata Hirofumi, Higuti Tomihiko, Chemical Constituents from the Peels ofCitrussudachi, 10.1021/np060217s
  7. Yang Ying, Zhao Xi Juan, Pan Yu, Zhou Zhiqin, Identification of the chemical compositions of Ponkan peel by ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry, 10.1039/c5ay02633d
  8. Hasegawa, Volume 758, 9 (2000)
  9. Hasegawa Shin, Miyake Masaki, Biochemistry and biological functions of citrus limonoids, 10.1080/87559129609541089
  10. Glabasnia Anneke, Hofmann Thomas, On the non-enzymatic liberation of limonin and C17-epilimonin from limonin-17-β-d-glucopyranoside in orange juice, 10.1007/s00217-008-0906-y
  11. Li Shaojie, Wang Zhuang, Ding Fan, Sun Da, Ma Zhaocheng, Cheng Yunjiang, Xu Juan, Content changes of bitter compounds in ‘Guoqing No.1’ Satsuma mandarin (Citrus unshiu Marc.) during fruit development of consecutive 3 seasons, 10.1016/j.foodchem.2013.09.040
  12. Baldwin Elizabeth, Plotto Anne, Manthey John, McCollum Greg, Bai Jinhe, Irey Mike, Cameron Randall, Luzio Gary, Effect of Liberibacter Infection (Huanglongbing Disease) of Citrus on Orange Fruit Physiology and Fruit/Fruit Juice Quality: Chemical and Physical Analyses, 10.1021/jf9031958
  13. Raithore Smita, Dea Sharon, McCollum Greg, Manthey John A, Bai Jinhe, Leclair Clotilde, Hijaz Faraj, Narciso Jan A, Baldwin Elizabeth A, Plotto Anne, Development of delayed bitterness and effect of harvest date in stored juice from two complex citrus hybrids : Development of delayed bitterness in juice of complex citrus hybrids, 10.1002/jsfa.7105
  14. KARIM M.R., HASHINAGA F., Possible Role of Carboxyl and Imidazole Groups in the Catalysis of Pummelo Limonoid Glucosyltransferase, 10.1016/s1872-2067(10)60130-1
  15. Roy Amit, Saraf Shailendra, Limonoids: Overview of Significant Bioactive Triterpenes Distributed in Plants Kingdom, 10.1248/bpb.29.191
  16. Todaro, Ital. J. Food Sci., 25, 465 (2013)
  17. Verma Jay Prakash, Singh Siddhartha, Ghosh Moushumi, Srivastava Pramod Kumar, Identification and characterization of cellular locus of limonin biotransforming enzyme inPseudomonas putida, 10.1111/j.1365-2621.2009.02138.x
  18. Patil, Volume 936, 18 (2006)
  19. Chaudhary P.R., Jayaprakasha G.K., Patil B.S., Porat R., GRAPEFRUIT DEGREENING INFLUENCE ON HEALTH PROMOTING LIMONOIDS AND FLAVONOIDS, 10.17660/actahortic.2012.939.14
  20. Chaudhary Priyanka R., Jayaprakasha G.K., Patil Bhimanagouda S., Ethylene degreening modulates health promoting phytochemicals in Rio Red grapefruit, 10.1016/j.foodchem.2015.04.044
  21. Chaudhary Priyanka, Jayaprakasha G.K., Porat Ron, Patil Bhimanagouda S., Degreening and postharvest storage influences ‘Star Ruby’ grapefruit (Citrus paradisi Macf.) bioactive compounds, 10.1016/j.foodchem.2012.05.095
  22. Bai Jinhe, Manthey John A, Ford Bryan L, Luzio Gary, Cameron Randall G, Narciso Jan, Baldwin Elizabeth A, Effect of extraction, pasteurization and cold storage on flavonoids and other secondary metabolites in fresh orange juice : Effect of extraction, pasteurization and storage on flavonoids in fresh orange juice, 10.1002/jsfa.6097
  23. Ram, Indian J. Agric. Sci., 82, 714 (2012)
  24. Arias Beatriz Álvarez, Ramón-Laca Luis, Pharmacological properties of citrus and their ancient and medieval uses in the Mediterranean region, 10.1016/j.jep.2004.10.019
  25. Chan Yu-Yi, Li Chan-Hao, Shen Yuh-Chiang, Wu Tian-Shung, Anti-inflammatory Principles from the Stem and Root Barks of Citrus medica, 10.1248/cpb.58.61
  26. Xu Huarong, Li Qing, Yin Yidi, Lv Chunxiao, Sun Wanyang, He Bosai, Liu Ran, Chen Xiaohui, Bi Kaishun, Simultaneous determination of three alkaloids, four ginsenosides and limonin in the plasma of normal and headache rats after oral administration of Wu-Zhu-Yu decoction by a novel ultra fast liquid chromatography-tandem mass spectrometry method: applicatio : Application of 4000Qtrap MS/MS system, 10.1002/jms.3183
  27. Lv Mengying, Tian Yuan, Zhang Zunjian, Liang Jingyu, Xu Fengguo, Sun Jianbo, Plant metabolomics driven chemical and biological comparison of the root bark of Dictamnus dasycarpus and Dictamnus angustifolius, 10.1039/c5ra00115c
  28. Zhao Hai-Yan, Yang Li, Wei Jian, Huang Ming, Jiang Jian-Guo, Bioactivity evaluations of ingredients extracted from the flowers of Citrus aurantium L. var. amara Engl, 10.1016/j.foodchem.2012.07.018
  29. Patil Bhimanagouda S., Jayaprakasha G. K., Chidambara Murthy K. N., Vikram Amit, Bioactive Compounds: Historical Perspectives, Opportunities, and Challenges, 10.1021/jf9000132
  30. Codoner-Franch, Curr. Top. Nutraceutical Res., 8, 173 (2010)
  31. Zou Zhuo, Xi Wanpeng, Hu Yan, Nie Chao, Zhou Zhiqin, Antioxidant activity of Citrus fruits, 10.1016/j.foodchem.2015.09.072
  32. Kaur Jasleen, Kaur Gurpreet, An insight into the role of citrus bioactives in modulation of colon cancer, 10.1016/j.jff.2014.12.043
  33. Harris E.D., Poulose S.M., Patil B., CITRUS LIMONOIDS ARE UNIQUE AND EFFECTIVE ANTICANCER AGENTS, 10.17660/actahortic.2007.744.16
  34. Sato Ryuichiro, Nomilin as an Anti-Obesity and Anti-Hyperglycemic Agent, Vitamins & Hormones (2013) ISBN:9780124077669 p.425-439, 10.1016/b978-0-12-407766-9.00018-3
  35. Ejaz Sohail, Ejaz Ahmed, Matsuda Kiku, Lim Chae Woong, Limonoids as cancer chemopreventive agents, 10.1002/jsfa.2396
  36. Patil, Volume 936, 1 (2006)
  37. Heasley Brian, Synthesis of Limonoid Natural Products, 10.1002/ejoc.201001218
  38. Nikkon, 317 (1987)
  39. Ruzicka L., The isoprene rule and the biogenesis of terpenic compounds, 10.1007/bf02167631
  40. Giles P. M., Revised Section F: Natural products and related compounds, 10.1351/pac199971040587
  41. Behenna Douglas C., Corey E. J., Simple Enantioselective Approach to Synthetic Limonoids, 10.1021/ja802376g
  42. Okogun Joseph I., Fakunle Christopher O., Ekong Donald E. U., Connolly Joseph D., Chemistry of the meliacins (limonoids). The structure of melianin A, a new protomeliacin from Melia azedarach , 10.1039/p19750001352
  43. Lakshmi Vijai, Gupta Poonam, An overview of the genus Xylocarpus, 10.1080/14786410701654909
  44. Fraser Leigh-Anne, Mulholland Dulcie A., Fraser David D., Classification of limonoids and protolimonoids using neural networks, 10.1002/(sici)1099-1565(199711/12)8:6<301::aid-pca373>3.0.co;2-2
  45. Yang Yun, Wang Xinhui, Zhu Qihua, Gong Guoqing, Luo Danmeng, Jiang Aidou, Yang Liyan, Xu Yungen, Synthesis and pharmacological evaluation of novel limonin derivatives as anti-inflammatory and analgesic agents with high water solubility, 10.1016/j.bmcl.2014.02.003
  46. Kim Jinhee, Jayaprakasha Guddadarangavvanahally K., Patil Bhimanagouda S., Limonoids and their anti-proliferative and anti-aromatase properties in human breast cancer cells, 10.1039/c2fo30209h
  47. Poulose Shibu M, Jayaprakasha Guddadarangavvanahally K, Mayer Richard T, Girennavar Basavaraj, Patil Bhimanagouda S, Purification of citrus limonoids and their differential inhibitory effects on human cytochrome P450 enzymes, 10.1002/jsfa.2891
  48. Patil Jaiprakash R., Chidambara Murthy K. N., Jayaprakasha G. K., Chetti Mahadev B., Patil Bhimanagouda S., Bioactive Compounds from Mexican Lime (Citrus aurantifolia) Juice Induce Apoptosis in Human Pancreatic Cells, 10.1021/jf901718u
  49. Perez Jose Luis, Jayaprakasha G. K., Valdivia Violeta, Munoz Diana, Dandekar Deepak V., Ahmad Hassan, Patil Bhimanagouda S., Limonin Methoxylation Influences the Induction of GlutathioneS-Transferase and Quinone Reductase, 10.1021/jf803712a
  50. Vanamala Jairam, Leonardi Tety, Patil Bhimanagouda S., Taddeo Stella S., Murphy Mary E., Pike Leonard M., Chapkin Robert S., Lupton Joanne R., Turner Nancy D., Suppression of colon carcinogenesis by bioactive compounds in grapefruit, 10.1093/carcin/bgi318
  51. El-Readi Mahmoud Zaki, Hamdan Dalia, Farrag Nawal, El-Shazly Assem, Wink Michael, Inhibition of P-glycoprotein activity by limonin and other secondary metabolites from Citrus species in human colon and leukaemia cell lines, 10.1016/j.ejphar.2009.09.040
  52. Patil Jaiprakash R., Jayaprakasha G.K., Murthy K.N. Chidambara, Chetti Mahadev B., Patil Bhimanagouda S., Characterization of Citrus aurantifolia bioactive compounds and their inhibition of human pancreatic cancer cells through apoptosis, 10.1016/j.microc.2009.09.008
  53. Han Yong-Long, Yu Hong-Liang, Li Dan, Meng Xiang-Le, Zhou Zhi-Yong, Yu Qi, Zhang Xiao-You, Wang Fu-Jing, Guo Cheng, Inhibitory effects of limonin on six human cytochrome P450 enzymes and P-glycoprotein in vitro, 10.1016/j.tiv.2011.09.023
  54. Shimizu Satomi, Miyamoto Shingo, Fujii Gen, Nakanishi Ruri, Onuma Wakana, Ozaki Yoshihiko, Fujimoto Kyoko, Yano Tomohiro, Mutoh Michihiro, Suppression of intestinal carcinogenesis in Apc-mutant mice by limonin, 10.3164/jcbn.15-28
  55. Langeswaran Kulanthaivel, Kumar Subbaraj Gowtham, Perumal Srinivasan, Revathy Rajendran, Balasubramaniam Maruthaiveeran Periyasamy, Limonin – A citrus limonoid, establish anticancer potential by stabilizing lipid peroxidation and antioxidant status against N-nitrosodiethylamine induced experimental hepatocellular carcinoma, 10.1016/j.bionut.2013.03.006
  56. Das Arabinda, Miller Rickey, Lee Philip, Holden Chrysanthe Alyssa, Lindhorst Scott M., Jaboin Jerry, Vandergrift William A., Banik Naren L., Giglio Pierre, Varma Abhay K., Raizer Jeffery J., Patel Sunil J., A novel component from citrus, ginger, and mushroom family exhibits antitumor activity on human meningioma cells through suppressing the Wnt/β-catenin signaling pathway, 10.1007/s13277-015-3388-0
  57. Chidambara Murthy Kotamballi N., Jayaprakasha G. K., Patil Bhimanagouda S., Citrus limonoids and curcumin additively inhibit human colon cancer cells, 10.1039/c3fo30325j
  58. Poulose Shibu M., Harris Edward D., Patil Bhimanagouda S., Antiproliferative Effects of Citrus Limonoids Against Human Neuroblastoma and Colonic Adenocarcinoma Cells, 10.1207/s15327914nc5601_14
  59. Ahmad Hassan, Li Jiaxing, Polson Maria, Mackie Kimberly, Quiroga Walter, Patil Bhimanagouda S., Citrus Limonoids and Flavonoids: Enhancement of Phase II Detoxification Enzymes and Their Potential in Chemoprevention, ACS Symposium Series (2006) ISBN:0841239576 p.130-143, 10.1021/bk-2006-0936.ch010
  60. Mahmoud Mona F., Hamdan Dalia I., Wink Michael, El-Shazly Assem M., Hepatoprotective effect of limonin, a natural limonoid from the seed of Citrus aurantium var. bigaradia, on D-galactosamine-induced liver injury in rats, 10.1007/s00210-013-0937-1
  61. Mahmoud Mona F., Gamal Samar, El-Fayoumi Hassan M., Limonin attenuates hepatocellular injury following liver ischemia and reperfusion in rats via toll-like receptor dependent pathway, 10.1016/j.ejphar.2014.06.010
  62. Kim Jinhee, Jayaprakasha Guddadarangavvanahally K., Muthuchamy Mariappan, Patil Bhimanagouda S., Structure–function relationships of citrus limonoids on p38 MAP kinase activity in human aortic smooth muscle cells, 10.1016/j.ejphar.2011.08.035
  63. Vikram Amit, Jayaprakasha Guddadarangavvahally K., Jesudhasan Palmy R., Pillai Suresh D., Patil Bhimanagouda S., Limonin 7-methoxime interferes with Escherichia coli biofilm formation and attachment in type 1 pili and antigen 43 dependent manner, 10.1016/j.foodcont.2012.01.030
  64. Ribeiro Alan Bezerra, Abdelnur Patrícia Verardi, Garcia Cleverson Fernando, Belini Adriana, Severino Vanessa G. Pasqualotto, da Silva M. Fátima das G. F., Fernandes João B., Vieira Paulo C., de Carvalho Sérgio A., de Souza Alessandra A., Machado Marcos A., Chemical Characterization ofCitrus sinensisGrafted onC. limoniaand the Effect of Some Isolated Compounds on the Growth ofXylella fastidiosa, 10.1021/jf801103p
  65. Pichaiyongvongdee, Kasetsart J. (Nat. Sci.), 43, 458 (2009)
  66. Mandadi Kranthi K., Jayaprakasha Guddadarangavvanahally K., Bhat Narayan G., Patil Bhimanagouda S., Red Mexican Grapefruit: A Novel Source for Bioactive Limonoids and their Antioxidant Activity, 10.1515/znc-2007-3-405
  67. Balestrieri Emanuela, Pizzimenti Francesco, Ferlazzo Angelo, Giofrè Salvatore V., Iannazzo Daniela, Piperno Anna, Romeo Roberto, Chiacchio Maria Assunta, Mastino Antonio, Macchi Beatrice, Antiviral activity of seed extract from Citrus bergamia towards human retroviruses, 10.1016/j.bmc.2011.01.024
  68. Bilal, J. Arthropod Borne Dis., 6, 104 (2012)
  69. Hafeez Faisal, Akram Waseem, Shaalan Essam Abdel-Salam, Mosquito larvicidal activity of citrus limonoids against Aedes albopictus, 10.1007/s00436-010-2228-9
  70. Perez Jose L, Jayaprakasha Guddarangavvanahally K, Cadena Adriana, Martinez Elvia, Ahmad Hassan, Patil Bhimanagouda S, In vivo induction of phase II detoxifying enzymes, glutathione transferase and quinone reductase by citrus triterpenoids, 10.1186/1472-6882-10-51
  71. Ono Eri, Inoue Jun, Hashidume Tsutomu, Shimizu Makoto, Sato Ryuichiro, Anti-obesity and anti-hyperglycemic effects of the dietary citrus limonoid nomilin in mice fed a high-fat diet, 10.1016/j.bbrc.2011.06.055
  72. Kimira Yoshifumi, Taniuchi Yuri, Nakatani Sachie, Sekiguchi Yuusuke, Kim Hyoun Ju, Shimizu Jun, Ebata Midori, Wada Masahiro, Matsumoto Akiyo, Mano Hiroshi, Citrus limonoid nomilin inhibits osteoclastogenesis in vitro by suppression of NFATc1 and MAPK signaling pathways, 10.1016/j.phymed.2015.08.013
  73. Murthy Kotamballi N. Chidambara, Jayaprakasha Guddadarangavvanahally K., Patil Bhimanagouda S, Cytotoxicity of obacunone and obacunone glucoside in human prostate cancer cells involves Akt-mediated programmed cell death, 10.1016/j.tox.2015.01.008
  74. Kim Jinhee, Jayaprakasha G.K., Patil Bhimanagouda S., Obacunone exhibits anti-proliferative and anti-aromatase activity in vitro by inhibiting the p38 MAPK signaling pathway in MCF-7 human breast adenocarcinoma cells, 10.1016/j.biochi.2014.06.002
  75. Murthy, Toxicol., 49, 1616 (2011)
  76. Vikram Amit, Jayaprakasha Guddadarangavvanahally K., Jesudhasan Palmy R., Pillai Suresh D., Patil Bhimanagouda S., Obacunone Represses Salmonella Pathogenicity Islands 1 and 2 in anenvZ-Dependent Fashion, 10.1128/aem.01326-12
  77. Vikram Amit, Jesudhasan Palmy R., Jayaprakasha G.K., Pillai B.S., Patil Bhimanagouda S., Grapefruit bioactive limonoids modulate E. coli O157:H7 TTSS and biofilm, 10.1016/j.ijfoodmicro.2010.04.012
  78. Horiba Taro, Katsukawa Masahiro, Mita Moeko, Sato Ryuichiro, Dietary obacunone supplementation stimulates muscle hypertrophy, and suppresses hyperglycemia and obesity through the TGR5 and PPARγ pathway, 10.1016/j.bbrc.2015.06.022
  79. Yu Xiang, Ding Guodong, Zhi Xiaoyan, Xu Hui, Insight into reduction of obacunone, and their ester derivatives as insecticidal agents against Mythimna separata Walker, 10.1016/j.bmcl.2014.11.027
  80. Yu Xiang, Shi Danfeng, Zhi Xiaoyan, Li Qin, Yao Xiaojun, Xu Hui, Synthesis and quantitative structure–activity relationship (QSAR) study of C7-oxime ester derivatives of obacunone as insecticidal agents, 10.1039/c5ra01411e
  81. Kim Jinhee, Jayaprakasha Guddadarangavvanahally K., Vikram Amit, Patil Bhimanagouda S., Methyl nomilinate from citrus can modulate cell cycle regulators to induce cytotoxicity in human colon cancer (SW480) cells in vitro, 10.1016/j.tiv.2012.06.005
  82. Lu Qun, Yang Li, Zhao Hai-Yan, Jiang Jian-Guo, Xu Xi-Lin, Protective effect of compounds from the flowers of Citrus aurantium L. var. amara Engl against carbon tetrachloride-induced hepatocyte injury, 10.1016/j.fct.2013.08.041
  83. Vikram A., Jesudhasan P. R., Jayaprakasha G. K., Pillai S. D., Patil B. S., Citrus limonoids interfere with Vibrio harveyi cell-cell signalling and biofilm formation by modulating the response regulator LuxO, 10.1099/mic.0.041228-0
  84. Vikram Amit, Jesudhasan Palmy R, Pillai Suresh D, Patil Bhimanagouda S, Isolimonic acid interferes with Escherichia coli O157:H7 biofilm and TTSS in QseBC and QseA dependent fashion, 10.1186/1471-2180-12-261
  85. Zunino Susan J., Storms David H., Freytag Tammy L., Adkins Yuriko C., Bonnel Ellen L., Woodhouse Leslie R., Breksa Andrew P., Manners Gary D., Mackey Bruce E., Kelley Darshan S., Dietary supplementation with purified citrus limonin glucoside does not alter ex vivo functions of circulating T lymphocytes or monocytes in overweight/obese human adults, 10.1016/j.nutres.2015.10.011
  86. Kim Jinhee, Jayaprakasha Guddadarangavvanahally K., Uckoo Ram M., Patil Bhimanagouda S., Evaluation of chemopreventive and cytotoxic effect of lemon seed extracts on human breast cancer (MCF-7) cells, 10.1016/j.fct.2011.10.057
  87. Jayaprakasha G. K., Jadegoud Y., Nagana Gowda G. A., Patil Bhimanagouda S., Bioactive Compounds from Sour Orange Inhibit Colon Cancer Cell Proliferation and Induce Cell Cycle Arrest, 10.1021/jf9027816
  88. Kelley Darshan S., Adkins Yuriko C., Zunino Susan J., Woodhouse Leslie R., Bonnel Ellen L., Breksa Andrew P., Manners Gary D., Mackey Bruce E., Citrus limonin glucoside supplementation decreased biomarkers of liver disease and inflammation in overweight human adults, 10.1016/j.jff.2014.11.026
  89. Poulose Shibu M., Harris Edward D., Patil Bhimanagouda S., Citrus Limonoids Induce Apoptosis in Human Neuroblastoma Cells and Have Radical Scavenging Activity, 10.1093/jn/135.4.870
  90. Lv Mengying, Xu Ping, Tian Yuan, Liang Jingyu, Gao Yiqiao, Xu Fengguo, Zhang Zunjian, Sun Jianbo, Medicinal uses, phytochemistry and pharmacology of the genus Dictamnus (Rutaceae), 10.1016/j.jep.2015.05.053
  91. Okamura Hiroaki, Yamauchi Keiko, Miyawaki Keiji, Iwagawa Tetsuo, Nakatani Munehiro, Synthesis and biological activities of degraded limonoids, (±)-fraxinellonone and its related compounds, 10.1016/s0040-4039(96)02277-0
  92. Tundis Rosa, Loizzo Monica Rosa, Menichini Francesco, An Overview on Chemical Aspects and Potential Health Benefits of Limonoids and Their Derivatives, 10.1080/10408398.2011.581400
  93. X. Fang, Y. T. Di, X. J. Hao, The Advances in the Limonoid Chemistry of the Meliaceae Family, 10.2174/138527211795378254
  94. Connolly Joseph D., Hill Robert A., Triterpenoids, 10.1039/b501301c
  95. Connolly Joseph D., Hill Robert A., Triterpenoids, 10.1039/b507872p
  96. Connolly Joseph D., Hill Robert A., Triterpenoids, 10.1039/b718038c
  97. Connolly Joseph D., Hill Robert A., Triterpenoids, 10.1039/b808530g
  98. Hill Robert A., Connolly Joseph D., Triterpenoids, 10.1039/c1np00012h
  99. Hill Robert A., Connolly Joseph D., Triterpenoids, 10.1039/c2np20027a
  100. Hill Robert A., Connolly Joseph D., Triterpenoids, 10.1039/c3np70032a
  101. Hill Robert A., Connolly Joseph D., Triterpenoids, 10.1039/c4np00101j
  102. Hopkins Andrew L., Keserü György M., Leeson Paul D., Rees David C., Reynolds Charles H., The role of ligand efficiency metrics in drug discovery, 10.1038/nrd4163
  103. Shultz Michael D., Setting expectations in molecular optimizations: Strengths and limitations of commonly used composite parameters, 10.1016/j.bmcl.2013.08.029
  104. ABADZAPATERO C, METZ J, Ligand efficiency indices as guideposts for drug discovery, 10.1016/s1359-6446(05)03386-6
  105. Gualdani Roberta, Maddalena Cavalluzzi Maria, Lentini Giovanni, Recent Trends in the Discovery of Small Molecule Blockers of Sodium Channels, 10.2174/0929867323666160517121458
  106. Ritchie Timothy J., Macdonald Simon J.F., The impact of aromatic ring count on compound developability – are too many aromatic rings a liability in drug design?, 10.1016/j.drudis.2009.07.014
  107. Ritchie Timothy J., Macdonald Simon J.F., Young Robert J., Pickett Stephen D., The impact of aromatic ring count on compound developability: further insights by examining carbo- and hetero-aromatic and -aliphatic ring types, 10.1016/j.drudis.2010.11.014
  108. Lovering Frank, Bikker Jack, Humblet Christine, Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success, 10.1021/jm901241e
  109. Kingwell Katie, Exploring the third dimension : Medicinal chemistry, 10.1038/nrd3058
  110. Hann Michael M., Molecular obesity, potency and other addictions in drug discovery, 10.1039/c1md00017a
  111. Ikegami, Wakanyaku, 689, 8 (2010)
  112. Schechter Milton S., Haller H. L., The Identity of Obaculactone, Evodin and Dictamnolactone with Limonin1, 10.1021/ja01862a509
  113. Online Etymology Dictionaryhttp://www.etymonline.com/index.php?search=lemon&searchmode=none
  114. Limonin, 10.1002/jlac.18410400340
  115. Phetkul Uraiwan, Wanlaso Nutthakran, Mahabusarakam Wilawan, Phongpaichit Souwalak, Carroll Anthony R., New acridone from the wood ofCitrus reticulataBlanco, 10.1080/14786419.2013.793687
  116. Wu Tian-Shung, Chan Yu-Yi, Kuo Yao-Haur, Chemical Constituents and Cytotoxicity from the Stem Bark of Citrus medica, 10.3987/com-08-11630
  117. Panthong Kanda, Srisud Yuranan, Rukachaisirikul Vatcharin, Hutadilok-Towatana Nongporn, Voravuthikunchai Supayang Piyawan, Tewtrakul Supinya, Benzene, coumarin and quinolinone derivatives from roots of Citrus hystrix, 10.1016/j.phytochem.2012.12.013
  118. Biavatti Maique W., Vieira Paulo C., Silva M. Fatima G. F. da, Fernandes João B., Albuquerque Sérgio, Limonoids from the Endemic Brazilian Species Raulinoa echinata, 10.1515/znc-2001-7-815
  119. Chansriniyom Chaisak, Ruangrungsi Nijsiri, Lipipun Vimolmas, Kumamoto Takuya, Ishikawa Tsutomu, Isolation of Acridone Alkaloids and N-[(4-Monoterpenyloxy)phenylethyl]-Substituted Sulfur-Containing Propanamide Derivatives from Glycosmis parva and Their Anti-herpes Simplex Virus Activity, 10.1248/cpb.57.1246
  120. Feng Tao, Wang Rui-Rui, Cai Xiang-Hai, Zheng Yong-Tang, Luo Xiao-Dong, Anti-human Immunodeficiency Virus-1 Constituents of the Bark of Poncirus trifoliata, 10.1248/cpb.58.971
  121. Sun Jian-Bo, Jiang Neng, Lv Meng-Ying, Wang Pei, Xu Feng-Guo, Liang Jing-Yu, Qu Wei, Limonoids from the root bark of Dictamnus angustifolius: potent neuroprotective agents with biometal chelation and halting copper redox cycling properties, 10.1039/c5ra00278h
  122. Lv Meng-ying, Tang Ben-qin, Teng Jing, Liang Jing-yu, Xu Feng-guo, Zhang Zun-jian, Sun Jian-bo, Chemotaxonomic significance of limonoids and triterpenoids from Dictamnus angustifolius G. Don ex Sweet, 10.1016/j.bse.2015.02.015
  123. Emerson Oliver H., Bitter Principles of Citrus. II. Relation of Nomilin and Obacunone1, 10.1021/ja01150a059
  124. Min Yong Deuk, Kwon Hak Cheol, Yang Min Cheol, Lee Kyu Ha, Choi Sang Un, Lee Kang Ro, Isolation of limonoids and alkaloids fromPhellodendron amurense and their multidrug resistance (MDR) reversal activity, 10.1007/bf02977779
  125. Yoon Jeong Seon, Sung Sang Hyun, Kim Young Choong, Neuroprotective Limonoids of Root Bark ofDictamnus dasycarpus, 10.1021/np070588o
  126. Yang Jun-Li, Liu Lei-Lei, Shi Yan-Ping, Limonoids and Quinoline Alkaloids fromDictamnus dasycarpus, 10.1055/s-0030-1250344
  127. Choodej Siwattra, Sommit Damrong, Pudhom Khanitha, Rearranged limonoids and chromones from Harrisonia perforata and their anti-inflammatory activity, 10.1016/j.bmcl.2013.04.064
  128. Garnier-Suillerot, Curr. Pharm. Des., 1, 69 (1995)
  129. Koller G., Czerny H., Über das Limonin, den Bitterstoff der Orangenkerne, 10.1007/bf02716102
  130. Emerson Oliver H., The Bitter Principles of Citrus Fruit. I. Isolation of Nomilin, a New Bitter Principle from the Seeds of Oranges and Lemons, 10.1021/ja01182a034
  131. Poulose, FASEB J., 20, A11 (2006)
  132. Breksa III Andrew P, Hidalgo Marlene B, Wong Rosalind Y, Stability of limonin glucoside in beverage matrices, 10.1002/jsfa.3344
  133. Ng Kwok Ming, Gray Alexander I., Waterman Peter G., But Paul P. H., Kong Yun-Cheung, Limonoids, Alkaloids, and a Coumarin from the Root and Stem Barks of Tetradium glabrifolium, 10.1021/np50054a029
  134. Gai, Acta Pharm. Sin., 36, 743 (2001)
  135. Melera A., Schaffner K., Arigoni D., Jeger O., Zur Konstitution des Limonins I. Über den Verlauf der alkalischen Hydrolyse von Limonin und Limonol, 10.1002/hlca.19570400529
  136. Dreyer D.L., Citrus bitter principles—II, 10.1016/s0040-4020(01)82204-3
  137. KONDO YOSHIKAZU, SUZUKI HISASHI, NOZOE SHIGEO, Two γ-Hydroxybutenolides from the Bark of Phellodendron amurense and Photooxidation of Limonoids, 10.1248/yakushi1947.105.8_742
  138. Biavatti Maique W., Westerlon Rosângela, Burger Cristiani, Mora Ticiana Camila, De Souza Márcia Maria, Antinociceptive action of limonexic acid obtained fromRaulinoa echinata, 10.1211/jpp.59.11.0016
  139. Biavatti Maique W., Westerlon Rosângela, Vieira Paulo C., Silva M. Fátima G. F. da, Fernandes João B., Peñaflor M. Fernanda G. V., Bueno Odair C., Ellena Javier, Leaf-cutting ants toxicity of limonexic acid and degraded limonoids from Raulinoa echinata.: X-ray structure of epoxy-fraxinellone, 10.1590/s0103-50532005000800025
  140. Coy Barrera Carlos Andres, Coy Barrera Ericsson David, Granados Falla Diana Susana, Delgado Murcia Gabriela, Cuca Suarez Luis Enrique, seco-Limonoids and Quinoline Alkaloids from Raputia heptaphylla and Their Antileishmanial Activity, 10.1248/cpb.59.855
  141. Breksa Andrew P., Dragull Klaus, Wong Rosalind Y., Isolation and Identification of the First C-17 Limonin Epimer, Epilimonin, 10.1021/jf800473z
  142. Manners Gary D., Jacob Robert A., Breksa, Schoch Thomas K., Hasegawa Shin, Bioavailability of Citrus Limonoids in Humans, 10.1021/jf0300691
  143. Jayaprakasha G.K., Mandadi K.K., Poulose S.M., Jadegoud Y., Nagana Gowda G.A., Patil Bhimanagouda S., Novel triterpenoid from Citrus aurantium L. possesses chemopreventive properties against human colon cancer cells, 10.1016/j.bmc.2008.04.063
  144. Bennett Raymond D., Hasegawa Shin, Herman Zareb, Glucosides of acidic limonoids in citrus, 10.1016/s0031-9422(00)98087-7
  145. Dreyer David L., Pickering Michael V., Cohan P., Distribution of limonoids in the rutaceae, 10.1016/0031-9422(72)80036-0
  146. Herman Z., Fong C. H., Hasegawa S., Analysis of Limonoids in Citrus Seeds, Modern Methods of Plant Analysis (1992) ISBN:9783662016411 p.361-375, 10.1007/978-3-662-01639-8_19
  147. Hasegawa S., Berhow M. A., Fong C. H., Analysis of Bitter Principles in Citrus, Fruit Analysis (1996) ISBN:9783642796623 p.59-80, 10.1007/978-3-642-79660-9_4
  148. Jayaprakasha, Volume 936, 34 (2006)
  149. Phetkul Uraiwan, Phongpaichit Souwalak, Watanapokasin Ramida, Mahabusarakam Wilawan, New depside fromCitrus reticulataBlanco, 10.1080/14786419.2014.896010
  150. Abbasi Soleiman, Zandi Parvin, Mirbagheri Esmaeil, Quantitation of limonin in Iranian orange juice concentrates using high-performance liquid chromatography and spectrophotometric methods, 10.1007/s00217-005-1136-1
  151. Zhao Pan, Duan Li, Guo Long, Dou Li-Li, Dong Xin, Zhou Ping, Li Ping, Liu E-Hu, Chemical and biological comparison of the fruit extracts of Citrus wilsonii Tanaka and Citrus medica L., 10.1016/j.foodchem.2014.10.010
  152. Chu Jun, Li Song-Lin, Yin Zhi-Qi, Ye Wen-Cai, Zhang Qing-Wen, Simultaneous quantification of coumarins, flavonoids and limonoids in Fructus Citri Sarcodactylis by high performance liquid chromatography coupled with diode array detector, 10.1016/j.jpba.2012.03.041
  153. Bilal, Pak. J. Sci. Ind. Res. Ser. B Biol. Sci., 56, 36 (2013)
  154. Liu Cuihua, Yan Fuhua, Gao Huijun, He Min, Wang Zhuang, Cheng Yunjiang, Deng Xiuxin, Xu Juan, Features of citrus terpenoid production as revealed by carotenoid, limonoid and aroma profiles of two pummelos (Citrus maxima) with different flesh color : Terpenoid production of two different color pummelos, 10.1002/jsfa.6689
  155. SUN C, CHEN K, CHEN Y, CHEN Q, Contents and antioxidant capacity of limonin and nomilin in different tissues of citrus fruit of four cultivars during fruit growth and maturation, 10.1016/j.foodchem.2004.10.037
  156. McIntosh, 73 (2000)
  157. Hasegawa Shin, Ou Peter, Fong Chi H., Herman Zareb, Coggins Charles W., Atkin Darwin R., Changes in the limonoate A-ring lactone and limonin 17-.beta.-D-glucopyranoside content of navel oranges during fruit growth and maturation, 10.1021/jf00002a008
  158. Fong Chi H., Hasegawa Shin., Coggins Charles W., Atkin Darwin R., Miyake Masaki., Contents of limonoids and limonin 17-.beta.-D-glucopyranoside in fruit tissue of Valencia orange during fruit growth and maturation, 10.1021/jf00019a019
  159. Breksa Andrew P., Zukas Audrius A., Manners Gary D., Determination of limonoate and nomilinoate A-ring lactones in citrus juices by liquid chromatography–electrospray ionization mass spectrometry, 10.1016/j.chroma.2004.12.046
  160. Raman Girija, Cho Minhee, Brodbelt Jennifer S., Patil Bhimanagouda S., Isolation and purification of closely relatedCitrus limonoid glucosides by flash chromatography, 10.1002/pca.835
  161. Breksa III Andrew P., Hidalgo Marlene B., Yuen Michelle Lee, Liquid chromatography–electrospray ionisation mass spectrometry method for the rapid identification of citrus limonoid glucosides in citrus juices and extracts, 10.1016/j.foodchem.2009.04.050
  162. Breksa Andrew P., Dragull Klaus, Development and validation of a decigram-scale method for the separation of limonin from limonin glucoside by C-18 flash chromatography, 10.1016/j.foodchem.2008.08.046
  163. Vikram Amit, Jayaprakasha G.K., Patil Bhimanagouda S., Simultaneous determination of citrus limonoid aglycones and glucosides by high performance liquid chromatography, 10.1016/j.aca.2007.03.029
  164. Jayaprakasha Guddadarangavvanahally K., Dandekar Deepak V., Tichy Shane E., Patil Bhimanagouda S., Simultaneous separation and identification of limonoids from citrus using liquid chromatography-collision-induced dissociation mass spectra, 10.1002/jssc.201000644
  165. Breksa Andrew P., Ibarra Phil, Colorimetric Method for the Estimation of Total Limonoid Aglycones and Glucoside Contents in Citrus Juices, 10.1021/jf063731c
  166. Breksa Andrew P, Kahn Tracy, Zukas Audrius A, Hidalgo Marlene B, Yuen Michelle Lee, Limonoid content of sour orange varieties, 10.1002/jsfa.4383
  167. Minamisawa Mayumi, Yoshida Shoichiro, Uzawa Atsushi, The functional evaluation of waste yuzu (Citrus junos) seeds, 10.1039/c3fo60440c
  168. Kuroyanagi Masanori, Ishii Hiromi, Kawahara Nobuo, Sugimoto Hiroyuki, Yamada Hideo, Okihara Kiyoshi, Shirota Osamu, Flavonoid glycosides and limonoids from Citrus molasses, 10.1007/s11418-007-0198-8
  169. Arbona Vicent, Iglesias Domingo J, Gómez-Cadenas Aurelio, Non-targeted metabolite profiling of citrus juices as a tool for variety discrimination and metabolite flow analysis, 10.1186/s12870-015-0430-8
  170. Vaclavik Lukas, Schreiber Andre, Lacina Ondrej, Cajka Tomas, Hajslova Jana, Liquid chromatography–mass spectrometry-based metabolomics for authenticity assessment of fruit juices, 10.1007/s11306-011-0371-7
  171. Pan Zhiyong, Li Yue, Deng Xiuxin, Xiao Shunyuan, Non-targeted metabolomic analysis of orange (Citrus sinensis [L.] Osbeck) wild type and bud mutant fruits by direct analysis in real-time and HPLC-electrospray mass spectrometry, 10.1007/s11306-013-0597-7
  172. Ledesma-Escobar C. A., Priego-Capote F., Luque de Castro M. D., Characterization of lemon (Citrus limon) polar extract by liquid chromatography-tandem mass spectrometry in high resolution mode : Characterization ofCitrus limonby LC-MS/MS, 10.1002/jms.3637
  173. Ren Wei, Li Yan, Zuo Ran, Wang Hong-Jie, Si Nan, Zhao Hai-Yu, Han Ling-Yu, Yang Jian, Bian Bao-Lin, Species-related difference between limonin and obacunone among five liver microsomes and zebrafish using ultra-high-performance liquid chromatography coupled with a LTQ-Orbitrap mass spectrometer : Comparative metabolism of limonin and obacunone, 10.1002/rcm.7026
  174. Ren Wei, Xin Shao-Kun, Han Ling-Yu, Zuo Ran, Li Yan, Gong Mu-Xing, Wei Xiao-Lu, Zhou Yan-Yan, He Jing, Wang Hong-Jie, Si Nan, Zhao Hai-Yu, Yang Jian, Bian Bao-Lin, Comparative metabolism of four limonoids in human liver microsomes using ultra-high-performance liquid chromatography coupled with high-resolution LTQ-Orbitrap mass spectrometry : Metabolic analysis of limonoids in human liver microsomes, 10.1002/rcm.7365
  175. Tian Qingguo, Miller Edward G., Jayaprakasha G.K., Patil Bhimanagouda S., An improved HPLC method for the analysis of citrus limonoids in culture media, 10.1016/j.jchromb.2006.09.012
  176. Habtemariam, Nat. Prod. Commun., 3, 1321 (2008)
  177. Habtemariam, Nat. Prod. Commun., 3, 1317 (2008)
  178. Habtemariam Solomon, Methyl-3-O-Methyl Gallate and Gallic Acid from the Leaves of Peltiphyllum peltatum: Isolation and Comparative Antioxidant, Prooxidant, and Cytotoxic Effects in Neuronal Cells, 10.1089/jmf.2010.0257
  179. Habtemariam Solomon, Cowley Raymond A., Antioxidant and Anti-α-glucosidase Compounds from the Rhizome ofPeltiphyllum peltatum(Torr.) Engl : PELTIPHYLLUM PELTATUMRHIZOMES: PHYTOCHEMISTRY AND BIOLOGICAL EFFECTS, 10.1002/ptr.4626
  180. Habtemariam Solomon, Dagne Ermias, Comparative Antioxidant, Prooxidant and Cytotoxic Activity of Sigmoidin A and Eriodictyol, 10.1055/s-0029-1240604
  181. Habtemariam, Nat. Prod. Commun., 10, 475 (2015)
  182. Habtemariam Solomon, Varghese George K., A Novel Diterpene Skeleton: Identification of a Highly Aromatic, Cytotoxic and Antioxidant 5-Methyl-10-demethyl-abietane-type Diterpene fromPremna serratifolia : A NOVEL DITERPENE SKELETON IDENTIFIED FROM PREMNA SERRATIFOLIA, 10.1002/ptr.5229
  183. Juan-Badaturugea, Nat. Prod. Commun., 4, 1561 (2009)
  184. Juan-Badaturuge Malindra, Habtemariam Solomon, Thomas Michael J.K., Antioxidant compounds from a South Asian beverage and medicinal plant, Cassia auriculata, 10.1016/j.foodchem.2010.08.065
  185. Roselli Mariagrazia, Lentini Giovanni, Habtemariam Solomon, Phytochemical, Antioxidant and Anti-α-glucosidase Activity Evaluations of Bergenia cordifolia : PHYTOCHEMICAL AND BIOLOGICAL ACTIVITY OF BERGENIA CORDIFOLIA, 10.1002/ptr.3655
  186. Habtemariam S, Dagne E, Differential cytotoxic and prooxidnant activity of knipholone and knipholone anthrone, 10.1055/s-0029-1234260
  187. Habtemariam Solomon, Cytotoxicity and Immunosuppressive Activity of Withanolides fromDiscopodium penninervium, 10.1055/s-2006-957594
  188. Habtemariam Solomon, Cytotoxicity of Diterpenes fromPremna schimperiandPremna oligotricha, 10.1055/s-2006-958105
  189. Habtemariam Solomon, Cytotoxic and cytostatic activity of erlangerins from Commiphora erlangeriana, 10.1016/s0041-0101(03)00048-5
  190. Mireku Evelyn A., Mensah Abraham Y., Mensah Merlin L. K., Tocher Derek A., Habtemariam Solomon, Antiinflammatory Properties of the Stem-bark ofAnopyxis klaineanaand its Major Constituent, Methyl Angolensate : ANTIINFLAMMATORY PROPERTIES OFAnopyxis klaineana, 10.1002/ptr.5212
  191. Cavalluzzi Maria Maddalena, Viale Maurizio, Bruno Claudio, Carocci Alessia, Catalano Alessia, Carrieri Antonio, Franchini Carlo, Lentini Giovanni, A convenient synthesis of lubeluzole and its enantiomer: Evaluation as chemosensitizing agents on human ovarian adenocarcinoma and lung carcinoma cells, 10.1016/j.bmcl.2013.06.077
  192. Yamashita Shuji, Naruko Akito, Nakazawa Yuki, Zhao Le, Hayashi Yujiro, Hirama Masahiro, Total Synthesis of Limonin, 10.1002/anie.201503794
  193. Xiang Yu, Cao Jinping, Luo Fenglei, Wang Dengliang, Chen Wei, Li Xian, Sun Chongde, Chen Kunsong, Simultaneous Purification of Limonin, Nomilin and Isoobacunoic Acid from Pomelo Fruit (Citrus grandis) Segment Membrane : Purification of limonoids…, 10.1111/1750-3841.12581
  194. Rodríguez, Rev. Colomb. Entomol., 40, 164 (2014)
Bibliographic reference Gualdani, Roberta ; Cavalluzzi, Maria ; Lentini, Giovanni ; Habtemariam, Solomon. The Chemistry and Pharmacology of Citrus Limonoids. In: Molecules, Vol. 21, no.11, p. 1530 (2016)
Permanent URL http://hdl.handle.net/2078.1/211400