Journal of Functional Foods 75 (2020) 104213 Contents lists available at ScienceDirect Journal of Functional Foods journal homepage: www.elsevier.com/locate/jff Limonoids from Citrus: Chemistry, anti-tumor potential, and other T bioactivities Yu-Sheng Shia,b,1, Yan Zhangc,1, Hao-Tian Lia, Chuan-Hai Wud, Hesham R. El-Seedie,f, ⁎ ⁎ Wen-Kang Yed,g, Zi-Wei Wangd, Chun-Bin Lia, Xu-Fu Zhangc, , Guo-Yin Kaib, a Key Laboratory of Biotechnology and Bioresources Utilization, Educational of Minister, College of Life Science, Dalian Nationalities University, Dalian 116600, China b Laboratory of Medicinal Plant Biotechnology, College of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 311402, China c School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China d Department of Ocean Science, Division of Life Science and Hong Kong Branch of the Southern Marine Science and Engineering Guangdong Laboratory, The Hong Kong University of Science and Technology, Hong Kong, China e Pharmacognosy Group, Department of Medicinal Chemistry, Uppsala University, Biomedical Centre, Uppsala 75 123, Sweden f International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang, 212013, China g SZU-HKUST Joint Ph.D. Program in Marine Environmental Science, Shenzhen University, Shenzhen 518061, China ARTICLE INFO ABSTRACT Keywords: Citrus limonoids are tetranortriterpenoids compounds mainly found in oranges, lemons, grapefruits, and other Rutaceae fruits of Citrus. They are proved to be the leading cause of bitterness in Citrus fruits and are mainly consumed for Citrus therapeutic purposes and as food. Numerous studies have focused on Citrus limonoids and intend to develop new Limonoid chemotherapeutic or complementary medicine in recent years. Citrus limonoids showed various bioactivities Chemical structure such as anti-tumor, antioxidative, anti-inflammatory, anti-neurological diseases, immunomodulatory, anti-in- Bioactivity sect, anti-bacteria, antiviral activities, etc. This review summarized limonoids from Citrus to date, along with Anti-tumor their chemical structures and biological activities with a particular focus on their anti-tumor potential. 1. Introduction were shown to be well tolerated by non-cancerous cell lines (Gualdani, Cavalluzzi, Lentini, & Habtemariam, 2016; Jayaprakasha et al., 2008; Limonoids, also known as tetranortriterpenoids, exist extensively in Jayaprakasha, Jadegoud, Gowda, & Patil, 2010), animal models Rutaceae and Meliaceae and less frequently in the Cneoraceae and (Guthrie, Morley, Hasegawa, Manners, & Vandenberg, 2000; Miller, Simaroubaceae (Tundis, Loizzo, & Menichini, 2014). The studies of li- Porter, Binnie, Guo, & Hasegawa, 2004; Tanaka et al., 2000, 2001), and monoids originate from the attempt on investigating responsible che- human body (Kelley et al., 2015; Manners, Jacob, Breksa, Schoch, & micals for bitterness in Citrus fruit, and the name of limonoid stems Hasegawa, 2003). Based on the above properties and bioactivities, li- from limonin, the first bitter tetranortriterpenoid separated from Citrus monoids present potential applications in food and pharmaceutical in- (Sandjo & Kuete, 2013). Limonoid aglycones, some of which contribute dustries (Patil, Jayaprakasha, Murthy, & Vikram, 2009; Roy & Saraf, to the bitter taste of Citrus fruits, and their glycosides widely occur in 2006), and have been used as functional food additives, pesticides, and the seeds and fruits of Citrus (Matheyambath, Padmanabhan, & feed additives. Paliyath, 2016). Limonoid from Citrus has been a research interest due This review covers the natural limonoids from Citrus to date and to its contribution to the bitter taste of Citrus fruits, which harms the their occurrence in different species, along with their chemical struc- global Citrus fruit and juice industry. In recent decades, limonoids from tures and biological activities. The multiple pathways that limonoids Citrus is becoming a research hotspot owning to their diverse bioac- were shown to be involved in were summarized, and the pharmacolo- tivities in vitro and in vivo such as anti-tumor, antioxidative, anti-in- gical potential of limonoids in different diseases was discussed to fa- flammatory, anti-neurogenic diseases, immunomodulatory, in- cilitate in-depth researches regarding bioactivity and the application of secticidal, antibacterial, and antiviral activities (Zhang et al., 2013). limonoids. Furthermore, limonoids from Citrus, as food-derived phytochemicals, ⁎ Corresponding authors. E-mail addresses: [email protected] (Y.-S. Shi), [email protected] (X.-F. Zhang), [email protected] (G.-Y. Kai). 1 Equal contribution. https://doi.org/10.1016/j.jff.2020.104213 Received 27 May 2020; Received in revised form 12 September 2020; Accepted 15 September 2020 Available online 23 September 2020 1756-4646/ © 2020 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Y.-S. Shi, et al. Journal of Functional Foods 75 (2020) 104213 Dragull, & Wong, 2008), deoxylimonol (27)(Bennett & Hasegawa, 1982) were the most representative limonoids. The cleavage of lactone bond in ring D of limonin generated limonoic acid A-ring lactone (29) (Maier & Margileth, 1969) and the further oxidation product 17-de- hydrolimonoate A-ring lactone (30)(Herman, Fong, & Hasegawa, 1992). Limonin glucoside (72)(Hasegawa, Bennett, Herman, Fong, & Ou, 1989) was the glycosylation product of limonin. The structural features of nomilin-type were similar to limonin-type, except for the ring A, which was a seven-membered lactone with the oxygen atom positioned between C-3 and C-4. The main nomilin-type limonoids included nomilin (4)(Ishii, Ohta, Nogata, Yano, & Hasegawa, 2003), obacunone (1)(Kim, Jayaprakasha, & Patil, 2014), 7α-obacunol (2)(Bennett & Hasegawa, 1982), 7α-obacunyl acetate (3)(Bennett & Hasegawa, 1982), obacunone 17-β-D-glucoside (65)(Hasegawa et al., 1989), deacetylnomilin (5)(Hamdan et al., 2011), 6-keto-7β-deace- tylnomilol (6)(Bennett & Hasegawa, 1981), 6-keto-7β-nomilol (7) (Herman, Bennett, Ou, Fong, & Hasegawa, 1987), citrusin (46)(Chan, Li, Shen, & Wu, 2010) and nomilin glycoside (66)(Hasegawa et al., 1989). Nomilinic acid type differs from nomilin type in the structure ofring Fig. 1. Structural features of limonin, the most representative limonoid from A. The lactone bond in ring A is cleaved and culminated in a C-3 car- Citrus. boxyl or a methoxycarbonyl group in nomilinic acid-type limonoids. Nomilinic acid (8)(Hashinaga, Fong, & Hasegawa, 1990), obacunoic 2. Chemistry acid (14)(Bennett, Hasegawa, & Herman, 1989), methylnomilinate (9) (Bennett & Hasegawa, 1980), methyldeacetyl nomilinate (11)(Bennett Limonoids are highly oxidized triterpenoid displaying homogenous & Hasegawa, 1981), calamin (12)(Bennett & Hasegawa, 1981), nomi- stereochemistry, featured with a structure either containing or origi- linic acid glucoside (8)(Hashinaga et al., 1990) and deacetylnomilinic nated from a precursor with a 4,4,8-trimethyl-17-furanylsteroid scaf- acid 17-β-D-glucoside (67)(Bennett et al., 1989) are the typical limo- fold. Citrus limonoids were characterized with a furan ring linked to the noids of this type. Overall, the diversification of Citrus limonoids mostly D-ring at C-17, and oxygen-containing functional groups at C-3, C-4, C- occurs in A and B rings along with different oxidized level, while D ring 7, C-16 and C- 17 (Fig. 1). The structural diversification of limonoids is either opened or lactonized. from Rutaceae is less than that in Meliaceae and are mostly limited to the change in A and B rings. The biosynthesis pathway of limonoids remained largely unin- 3. Distribution vestigated and was only tentatively proposed (Wang et al., 2017). Li- monoids were commonly considered to derive from euphane (20-S) or Limonoids are widely distributed in many Citrus fruits such as sweet tirucallane (20-R) involved in the triterpenoid biogenetic route (Fig. 2). orange (Citrus sinensis), lemon (Citrus limon), grapefruit (Citrus paradisi), The Δ7-bond was oxidized into 7-epoxide, which was open subse- lime (Citrus aurantiifolia), sour orange (Citrus aurantium), pummelo quently. Then, Me-14 transferred to C-8 through the Wagner-Meerwein (Citrus maxima)(Russo et al., 2016). The detailed distribution of li- rearrangement, accompanied by the formation of the 7-OH and a monoids in different Citrus species so far is summarized in Table 1. double bond at C-14/C-15. After that, the side chain cyclized and lost Generally, the water-insoluble limonoid aglycones such as limonin, four carbons to form the 17 β-furan ring. Based on the basic skeleton of nomilin, obacunone, ichangin, deacetyl nomilin are mainly distributed limonoids, a series of oxidations and skeletal rearrangements occurred within seeds and peels. In contrast, the water-soluble limonoid gluco- to generate a variety of limonoids. For example, rings A and ring D are sides, such as limonin glucoside, nomilin glucoside, obacunone gluco- sometimes oxidized A and D-seco limonoids by Baeyer-Villiger oxida- side, and nomilinic acid glucoside, are more abundant within juices and tion reaction of the C-3 and C-16 keto groups; rearrangement of the ring pulps (Breksa, Hidalgo, & Yuen, 2009). Several recent reports have A result in the maturation of typical limonoids such as limonin. The described the limonoid content in different parts of Citrus fruits (Celano biosynthesis correlation between limonoids from Citrus has