Overview of sesquiterpenes and chromones of agarwood originating from four main species of the genus Aquilaria

The main chemical constituents of agarwood are sesquiterpenes and chromones, which can be divided into different categories depending on their molecular skeletons. Agarwoods are obtained from different plant species: Aquilaria sinensis, A. malaccensis, A. crassna, and A. subintegra. In this review, we systematically summarized the structures of 367 compounds isolated from agarwoods originating from four main species. We structurally classified all the components into 11 different types and summarized the number of compounds in each type. Different and identical components were obtained by enumerating the chemical compositions of the different species. Knowledge regarding the chemical constituents of agarwoods of different species will aid understanding of the chemical compositions of agarwoods and will subsequently identify similar compounds that can serve as standards for quality control to provide a reference for future studies on agarwoods from different species and to increase their usefulness.


Introduction
Agarwood is a resinous portion of Aquilaria trees, a genus belonging to the family Thymelaeaceae. Agarwoods have wide uses in traditional medicine, for example, as aphrodisiacs, sedatives, cardiotonics, and carminatives, as well as in the relief of gastric problems, coughs, rheumatism, and high fever. 1 In addition, agarwoods are present in important spices and are also used as incense. Agarwood is known as 'chenxiang' in Chinese and 'aloeswood', 'agalloch', 'eaglewood', 'jinkoh', 'gaharu', and 'kanankoh' in other parts of the world. 2 Approximately 15 species of Aquilaria are well known for their production of fragrant heartwood, also known as gaharu, aloeswood or agarwood. Wounding of the tree appears to be essential for the initiation of gaharu production, and fungal infection is likely to enhance the process. According to Eurlings et al., 3 the following nine Aquilaria species produce gaharu: A. beccariana, A. crassna, A. laria (Oken), A. hirta, A. khasiana, A. malaccensis, A. microcarpa, A. rostrata and A. sinensis; these are mainly sourced from India, Southeast Asia, Papua New Guinea, and China (chiey in Hainan and Guangdong). 3 As stated in reports, sesquiterpenoids and phenylethyl chromone derivatives are the principal compounds in the oleoresin of agarwood, which are mostly found in the species Aquilaria, A. malaccensis, A. agallocha, A. sinensis, and A. crassna. 1,4 In 2016, a review of agarwood noted A. agallocha Roxb. (endemic in India), of which the species name is unresolved (Table 1). 5 The index of CITES species, 6 Missouri Botanical Garden website, 7 and the Ayurvedic and Unani Pharmacopoeias all list A. agallocha Roxb. as a synonym of A. malaccensis Lam. Since then, there have been other reports on this species. [8][9][10] Therefore, this article will incorporate all the chemical constituents reviewed in A. agallocha into A. malaccensis. Other genera of the family Thymelaeaceae, such as Aetoxylon, Gyrinops, Phaleria, and Gonystylus, have also been reported to produce agarwoods. 3 It has been reported that different countries have endemic species; for example, A. crassna principally grows in Indochina, A. malaccensis is an Indomalesian type found in Malaysia, Thailand and India, and A. sinensis is endemic in China. A. subintegra is principally found in Thailand. 8 All nine of the known Aquilaria species can produce agarwood; however, it is not known which species are most productive. Studies have shown that specic species produce specic chemical components which are quite different from one another. 11 Assessing the similarities and differences between these components is a good way to identify species, determine their quality and classify specic species.

Sesquiterpenes in A. sinensis
The sesquiterpenoids of agarwood are mainly derived from agarwood oil. Early publications on agarwood essential oils reect the fact that the agarwood resin components are separated by solvent extraction, followed by column chromatography for purication and structural analysis using spectroscopy, including NMR. For example, Yang et al. 12,21,27 and Xu et al. 17 isolated sesquiterpenes F1-F2, F7-F9, F11, S1-S3, and G14 from A. sinensis. Yang and coworkers 64 isolated G19, G23, O12-O13, and O16 from ethanol and petrol ether extracts of A. sinensis and later found two new sesquiterpenes, G27 and O2.

Chromone derivatives in agarwoods
Chromone derivatives are other major constituents of agarwoods. They have been obtained from only a few plant species, including Eremophila georgei, Bothriochloa ischaemum         Table 3, the variation of chromones in different species is striking. Regarding the study of chromones, most researchers use agarwood extracts, usually ethanol (EtOH) extracts, to extract and separate the monomers. The structures of the compounds are determined by a series of assays, including LC/MS, and nuclear magnetic resonance.
Liu et al. 83 separated and identied 44-46 and 117 from an EtOH extract of agarwood produced via the whole-tree agarwood-inducing technique.

Discussion
Among the 367 new main chemical constituents from agarwoods that were statistically assessed in this paper, chromone derivatives and sesquiterpenes accounted for 44.14% and 55.86%, respectively, of the total constituents. It can be seen in Fig. 1(a) that the largest numbers of sesquiterpenes in agarwood are eudesmanes, guaianes and eremophilanes. Fig. 1(b) reects the number of different chromones in agarwood, where 2-(2-phenylethyl)chromones are currently the most commonly isolated types.
From the statistical results (shown in Fig. 2), researchers are currently mainly engaged in the study of the chemical constituents of agarwood originating from A. sinensis, A. malaccensis, and A. crassna, respectively, of which most of the new compounds were isolated from A. sinensis. It can be seen that resources are important prerequisites for the study of agarwood; thus, there are many studies on species with relatively abundant resources, such as A. sinensis, A. malaccensis, and A. crassna. Of course, this is also closely related to geographical distribution. Agarwoods originating from different Aquilaria plants contain some common compounds as well as some different compounds. Among different species of agarwood, the chemical compositions are quite different. Therefore, it is necessary to indicate the species from which the used agarwood is derived. However, during the writing process, we found that many articles on the separation of compounds from agarwood did not indicate which species of the genus Aquilaria the agarwood was derived from. Therefore, we encourage researchers studying agarwood to indicate more information about the origin and tree species to clarify the source of the material.
According to the data, the number of sesquiterpenes isolated from agarwood has thus far been higher than the number of chromones, and the proportion of articles is also the same. In the past 10 years, the number of articles on chromones has increased rapidly. The study of the chemical constituents of agarwood from sesquiterpenes to chromone derivatives shows that increasing numbers of researchers are beginning to focus on revealing the main components of agaric pharmacologically active substances rather than only fragrance components. Therefore, we can see that research on the separation and activity of chromone derivatives still has broad research prospects.
By summarizing and comparing the chemical compositions of different tree species, we can provide more research ideas. The same components can be used as standards for quality assessment, with reliable and stable characteristics, and different components can guide the selection of high quality agarwood species. By reviewing the chemical compositions of agarwoods from the four species, we believe that the following characteristics should be considered when selecting quality control standards. Due to the complex composition of agarwood, sesquiterpenes and chromone derivatives should be considered rst, especially chromones, mainly because they are characteristic components of agarwood, and chromone derivatives are easier to separate and preserve. Due to the extremely complex sources and types of agarwood, researchers in different countries should fully consider the common chemical composition when selecting control indicators and formulating quality testing methods to improve the scope and scienticity of the testing methods, such as F2 and F3. Of course, even with the limited amounts of research on individual species, it is possible to exibly select components, such as chromone 1.

Conclusion
Agarwood, which is expensive and widely used, is derived from the resin-containing wood of Aquilaria species trees. The chemical components of agarwood are diverse and complex; 367 new chemical constituents from agarwood were statistically assessed in this paper. This review summarizes the main molecular skeletons of agarwood compounds, revealing the differences in the chemical compositions of agarwood originating from different Aquilaria species. This will help researchers to better understand research on agarwood and select more suitable detection indicators.
With the continuous exploration and efforts made by scientists in recent years, the understanding of the chemical compositions of agarwood from different sources is continuously improving, and some specic chemical compositions may become identication indices and judgement standards of agarwood samples from different sources. In the future, we expect to see more research on the chemical components of agarwood from different species in order to help identify characteristic compounds of agarwood, establish a stable, effective, comprehensive, and reliable quality evaluation system, and consequently elucidate which species best produce agarwood.

Conflicts of interest
The authors declare no conict of interest.