Natural Nitrogenous Sesquiterpenoids and Their Bioactivity: A Review

Nitrogenous sesquiterpenoids fromnatural sourcesare rare, so unsurprisingly neither the potentially valuable bioactivity nor thebroad structural diversity of nitrogenous sesquiterpenoids has been reviewed before. This report covers the progressduring the decade from 2010 to February 2020 on the isolation, identification, and bioactivity of 391 nitrogen-containing natural sesquiterpenes from terrestrial plant, marine organisms, and microorganisms. This complete and in-depth reviewshouldbe helpful for discovering and developing new drugs of medicinal valuerelated to natural nitrogenous sesquiterpenoids.


Introduction
The natural products commonly termed 'secondary metabolites' in contrast to 'primary metabolites', are produced byorganisms in order to provide an evolutionary benefit [1]. Natural products as a major chemical resource, have played a significant role over the last 200 years in treating and preventing diseases, and continue to serve as important agents in modern drug discovery due to their characteristic chemical spatial orientation, which enables them tointeract with their natural and other biological targets [1][2][3][4]. Recently, half of new drugs reported were naturally occurring or constructed on the basis of some natural chemical framework [4][5][6].
Sesquiterpenoids are the largest class of natural terpenoids, with a structural diversity that includes thousands of compounds and more than 100 skeletal types [7]. Many of them show 'drug-like' chemical properties, including alkylating center reactivity, lipophilicity, and favorable molecular geometry and electronic features, and have attracted considerable interest due to their pronounced biological activities [8,9]. Meanwhile, sesquiterpenoids that contain nitrogen bonds constitute a fascinating group with enormous structural diversity [10]. Interestingly, it is notable that nitrogenous sesquiterpenoids are rare innatural sources, and there are only a few hundred such compounds that contain the element N known to be produced bycertain species. Functionally and biologically important to humans, have caught the attention of a number of scientists, and extensive phytochemical and biological investigations of nitrogenous sesquiterpenoids from natural sources have been carried out by researchers at the recent ten years [10][11][12].
tetracyclic ring system derived from bergamotane sesquiterpenoid, were isolated from a marinederived fungus Paraconiothyrium sporulosum YK-03 [87]. Volvalerine A (366) (Figure 10), a novel N-containing valerane bisesquiterpenoid derivative with a dihydroisoxazole ring, was isolated from the roots of Valeriana officinalis var. latifolia [88]. Compound 366 was also evaluated for their enhancing activity on NGF mediated neurite outgrowth in PC12 cells. The result indicatedthat the proportion of the NGF-induced neurite-bearing cells (with NGF 5 ng/mL) was not enhanced by compound 366 at 50 μM [88].

Occurrence
Natural nitrogenous sesquiterpenoids are mainly distributed in species of plants belonging to the Celastraceae, Saxifragaceae, Zingiberaceae, Asteraceae, Burseraceae, Phyllanthaceae, Magnoliaceae, Lamiaceae, Myoporaceae, and Valerianaceae families, marine sponges belonging to the Dysiseidae, Thorectidae, Spongiidae, and Halichodriae families, soft corals belonging to the Xeniidae and Clavulariidae families, phyllidid nudibranchs belonging to the Phyllidiidae family, marine slugs belonging to the Dotidae family), fungi belonging to the Trichocomaceae, Eurotiaceae, Parmulariaceae, Phanerochaetaceae, Diaporthaceae, and Pezizaceae families, bacteria belonging to the Pseudomonadaceae family, and actinomyces belonging to the Streptomycetaceae family (Table  3). Dihydroagarofuran sesquiterpenoids have been isolated from the roots of Maytenusmekongensis, the stems of M. oblongata, the leaves of M. spinosa, the roots and leaves of Tripterygium wilfordii, the

Conclusions
In summary, a total of 391 bioactive nitrogenous sesquiterpenoids have been isolated and characterized from plants, microorganisms, and marine organisms at the past ten years. This report systematically describes the occurrence, isolation, structures and biological activities ofthese nearly 400 natural products that contain a nitrogen-carbon/nitrogen-nitrogen/nitrogen-sulfurbond. These natural products are dispersed over severalstructural classes, isolated from many different sources (bothmarine and terrestrial) and possess a diverse array of biological activities. It can be concluded that the structure types are obviously related to the species sources, and the bioactivities of nitrogenous sesquiterpenoids are obviously related to structure types, being particularly important their cytotoxic activities. The important points arising from this review are the following: (1) There are few structural types of N-containing sesquiterpenes in plants, while the structural types of sesquiterpenes with nitrogen in marine resources and microorganisms are various and diverse. (2) Dihydroagarofuran sesquiterpenoids were considered the most widespread and characteristic metabolites of the plants of Celastraceae, which are well recognized as characteristic metabolitesand important chemotaxonomic markers or indicators of the family, exceptforsome β-dihydroagarofurans obtained from the Saxifragaceae species Parnassia wightiana. (3) Sponges and their associated microorganisms are the largest contributors of nitrogenous sesquiterpenoids. Rearranged 4,9-friedo-drimaneterpenoid skeletons represent the majority ofnitrogen-contenting sesquiterpenes isolated from marine sponges. The types of sesquiterpenoids that are the most abundant among the marine organisms, Halichondria sp. (sponge) and Phyllidiella sp. (nudibranchs), are all sesquiterpene isocyanides, isothiocyanates, thiocyanates, and formamides. (4) Nitrogenous sesquiterpenes are rich in microorganisms, such as fungus, bacteria and actinomyces and the main skeleton types are drimane, bisabolane, farnesane, tremulane sesquiterpenoids and so on. (5) Dihydroagarofuran sesquiterpenoids show significant anti-inflammatory, neuroprotective, and immunosuppressive effects, while sesquiterpenes isolated from marine organisms exhibit remarkable antitumor cytotoxic activities. Due to the rich activities and structural diversity of N-contenting sesquiterpenes, researchers have not stopped exploring and studying such compounds. We hope this review will stimulate further researchinto this interesting class of nitrogenous secondary metabolites.

Conflicts of Interest:
The authors declare no conflict of interest.