Characteristic metabolites of Hypericum plants: their chemical structures and biological activities

Plants belonging to the genus Hypericum (Hypericaceae) are recognized as an abundant source of natural products with interesting chemical structures and intriguing biological activities. In the course of our continuing study on constituents of Hypericum plants, aiming at searching natural product-based lead compounds for therapeutic agents, we have isolated more than 100 new characteristic metabolites classified as prenylated acylphloroglucinols, meroterpenes, ketides, dibenzo-1,4-dioxane derivatives, and xanthones including prenylated xanthones, phenylxanthones, and xanthonolignoids from 11 Hypericum plants and one Triadenum plant collected in Japan, China, and Uzbekistan or cultivated in Japan. This review summarizes their chemical structures and biological activities.


Introduction
Hypericum plants of the family Hypericaceae, consisting of over 500 perennial herbs or shrubs subdivided into 30 sections, are mainly distributed in temperate area [1]. Some of Hypericum plants have been used as traditional remedies in various parts of the world. A number of researches on the constituents of Hypericum plants have resulted in the isolation of various classes of natural products including terpenoids, flavonoids, xanthones, naphthodianthrones, and prenylated acylphloroglucinols (PAPs) [2]. Among others, hypericin, a naphthodianthrone derivative found in Hypericum plants belonging to the sections Hypericum, Adenotras, and Drosocarpium, is recognized as one of the most potent naturally occurring photodynamic agents [3]. PAPs are specialized metabolites of plants belonging to some genera of the Hypericaceae and Clusiaceae families including Hypericum, Garcinia, Clusia, and so on [4][5][6], while several meroterpenes structurally and biosynthetically related to PAPs have also been reported from these plant species [7]. Since diverse and complex chemical structures and intriguing biological activities of the PAPs have attracted huge interests of researchers, some excellent systematic reviews for PAPs have been published [4][5][6]8].
Our research group has been conducting a study searching for new plant metabolites with unique chemical structures and biological activities [9][10][11]. In the course of this research project, we investigated 11 Hypericum species belonging to the sections Roscyna (H. ascyron), Ascyreia (H. monogynum and H. patulum), Hypericum (H. sikokumontanum, H. kiusianum, H. yojiroanum, H. yezoense, and H. erectum), Myriandra (H. frondosum 'Sunburst'), Elodeoida (H. elodeoides), and Hirtella (H. scabrum) collected in Japan, China, and Uzbekistan or cultivated in Japan together with one species of Triadenum (T. japonicum), a sister genus of Hypericum, to isolate more than 100 of new characteristic metabolites. In this review, their chemical structures and biological activities as well as related studies conducted by other research groups are summarized.
Hypericum erecturm is a perennial herb widely distributed in east Asia. This plant is called "Otogirisou" in Japanese and a representative species of Hypericum plants seen in Japan. The aerial parts of H. erectum have been used as a traditional remedy to heal wounds, burn wounds, bruises, swelling, and rheumatism. Interestingly, the aerial parts of H. erectum were also used for treating disorders of birds. We, however, had an interest in the root constituents of H. erectum, and investigated them to isolated PAPs named erecricins A-E (87-91) and adotogirin (92) (Fig. 11) [56].    H. scabrum is one of the most popular medicinal herbs in Uzbekistan to treat numerous disorders, such as liver, gall bladder, intestinal, and heart diseases, rheumatism, and cystitis. Investigation on constituents of the aerial parts of H. scabrum collected at Chimgan, Uzbekistan showed this plant to be a rich source of polycyclic PAPs with a benzoyl group as their acyl moieties. Hyperibone K (99) is the first example of type B PAP possessing a "diamond-like" adamantane skeleton (Fig. 14) [60], whereas a number of type A adamantane or homoadamantane polycyclic PAPs have been reported to date [4,5]. The absolute configuration of hyperibone K (99) was assigned based on the enantioselective total synthesis of an enantiomer of 99 by Porco, Jr. et al. [61]. Hyperibone L (100) is a polycyclic PAP with bicyclo[3.3.1]nonane-2,4,9-trione core (Fig. 14) [60]. The  [62]. We reported a moderate cytotoxicity of hyperibones K (99) and L (100) against human cancer cell lines (A549 and MCF-7) [60], while a neuroprotective effect on the glutamate-induced toxicity in SK-N-SH cells and a hepatoprotective activity against paracetamol-induced HepG2 cell damage of 99 were reported by Gu et al. [63]. We also isolated prenylated xanthones, hyperxanthones A-F [60], from the same plant material. An inhibitory effect of hyperxanthone E (101) (Fig. 14) on interferon-γ plus LPSinduced NO production in RAW 264.7 cells was reported by Xu et al. [64].

Conclusion
This review summarized the chemical structures of 107 characteristic metabolites isolated from 11 Hypericum plants and one Triadenum plant by our research. Their structures were elucidated mainly on the basis of NMR, MS, X-ray, and ECD analyses including a TDDFT ECD calculation method, which has been widely applied to assignment of the absolute configuration of natural products in recent years [67]. Interesting biological activities of the characteristic metabolites, such as antiviral activities against HIV and HCV, antiproliferative activities against cancer cell lines including MDR cancer cell lines, and antimicrobial activities against various bacteria and fungus were also demonstrated. Our phytochemical studies suggested that Hypericum plants are a rich source of not only well-known PAPs and xanthones but also meroterpenes. Biyoulactones A-E (24-28) isolated from H. monogynum, hypatulins A (44) and B (45) isolated from H. patulum, Fig. 14 The structures of hyperibones K (99) and L (100) and hyperxanthone E (101) isolated from Hypericum scabrum Fig. 15 The structures of (−)-nemorosonol (102) and trijapins A-E (103-107) isolated from Triadenum japonicum and yezo'otogirins A-C (79-81) isolated from H. yezoense were meroterpenes structurally and biosynthetically related to PAPs, while plausible biosynthetic pathway of the PAPs was summarized in previous reviews [4,5]. In contrast, some meroterpenes were conjugates with unprecedented structures composed of sesquiterpenes and a dibenzo-1,4-dioxane derivative {hyperdioxane A (18) isolated from H. ascyron} or a spirolactone derivative {biyouyanagins A (29) and B (30) isolated from H. monogynum}. Simple meroterpenes {yojironins A (77) and B (78) isolated from H. yojiroanum and yezo'otogirins D (85) and E (86) isolated from H. yezoense} and ketides {frondhyperins A-D (93-96) isolated from a cultivar H. frondosum 'Sunburst'} were also biogenetically interesting compounds. Thus, Hypericum plants are an attractive source of various characteristic metabolites, and therefore a systematic biological evaluation of our compounds isolated from Hypericum plants is in progress.
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