Ent-eudesmane sesquiterpenoids from the Chinese liverwort Chiloscyphus polyanthus.

- Seven previously undescribed ent-eudesmane sesquiterpenoids (1-7), as well as seven known analogs (8-14), were isolated from the Chinese liverwort Chiloscyphus polyanthus var. rivularis. Their structures were established based on comprehensive spectroscopy analysis, electronic circular dichroism calculations, as well as biosynthetic considerations. The cytotoxicity against HepG2 (Human hepatocellular carcinomas) cancer cell line, and antifungal activity against Candida albicans SC5314 of all isolated ent-eudesmane sesquiterpenoids were preliminarily tested, results showed that the tested compounds did not display obvious cytotoxicity and antifungal activities under the tested concentration.

Bisbibenzyls from Serbian Primula veris subsp. Columnae (Ten.) Lȕdi and P. acaulis (L.) L.

Bisbibenzyls are specialized metabolites found exclusively in liverworts, until recently; they represent chemical markers of liverworts. Their occurrence in vascular plants was noticed in 2007, when they were found in Primula veris subsp. macrocalyx from Russia. This report prompted us to chemically analyze the two most common Serbian Primula species, P. veris subsp. columnae and P. acaulis, in order to determine the presence of bisbibenzyls in them. Our study revealed nine structurally distinct bisbibenzyls (1-9), identified based on 1D and 2D NMR, IR, UV and HRESIMS data. Among them were five previously undescribed compounds (2-6). The remaining compounds found and previously described in the literature were: the bisbibenzyls riccardin C (1), isoperrottetin A (7), isoplagiochin E (8) and 11-O-demethylmarchantin I (9), as well as 4-hydroxyphenylmethylketone (10) and 4-hydroxy-3-methoxyphenylmethylketone (11). Riccardin C was the most dominant bisbibenzyl in both species studied. Previously, it was the first bisbibenzyl found in vascular plants (P. veris subsp. macrocalyx). An assessment of the cytotoxic activity of the isolated compounds against A549 lung cancer and healthy MRC5 cell lines was also the subject of our study. Compounds 6 and 9 exhibited significant cytotoxic activity expressed by IC50 values of 12 µM, but the selectivity was not satisfactory.

Cembrane-type diterpenoids from the Chinese liverwort Chandonanthus birmensis.

A chemical investigation of the Chinese liverwort Chandonanthus birmensis Steph identified five undescribed cembrane-type diterpenoids, together with six known cembrane diterpenes, one fusicoccane-type diterpenoid, and a dolabellane-type diterpenoid. Their structures were established by comprehensive analysis of HRESIMS, NMR spectroscopic data, electronic circular dichroism (ECD) calculations and single-crystal X-ray diffraction analysis. Cytotoxicity tests of the isolated diterpenoids against five cancer cell lines (A2780, A549, H460, H460RT, and HeLa) revealed that several compounds showed moderate inhibitory effects with IC50 values ranging from 11.1 to 36.2 µM.

Unprecedented 4,9-Seco-Oplopanane and Seven Drimane Sesquiterpenoids from the Chinese Liverwort Lejeunea flava (Sw.) Nees.

An unprecedented 4,9-seco-oplopanane (1), two undescribed drimane epimers (2 and 3), and five known drimane sesquiterpenoids (4-8) were isolated from the Chinese liverwort Lejeunea flava (Sw.) Nees. The structures of the new sesquiterpenoids were determined using nuclear magnetic resonance spectroscopy, electronic circular dichroism calculations, and single-crystal X-ray diffraction measurements. The inhibitory capacity of the new compounds against nitric oxide production in lipopolysaccharide-induced RAW 264.7 murine macrophages, along with the cytotoxicity of the new compounds against A549 and HepG-2 human cancer cell lines, were discussed.

Pharmacological, Cytotoxic, Immunostimulant, and Auto-Immune Activity of Thalloid Liverworts: An Overview.

Bryophytes have historically been employed as verdant medicine in China, Native America and India. Phenolics, glycosides, fatty acids, other rare aromatic compounds and Terpenoids found in bryophytes may help prevent cancer and other chronic disorders. Liverworts have historically been utilized in traditional medicine and also as immu-nomodulators or immunostimulants. Diterpenoids, Lipophilic mono-, sesqui- and aromatic compounds assisting to the biological activities of liverworts. For their biological functions more than 220 aromatic compounds and 700 terpenoids and other chemicals discovered in liverworts scrutinized for their pharmacological, cytotoxic, immunostimulant and auto-immune efficacies.

Prenylated bibenzyls from the Chinese liverwort Radula apiculata.

Three new prenylated bibenzyls (1-3) and seven known congeners were purified from the Chinese liverwort Radula apiculata. Their structures were identified by the analysis of spectroscopic data and comparison of reported NMR data. All isolated compounds were tested for several human cancer cell lines with adriamycin served as a positive control.

Pinguisane Sesquiterpenoids from the Chinese Liverwort Trocholejeunea sandvicensis and Their Anti-Inflammatory Activity.

Nine new pinguisane sesquiterpenoid compounds, 1-9, including a highly oxygenated compound (1) and two amides (7 and 8), along with three known compounds (10, 11, and 12), were isolated from the Chinese liverwort Trocholejeunea sandvicensis Mizut (Lejeuneaceae). The structures of these compounds were determined by analysis of IR, UV, HRESIMS, NMR spectroscopic data, electronic circular dichroism calculations, and single-crystal X-ray diffraction analysis. Inhibitory effects against lipopolysaccharide (LPS)-induced NO production in RAW 264.7 murine macrophages indicated that the maximum inhibition rates of NO production of compounds 1, 9, and 10 were 83.15%, 83.54%, and 96.28% under the nontoxic tested concentration, respectively. Compound 9 also displayed moderate anti-inflammatory activity in vivo in a CuSO4-induced transgenic zebrafish model.

Cytotoxic Activities of 9,10-seco-Cycloartane-Type Triterpenoids from the Chinese Liverwort Lepidozia reptans.

Ten new triterpenoids, including nine 9,10-seco-cycloartanes (1-9) and one 9,19-cyclolanostane (10), as well as one sesquiterpenoid (11) and four known compounds (12-15), were extracted and purified from the whole plant of the Chinese liverwort Lepidozia reptans. Multiple techniques (NMR, HRESIMS, IR, and X-ray crystallographic analysis) were applied to determine the structures of the isolated compounds. Bioassay determinations showed that compound 7, which contains an α,ß-unsaturated carbonyl moiety in its structure, inhibited the growth of a panel of cancer cell lines with IC50 values ranging from 4.2 ± 0.2 to 5.7 ± 0.5 µM. Further investigation revealed that compound 7 induces PC-3 cell death via mitochondrial-related apoptosis.

Diverse Prenylated Bibenzyl Enantiomers from the Chinese Liverwort Radula apiculata and Their Cytotoxic Activities.

An EtOH extract of the Chinese liverwort Radula apiculata showed cytotoxic activity against the A549 lung cancer cell line. Bioassay-guided fractionation led to the isolation of 19 prenylated bibenzyls, including eight previously unknown dimeric prenylated bibenzyls [radulapins A-H (1-8)], four new prenylated bibenzyls (9-12), and seven known compounds (13-19). Compounds 1-11 were analyzed as racemates by chiral-phase separation. Their structures were determined by detailed analysis of their spectroscopic data and by single-crystal X-ray diffraction, chiral resolutions, and electronic circular dichroism measurements. Using an MTT assay, these dimers (1-8) showed significant cytotoxic activity against a panel of human cancer cell lines. Further investigation revealed that compound 4 induces PC-3 cell death via mitochondrial-derived apoptosis.

Terpenoids from Chinese Liverworts Scapania spp.

An investigation of the chemical composition of Chinese liverworts led to the isolation of six new caged clerodane-type diterpenoids, scaparins A-C (1-3) from Scapania koponenii and scaparins D-F (4-6) from S. verrucosa. An unknown ent-trachylobane diterpenoid (7) and three known terpenoid derivatives (8-10) were obtained from S. verrucosa. The structures of the compounds were established on the basis of physical data (IR, UV, HRESIMS, and 1D and 2D NMR), and the absolute configurations were unequivocally confirmed by comparison of the experimental and calculated electronic circular dichroism spectra. Preliminary bioassays showed that compounds 1-7 exhibited moderate to weak quinone reductase-inducing activity in Hepa-1c1c7 cells.

Chemotaxonomy and cytotoxicity of the liverwort Porella Viridissima.

The first chemotaxonomic study based on volatile components of Porella viridissima (Mitt.) Grolle is reported. The GC-MS analysis of ether extract was performed; ten santalane and five pinguisane-type sesquiterpenes were identified together with perrottetianal A as major diterpene. Most of detected santalane-type sesquiterpenes are reported for the first time in liverwort. P. viridissima was found to belong to the chemotype III (pinguisane/sacculatane) and shared chemical similarities with P. navicularis. Perrotettianal A was isolated and has shown strong cytotoxicity against ovarian cancer.

Bibenzyls and bisbybenzyls of bryophytic origin as promising source of novel therapeutics: pharmacology, synthesis and structure-activity.

BACKGROUND: The amphibian, non-vascular, gametophyte-dominant, bio-indicator class, bryophytes; with their wide ranges of habitat have attained importance due to their promising medicinal attributions and therapeutic role; mostly aided by presence of aromatic bibenzyl and bisbybenzyl class of compounds. Bibenzyls are steroidal ethane derivatives, resembling the structural moiety of bioactive dihydro-stilbenoids or iso-quinoline alkaloids. These stress triggered secondary metabolites are the by-products of the flavonoid biosynthetic pathway. Different classes of bryophytes (Bryophyta, Marchantiophyta and Anthocerotophyta) possess different subtypes of bibenzyls and dimeric bisbibenzyls. Among the liverwort, hornwort and mosses, former one is mostly enriched with bibenzyl type constituents as per the extensive study conducted for phytochemical deposit. Considering macrocyclic and acyclic group of bibenzyls and bisbybenzyls, generally marchantin type compounds are reported vividly for significant biological activity that includes neuro-nephro-cardio-protection besides anti-allergic, anti-microbial, anti-apoptotic and cytotoxic activities studied on in-vitro and in-vivo models or on cell lines. RESULT: The critical analysis of reported chemical and pharmaceutical attributions of bibenzyls and bis-bibenzyls yielded detailed report on this compound class along with their application, mode of action, natural source, techniques of synthesis, extraction procedure, isolation and characterization. Further, the structure activity relationship studies and bioactivity of bibenzyls derived from non-bryophytic origin were also summarized. CONCLUSION: This review encompasses prospective biological application of botanical reservoir of this primarily ignored, primeval land plant group where recent technical advances has paved the way for qualitative and quantitative isolation and estimation of novel compounds as well as marker components to study their impact on environment, as bio-control agents and as key leads in future drug designing. Graphical abstract.

Distribution of Bibenzyls, Prenyl Bibenzyls, Bis-bibenzyls, and Terpenoids in the Liverwort Genus Radula.

Plants of the Radula genus are chemically very distinct from the other liverworts since they mainly elaborate bibenzyls including bibenzyl cannabinoids and prenyl bibenzyl derivatives, as well as bis-bibenzyls. Several of these components show biological activities such as psychoactivity, vasopressin antagonist, antimicrobial, antifungal, and NO production inhibitory activity, and cytotoxic activity against human cancer cell lines. While distribution of terpenoids in Radula species is in general very limited, some Portuguese species are rich sources of sesquiterpenoids. Among 679 liverwort species so far examined chemically, 264 species contained α-tocopherol, which may play an important antioxidative role for the constituents of oil bodies of liverworts.

Prenylated Bibenzyls from the Chinese Liverwort Radula constricta and Their Mitochondria-Derived Paraptotic Cytotoxic Activities.

Nine new prenylated bibenzyls, radstrictins A-I (1-9), and 11 known congeners were obtained from the Chinese liverwort Radula constricta. Their structures were identified by analysis of HRMS, NMR, and electronic circular dichroism data. Radstrictins A-F (1-6) were isolated as a racemate or scalemic mixtures. All the isolated compounds were subjected to cytotoxicity assessment. Methyl 2,4-dihydroxy-3-(3-methyl-2-butenyl)-6-phenethylbenzoate (10) exhibited significant activity against human lung cancer cell lines A549 and NCI-H1299 with IC50 values of 6.0 and 5.1 µM, respectively. Further research revealed that cell death triggered by 10 occurred via mitochondria-derived paraptosis.

Bryophytes as a source of bioactive volatile terpenoids - A review.

Bryophytes, phylogenetically placed between the algae and pteridophytes, are divided into three classes: mosses, liverworts, and hornworts. Traditional system of medicine throughout the world has been utilizing this group of plants to treat various ailments. One of the outstanding features of these spore forming plants is their chemistry, especially that of the liverworts. Liverworts have yielded a rich array of terpenoids, especially sesqui- and diterpenoids. Many of these compounds are characterized by unprecedented structures, and some have not been found in any other plants, fungi or marine organisms. Among the bryophytes, the chemical constituents of liverworts and their biological activity have been studied in the most detail. In this review the chemistry of the terpenoids found in bryophytes have been presented, and their phytotoxic, antimicrobial, antifungal, cytotoxic, anti-inflammatory, piscicidal, insect repellent, antileishmanial and antitrypanosomal activities.

Sacculatane diterpenoids from the Chinese liverwort Pellia epiphylla with protection against H2O2-induced apoptosis of PC12 cells.

Eight previously undescribed sacculatane diterpenoids, epiphyllins A-H, and one unknown bibenzyl-based isopentene along with seven known compounds were isolated from the Chinese liverwort Pellia epiphylla (L.) Corda. Their structures were established unequivocally on the basis of spectroscopic data and CD measurement. The quinine reductase-inducing activity evaluation demonstrated that epiphyllins A-D, 1ß-hydroxysacculatanolide and pellianolactone B displayed moderate antioxidant effect. Further investigation of pellianolactone B revealed its protective effects on H2O2-induced oxidative insults and apoptosis in PC12 cells.

Cytotoxic Activity of Riccardin and Perrottetin Derivatives from the Liverwort Lunularia cruciata.

Seven new bisbibenzyls (1-7) were isolated from the methanol extract of the liverwort Lunularia cruciata along with one previously known bibenzyl and five known bisbibenzyls. The structures of compounds 1-7 were elucidated on the basis of the spectroscopic data. These newly isolated bisbibenzyls may be divided into two groups, the acyclic bisbibenzyls, perrottetins (1-3), and the cyclic analogues, riccardins (4-7). Besides standard perrottetin and riccardin structures (1 and 4, respectively), they contain phenanthrene (3 and 5), dihydrophenanthrene (2), and quinone moieties (6 and 7), rarely found in natural products. The new compounds 3 and 5, as well as the known riccardin G, exhibited cytotoxic activity against the A549 lung cancer cell line with IC50 values of 5.0, 5.0, and 2.5 µM, respectively.

Clerodane diterpenoids from the Chinese liverwort Jamesoniella autumnalis and their anti-inflammatory activity.

Nine previously undescribed clerodane-type diterpenoids, jamesoniellides M-T and one ent-labdane-type diterpenoid, as well as one known analogue, were isolated from the Chinese liverwort Jamesoniella autumnalis (DC.) Stephani. Their structures were determined using MS, NMR spectroscopy, and electronic circular dichroism (ECD) calculations. Inhibition on LPS-induced NO production in RAW 264.7 murine macrophages was investigated, and the results showed that jamesoniellides Q-S exhibited moderate anti-inflammatory activity, with 50-80% maximum inhibition rate of NO production under the nontoxic tested concentration.

Terpenoids with vasorelaxant effects from the Chinese liverwort Scapania carinthiaca.

Four new diterpenoids scapanacins A-D (1-4) including one kaurane and three clerodane derivatives, along with eleven known compounds (9-15), were isolated from the Chinese liverwort Scapania carinthiaca J.B. Jack ex Lindb. Their structures were determined based on extensive spectroscopic analyses, and electronic circular dichroism (ECD) calculations. Vasorelaxant activity assays of the clerodane-type diterpenoids 2, and 4-8 revealed that they relaxed 3rd-order rat mesenteric arterioles pre-contracted with norepinephrine (NE). Further assays with scapanacin D (4) confirmed that the vasodilatation was mediated through inhibition of Ca2+ influx via voltage-dependent Ca2+ channels (VDCs), and this Ca2+ channel blocking effect was also confirmed by inhibiting the extracellular Ca2+ influx in MOVAS cells. Besides, very little decrease of the relaxant activity caused by 4 on endothelium-denuded mesenteric arterioles with NE also suggested the vasodilatation was mainly produced by inhibiting Ca2+-induced contraction of smooth muscle. In addition, cytotoxicity testing showed that compounds 1 and 9 with α,ß-unsaturated ketone exhibited inhibitory activities against a small panel of human cancer cell lines.

Terpenoids isolated from Chinese liverworts Lepidozia reptans and their anti-inflammatory activity.

Five new terpenoids (1-5) including two dollabellane-type, one ent-kaurane-type diterpenoids and two sesquiterpenoids were isolated from the Chinese liverwort Lepidozia reptans (L.) Dumort., together with nine known terpenoids (6-14). Their structures were determined on the basis of analysis of MS and NMR spectroscopic data, single-crystal X-ray diffraction and electronic circular dichroism calculations. The selected compounds 1, 2, 6, 7, 9 and 14 were screened for anti-inflammatory activities by the model of LPS-induced nitric oxide (NO) production with macrophage cells, and the mechanism of the active compounds 1 and 2 were further explored.