Chinese Journal of Natural Chinese Journal of Natural Medicines 2019, 17(3): 01610186 Medicines •Review• Non-volatile constituents and pharmacology of Chimonanthus: A review SHU Ren-Geng1*, WAN Yi-Li1, 2, WANG Xiao-Min3 1 School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China; 2 School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China; 3 School of Life Science, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China Available online 20 Mar., 2019 [ABSTRACT] Chimonanthus plants widely distributed in southern area of China, which have a long history of edibles and medicine. Phytochemical investigations have shown that Chimonanthus produced 143 non-volatile constituents, including alkaloids, flavonoids, terpenoids, coumarins and others, which exhibit significant anti-oxidant, anti-bacterial, anti-cancer, anti-inflammatory, antihypergly- cemic, antihyperlipidemic and other biological activities. On the basis of systematic reviewing of literatures, this article overviews the non-volatile constituents and pharmacology of Chimonanthus from domestic and foreign over the last 30 years (until June 2018), and may provide a useful reference for the further development of Chimonanthus. [KEY WORDS] Chimonanthus; Non-volatile constituents; Pharmacology; Review [CLC Number] R965 [Document code] A [Article ID] 2095-6975(2019)03-0161-26 Introduction oxidant, anti-inflammatory, anti-cancer, antihyperglycemic, antihyperlipidemic effects [3-9]. Further more, some species of The genus Chimonanthus, a popular garden and ornamental Chimonanthus have been processed into beverages and plant, is a member of the family Calycanthaceae endemic to preparations, like Golden Tea, Xiang-Feng Tea, Shi-Liang Tea, [1] China, which has survived since the tertiary relic period . Shanlameiye Granule, Tiekuaizi, Fufangxianlingfengshijiu, According to the Flora of China, the genus comprises only six Malanganhan Capsule, Piweishu, Huatuo bill ointmentetc. species, C. praecox, C. nitens, C. salicifolius, C. zhejiangensis, C. grammatus and C. campanulatus [2]. Methods Phytochemical studies reveal that Chimonanthus contains All relevant databases were searched for the key words abundant secondary metabolites, such as alkaloids, flavonoids, “Chimonanthus”, the names of its proper constituents include coumarins, terpenoids, essential oils and other ingredients. Its “calycanthine” and “chimonanthine”, or the aliases of roots, leaves, flowers, fruits are popularly applied as folk Chimonanthus plants like “Tiekuaizi”, “Shiliang Tea”, and medicines for treatment of influenza, fever, headache, sore “Wintersweet”. By searching through the foreign language throat, cough relieving, sputum reducing, asthma, epigastric databases like PubMed and SpringerLink, Chinese databases fullness, gastric distention, stomachache, gastric acid, diarrhea, like Blyun and Cintmed, more than 300 Chinese and English urethritis, traumatic injury, hand-foot-and-mouth disease, articles are selected in total and about 80 literatures are cited rheumatic arthritis etc. Modern pharmacological studies have in this paper. As there are related literatures [10-11] that have shown that plants of Chimonanthus have anti-bacterial, anti- overviewed the studies of Chimonanthus volatile oil in detail, this paper would not go into. Instead, in this paper, we aim to [Received on] 20-Oct.-2018 highlight non-volatile constituents and pharmacological [Research funding] This work was supported by the National Natural effects of Chimonanthus and to point out several aspects, Science Foundation of China (No. 81360631). which should be attended in future research. [*Corresponding author] Tel: 86-18970069203, E-mail: shurg@ Non-volatile constituents 163.com These authors have no conflict of interest to declare. Nowadays the studies of Chimonanthus non-volatile Published by Elsevier B.V. All rights reserved constituents are more concentrated on C. praecox, C. nitens, – 161 – SHU Ren-Geng, et al. / Chin J Nat Med, 2019, 17(3): 161186 and C. salicifolius, only a few literatures reported the studies another poentical Chimonanthus alkaloids series, namely of C. grammatus and C. zhejiangensis, and no research about pyrrolidinoquinoline-type or iso-calycanthine-type. These C. campanulatus has been found. To date, 143 non-volatile skeletons both contain the structure of Ph-N-CH-N, which is components have been separated and identified from the simple structure segment of Calycanthaceae alkaloids (see Chimonanthus, including 20 alkaloids, 16 flavonoids, 25 Fig. 1). The same potential biogenetic pathway from coumarins, 39 terpenoids (containing 8 nor-sesquiterpenoids), N-methyltrylptamine of these alkaloids may explain the 6 steroids, 20 organic acids, 17 glycosides and others. phenomenon. Alkaloids (+)-Calycanthine (1), with a dimeric piperidinoquinoline skeleton, was the first Calycanthaceae alkaloid isolated from the seeds of C. glaucus Willd. [12]. With further investigation on Chimonanthus alkaloids, researchers have isolated 20 alkaloids (1–20) from the genus, and they were most distributed in C. praecox (especially in seeds), followed by C. salicifolius and C. nitens. Fig. 1 Skeletons of alkaloid from Chimonanthus A number of studies have reported the alkaloids exist in different parts of C. praecox. Up to now, more than 15 alkaloids By analyzing the 20 alkaloids isolated from Chimo- have been founded in C. praecox. Yang investigated the nanthus (see Fig. 2), we can find that the skeletons of these alkaloids from the leaves of C. praecox anddetermined that alkaloids have a high similarity and always contain four chiral [13] the main alkaloid was Chimonanthine, account for 85% . centers. For example, the compounds 1–4, 8 and 9 are Takayama et al. isolated six alkaloids from the seeds of C. identical in chemical structural formula C22H26N4 but different praecox (1, 4–7, 17), including two new alkaloids (7, 17), and in stereostructure and optical rotation or malting point per- their absolute configuration were established by biomimetic formance. Unlike (+)-calycanthine (1) and (–)-calycanthine (2) total synthesis. As a result, the optical rotation of natural enantiomers as well as (–)-iso-calycanthine (8) and CPC-2 (9), D chimonamidine (17) showed ([]19 −12.6 (c 0.06, EtOH), meso-chimonanthine (3) and (–)-chimonanthine (4), salici- which was significantly different with (R)-(–)-chimonamidine foxazine A (11) and salicifoxazine B (12) are two groups D ([]23 −177.8, c 0.17, EtOH) and the enantiomeric (S)-(+)- diastereoisomers at C-3a/C-8a or at C-3a'/C-8a'. Each isomer D 1 chimonamidine (([]23 +170.7, c 0.18, EtOH)), suggesting group has the same skeleton and almost identical in H NMR, 13 that natural chimonamidine was a mixture slightly enriched C NMR, and UV spectroscopic data. But the values of with the (R)-(–)-enantiomer [14]. In 2006, a new pyrroli- optical rotation and malting points or the ion abundances of dinoindoline-type alkaloid, CPC-1 (18), and a new trypta- them show a significant difference (see Table 1), which mine-derived dimeric alkaloid, CPC-2 (9), together with eight provided a powerful evidence for structural identification of known alkaloids (1, 3–7, 15, 16) were isolated from the seeds Chimonanthus alkaloids. Since the yield of these novel and and rinds of C. praecox. The absolute configuration of CPC-1 bio-active alkaloids is low, the synthesis of these interesting was determined by chiral total synthesis [3]. Later, Wang’s constituents has been a hot topic of interest during the past group obtained four dimeric alkaloids (1, 4–6) and one indole decades. glucoside (14) from the fruits of C. praecox f. concolor [4]. Flavonoids Meanwhile, Morikawa et al. found five alkaloids (1, 3–6) Chemical investigations in Chimonanthus revealed that from flower buds [15]. From seeds of C. praecox var. concolor, this plant has high content of flavonoids. Quercetin and kaem- seven alkaloids (1, 4–6, 16, 17, 20) were isolated, among pferol glucosides are two major groups exist in Chimonanthus. which compound 20 is a new alkaloid [16-17]. In 2015, Ma’s Some flavonoids (see Fig. 3), such as kaempferol, quercetin, group investigated five indoline-type (3–5, 11, 12) from the rutin and astragalin are common ingredients for many species. leaves of C. salicifolius, including three quinoline-type (1, 8, In addition, flavonoids have been considered as standard for 10) dimeric tryptamine-derived alkaloids and two new the quality control of products of Chimonanthus plants, and alkaloids (11, 12) [18]. While the L-isomer of calycanthine (2) the content of quercetin and kaempferol are the target and berberine (13) were only isolated from the leaves of flavonoids to be tested. Liu has used four common flavonoids C. nitens [19]. (21, 22, 24, 27) as standard substances to establish the HPLC Dimeric piperidinoquinoline-type or calycanthine-type (1, fingerprints of the five Chimonanthus species, and find that 2), and dimeric pyrrolidinoindoline-type or chimonanthine- the contents of them have significant difference. In addition, type (3–7) were two alkaloids series of Chimonanthus, which the harvest time may affect the contents and should be taken have been well-reported. While the members of 8, 9, whose into attention for utilization of the chemical compositions of skeleton are different from these two known types, could be Chimonanthus leaves [26]. – 162 – SHU Ren-Geng, et al. / Chin J Nat Med, 2019, 17(3): 161186 Fig. 2 Structures of alkaloids from Chimonanthus