Polyhydroxylated Spirostanol Saponins from the Rhizomes of Paris dulongensis.

Three new polyhydroxylated spirostanol steroidal saponins, dulongenosides B-D (2-4), along with 14 known compounds, dulongenoside A (1), padelaoside B (5), parisyunnanoside G (6), polyphyllin D (7), ophiopogonin C' (8), formosanin C (9), dioscin (10), paris saponin VII (11), paris H (12), parisyunnanoside I (13), protodioscin (14), proprotogracillin (15), crustecdysone (16), and stigmasterol-3-O-ß-d-glucopyranoside (17), were isolated from the rhizomes of Paris dulongensis (Melanthiaceae). Their chemical structures were elucidated based on extensive analyses of NMR and MS data and acidic hydrolyses. The isolates were evaluated for their cytotoxicity to five human cancer cell lines (HL-60, SW480, MDA-MB-231, A549, and A549/Taxol) and the normal human bronchial epithelial cell line BEAS-2B by the MTS test. Compounds 7-12 and 14 showed cytotoxic activity, with IC50 values ranging from 0.20 to 4.35 µM. Proprotogracillin selectively inhibited A549 (IC50=0.58 µM) and A549/Taxol (IC50=0.74 µM) cells, with no significant cytotoxic activity against HL-60, SW480, MDA-MB-231, or BEAS-2B cells, with IC50 values greater than 40 µM.

A new amide from the fruiting bodies of Tricholoma bakamatsutake.

A new amide tricholomine C was isolated from the dried fruiting bodies of Tricholoma bakamatsutake. Its structure was identified by a combination of nuclear magnetic resonance spectroscopic analysis and electronic circular dichroism (ECD) calculations. The ethyl alcohol crude extract and tricholomines A-C from T. bakamatsutake were evaluated for neuroprotective activities. Of these substances, the crude extract showed weak neurite outgrowth-promoting activity in rat pheochromocytoma (PC12) cells, as well as weak inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE).

Heterodimers with a cucurbitane-type triterpenoid skeleton from the branches of Elaeocarpus dubius.

Four undescribed and two known cucurbitane-type triterpenoids, including two heterodimers, elaeocarpudubins A and B, were isolated from the branches of Elaeocarpus dubius (Elaeocarpaceae). The chemical structures of these undescribed isolates were determined by analyses of 1D and 2D NMR and MS data, electronic circular dichroism (ECD) calculations, and chemical transformation. Biogenetically, elaeocarpudubins A and B might be derived from cucurbitacin F through Michael addition with vitamin C and (-)-catechin, respectively. These six isolates were evaluated for their cytotoxic activities against human leukemia HL-60, human lung adenocarcinoma A549, human hepatoma SMMC-7721, human breast cancer MCF-7, human colon cancer SW480, and paclitaxel-resistant A549 (A549/Taxol) cell lines, for their antioxidant properties using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, and for their differentiation effects on nerve growth factor (NGF)-mediated neurite outgrowth in rat pheochromocytoma PC12 cells. Cucurbitacins F (IC50 of 4.98-38.11 µM) and D (IC50 of 0.03-4.40 µM) showed growth-inhibitory activities against these six cancer cell lines. Elaeocarpudubin B (IC50 of 61.04 µM) and elaeocarpudoside B (IC50 of 6.93 µM) showed antioxidant activities. Elaeocarpudubin B and elaeocarpudoside B also showed neurite outgrowth-promoting activities in PC12 cells at a concentration of 10 µM.

Bioassay-guided isolation of cytotoxic constituents from the flowers of Aquilaria sinensis.

Bioassay-guided fractionation of the EtOH extract from the flowers of Aquilaria sinensis (Lour.) Spreng. (Thymelaeaceae) led to the isolation of a new cucurbitane-type triterpenoid, aquilarolide A (1), along with five known compounds (2-6). The structure of 1 was elucidated by extensive 1D and 2D nuclear magnetic resonance (NMR) experiments and mass spectrometry (MS) data and theoretical calculations of its electronic circular dichroism (ECD) spectra. Aquilarolide A, cucurbitacin E (3), cucurbitacin B (4), and 7-hydroxy-6-methoxy-2-[2-(4-methoxyphenyl)ethyl]-4H-1-benzopyran-4-one (6) showed significant cytotoxicity against human lung adenocarcinoma SPC-A-1, human lung squamous cell carcinoma NCI-H520, human lung adenocarcinoma A549, and paclitaxel-resistant A549 (A549/Taxol) cell lines. All four active compounds, with IC50 values ranging from 0.002 to 0.91 µM, had better inhibitory activities against A549/Taxol cells than paclitaxel (IC50 = 1.80 µM). Among them, cucurbitacin E (IC50 = 0.002 µM) is the most active. Further studies are needed to evaluate their in vivo antitumor activities and to clarify their mechanisms.

Five new 2-(2-phenylethyl)chromone derivatives and three new sesquiterpenoids from the heartwood of Aquilaria sinensis, an aromatic medicine in China.

Five new 2-(2-phenylethyl)chromone derivatives, (5S,6R,7R,8S,7'R)-7'-hydroxyagarotetrol (1), (5S,6R,7R,8S,7'S)-7'-hydroxyagarotetrol (2), (6S,7S,8R)-2­[2­(4-methoxyphenyl)ethyl]­6,7,8­trihydroxy­5,6,7,8­tetrahydrochromone (3), (6S,7S,8R)-2­(2-phenylethyl)­6,7,8­trihydroxy­5,6,7,8­tetrahydrochromone (4), (5S,6R,7S,8R)-2-(2-phenylethyl)-5,6,7-trihydroxy-5,6,7,8-tetrahydro-8-[2-(2-phenylethyl)-7-methoxychromonyl-6-oxy]chromone (5), three new sesquiterpenoids, (4S,5S,7S,8S,10S,13R)-7,8,13-trihydroxyrotunda-1,11-dien-3-one (6), (4S,5S,7S,8S,10S,13S)-7,8,13-trihydroxyrotunda-1,11-dien-3-one (7), and (4R,5S,7S,8S,10S,13S)-7,8,13-trihydroxyrotunda-1,11-dien-3-one (8), along with 14 known compounds were isolated from the resinous heartwood of Aquilaria sinensis (Thymelaeaceae). The chemical structures of these new compounds were elucidated by 1D and 2D NMR and MS data, single-crystal X-ray diffraction analysis, and electronic circular dichroism (ECD) calculations. The neuroprotective activities of these isolates were evaluated using an in vitro model of rat adrenal pheochromocytoma (PC12) cell injury induced by corticosterone. At concentrations from 5 to 40 µM, compounds 4 and 6, agarotetrol (9), and 6-hydroxy-2-(2-phenylethyl)chromone (17) showed significant protective activities against corticosterone-induced PC12 cell injury (P < 0.001).

Traditional uses, chemical constituents, pharmacological activities, and toxicological effects of Dendrobium leaves: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: In China, shi hu (stems of Dendrobium chrysotoxum Lindl, D. fimbriatum Hook. D. huoshanense Z.Z. Tang & S.J. Cheng, or D. nobile Lindl) and tie pi shi hu (stems of D. officinale Kimura et Migo) are famous traditional medicines and are listed in the Chinese Pharmacopoeia. However, the leaves of these Dendrobium plants are largely discarded. AIM OF THE STUDY: To better utilize Dendrobium leaves, we summarize their traditional uses, chemical constituents, pharmacological activities, and toxicological effects. MATERIALS AND METHODS: "Orchidaceae", "Dendrobium", "leaf", "traditional use", and "ethnobotany" were used as search terms to screen the literature. Cited references were collected between 1960 and 2020 from the Web of Science, China National Knowledge Internet (CNKI), SciFinder, and Google Scholar, primarily in English and Chinese. RESULTS: Traditional uses of leaves from 16 Dendrobium species were identified in the literature. The major uses of Dendrobium leaves include treatments for dermatologic disorders, metabolic syndromes, nervous system disorders, and musculoskeletal system disorders. More than 50 chemical compounds have been identified in the leaves of 10 Dendrobium species, which primarily include flavonoids, bibenzyls, coumarins, N-containing compounds, and polysaccharides. Antihyperlipidemia, antihypertensive, antihyperuricemia, anti-inflammatory, antimicrobial, antioxidant, cytotoxic and antitumor, hepatoprotective, immunomodulatory, lipase-inhibitory, and/or tyrosinase-inhibitory activities have been reported for the leaves of six Dendrobium species. D. officinale leaves have been shown to exhibit no reproductive toxicity against male rats, while D. speciosum Sm. leaves have been observed to exhibit slight genotoxicity in an in vitro study. Among Dendrobium species, D. officinale leaves are the most widely studied. CONCLUSIONS: D. officinale leaves represent a good example of the utilization of leaf resources of the Dendrobium genus. In the future, more extensive research for the development of Dendrobium leaves is needed.

A new p-terphenyl derivative from the fruiting bodies of Sarcodon imbricatus (L.) P. Karst.

A new p-terphenyl, 2',3'-diacetoxy-4,5,5',6',4'',5''-hexahydroxy-p-terphenyl (1), along with 12 known compounds were isolated from the fruiting bodies of Sarcodon imbricatus (Bankeraceae). Their structures were confirmed on the basis of extensive spectroscopic analysis and comparison with the spectral data in the literature. Compound 1 exhibited weak cytotoxicity against colon cancer SW480 and leukemia HL-60 cell lines, with IC50 values of 55.02 ± 1.79 µM and 44.71 ± 2.15 µM, respectively.

[Mechanism of Paris Forrestii (Takht.) H. Li-Suppressing the Proliferation of Acute Myeloid Leukemia Cell Lines].

OBJECTIVE: To investigate the mechanism of Paris forrestii (Takht.) H. Li (PCT3)-suppressing the proliferation of HL-60, K562, KG-1 and HT-93 cells. METHODS: cute myeloid leukemia cell lines such as HL-60, K562, KG-1 and HT-93 were treated with Paris forrestii (Takht.) H. Li (PCT3) for 24, 48, and 72 h, and MTT assay was employed to determine the cells proliferation. Meanwhile, the apoptosis of K562, HL-60, KG-1 and HT-93 cells were detected by flow cytometry after PCT3 (Control, 4 µg/ml, 8 µg/ml) treated for 24 h and the Western blot was performed to detect the expression of PARP,Caspase-3, MCL-1, BAX, BCL-2, P53, and P27. GAPDH was used as an internal loading control. RESULTS: MTT assay showed that Paris forrestii (Takht.) H. Li (PCT3) significantly inhibited the proliferation of HL-60, K562, KG-1 and HT-93 cells in concentration and time-dependent manners. Compared with the control group, the leukemia cell viabilities were significantly suppressed (r =0.9436; r =0.8623; r =0.9922; r =0.8918). Paris forrestii (Takht.) H. Li (PCT3) induced apoptosis of leukemia cells in a concentration dependent manner, compared with the control group (P＜0.05 or P＜0.01). Western blot revealed that PARP, a major enzyme in DNA damage repair, and Caspase-3 another one of the major executive apoptotic enzymes were cleaved in cell lines examined, and this cleavage was concentration dependent. Anti-apoptotic proteins such as MCL-1 and BCL-2 were down regulated by Paris forrestii (Takht.) H. Li (PCT3), and Pro-apoptotic protein BAX was upregulated. And the protein of tumor suppressor gene P53 and its downstream signaling protein P27 increased. CONCLUSION: Paris forrestii (Takht.) H. Li (PCT3) can inhibit the proliferation of leukemia cells by activating endogenous apoptosis pathway, and provide a potential new drug selection for clinical treatment of AML leukemia.

Substituting one Paris for another? In vitro cytotoxic and in vivo antitumor activities of Paris forrestii, a substitute of Paris polyphylla var. yunnanensis.

ETHNOPHARMACOLOGICAL RELEVANCE: Chong-lou (Paris polyphylla var. yunnanensis or P. polyphylla var. chinensis) is traditionally used as an anticancer medicine in China. It is also the material basis of some Chinese patent anticancer medicines, such as Gan-Fu-Le capsules, Bo-Er-Ning capsules, Lou-Lian capsules, Ruan-Jian oral liquid, and Qi-Zhen capsules. P. forrestii, a substitute for Chong-lou, is planted at a large scale in the Yunnan Province of China. AIM OF THE STUDY: To clarify the active chemical constituents of P. forrestii and evaluate the in vitro and in vivo anticancer activities of the total saponins from P. forrestii. MATERIALS AND METHODS: The total saponins of P. forrestii were extracted and separated to yield pure compounds by chromatographic techniques, and the structures of the isolates were elucidated by spectroscopic methods. The cytotoxicity of the crude extracts, total saponins, and chemical constituents were evaluated using an MTS assay. In vivo antitumor activities of the total saponins from P. forrestii were measured using H22 tumor-bearing mice by intraperitoneal (ip) administration. RESULTS: Eight compounds, including polyphyllin D (1), formosanin C (2), dioscin (3), diosgenin-3-O-α-l-rhamnopyranosyl-(1→2)-ß-d-glucopyranoside (4), paris saponin H (5), pennogenin-3-O-α-l-rhamnopyranosyl-(1→2)-[α-l-rhamnopyranosyl-(1→4)]-ß-d-glucopyranoside (6), pariposide A (7), and crustecdysone (8), were isolated from the total saponins of P. forrestii. The total saponins and compounds 1-6 showed significant inhibitory activity against the growth of the HL-60, SMMC-7721, A-549, MCF-7, and SW480 cell lines. The total saponins from P. forrestii had a tumor-inhibitory effect in H22 tumor-bearing mice upon ip (2.25 mg/kg dose) administration, with an inhibition rate of 42.6% compared with cisplatin (ip, 2 mg/kg dose, 53.9% inhibition rate). CONCLUSION: The results support that P. forrestii could be a substitute for P. polyphylla var. yunnanensis as an anticancer medicine.

Modified Abietane Diterpenoids from Whole Plants of Selaginella moellendorffii.

A new modified abietane diterpenoid, (3S,4S,5R,10S)-18(4→3)-abeo-3,4,12,18-tetrahydroxy-8,11,13-abietatrien-7-one (1), and two novel dimers, selaginedorffones A (2) and B (3), featuring a new cyclohexene moiety that was biogenetically constructed from two modified abietane diterpenoids through a Diels-Alder reaction were obtained from a methanolic extract of Selaginella moellendorffii, a traditional Chinese herb. The structures of 1-3 were identified by a combination of NMR spectroscopic analysis and ECD calculations. In the present study, diterpenoids were identified from S. moellendorffii for the first time, which supports the presence of diterpene synthases in this plant. These three diterpenoids (1-3) were evaluated for their growth-inhibitory activities against several human cancer cell lines. Of these substances, selaginedorffone B (3) showed cytotoxicity against the MCF-7 human-breast-cancer-cell line (IC50 9.0 µM).

Tabercorymines A and B, Two Vobasinyl-Ibogan-Type Bisindole Alkaloids from Tabernaemontana corymbosa.

Tabercorymines A (1) and B (2), two new vobasinyl-ibogan-type bisindole alkaloids with an unprecedented skeleton, were isolated from Tabernaemontana corymbosa. Their structures were established by a combination of spectroscopic data, chemical transformation, single-crystal X-ray diffraction, and ECD calculation. Compound 1 represents a novel bisindole alkaloid, characterized by a caged heteropentacyclic ring system incorporating an unprecedented C-7/C-20 bond in the vobasinyl unit. Alkaloids 1 and 2 showed potent antiproliferative activity against several human cancer cell lines, including vincristine-resistant KB.

Amides and neolignans from the aerial parts of Piper bonii.

Six amides, piperbonamides A-F, three neolignans piperbonins A-C, and 11 known compounds were isolated from the aerial parts of Piper bonii (Piperaceae). The structures of piperbonamides A-F and piperbonins A-C were elucidated based on the analysis of 1D and 2D NMR and MS data. Piperbonin A, (+)-trans-acuminatin, (+)-cis-acuminatin, (+)-kadsurenone, and pipernonaline showed weak activity against platelet aggregation with IC50 values of 118.2, 108.5, 90.02, 107.3, and 116.3 µM, respectively, as compared with the positive control, tirofiban, with an IC50 value of 5.24 µM. Piperbonamides A-F were inactive against five tumor cell lines at concentrations up to 40 µM.

The pyrrolidinoindoline alkaloid Psm2 inhibits platelet aggregation and thrombus formation by affecting PI3K/Akt signaling.

AIM: Psm2, one of the pyrrolidinoindoline alkaloids isolated from whole Selaginella moellendorffii plants, has shown a potent antiplatelet activity. In this study, we further evaluated the antiplatelet effects of Psm2, and elucidated the underlying mechanisms. METHODS: Human platelet aggregation in vitro and rat platelet aggregation ex vivo were investigated. Agonist-induced platelet aggregation was measured using a light transmission aggregometer. The antithrombotic effects of Psm2 were evaluated in arteriovenous shunt thrombosis model in rats. To elucidate the mechanisms underlying the antiplatelet activity of Psm2, ELISAs, Western blotting and molecular docking were performed. The bleeding risk of Psm2 administration was assessed in a mouse tail cutting model, and the cytotoxicity of Psm2 was measured with MTT assay in EA.hy926 cells. RESULTS: Psm2 dose-dependently inhibited human platelet aggregation induced by ADP, U4619, thrombin and collagen with IC50 values of 0.64, 0.37, 0.35 and 0.87 mg/mL, respectively. Psm2 (1, 3, 10 mg/kg) administered to rats significantly inhibited platelet aggregation ex vivo induced by ADP. Psm2 (1, 3, 10 mg/mL, iv) administered to rats with the A-V shunt dose-dependently decreased the thrombus formation. Psm2 inhibited platelet adhesion to fibrinogen and collagen with IC50 values of 84.5 and 96.5 mg/mL, respectively, but did not affect the binding of fibrinogen to GPIIb/IIIa. Furthermore, Psm2 inhibited AktSer473 phosphorylation, but did not affect MAPK signaling and Src kinase activation. Molecular docking showed that Psm2 bound to phosphatidylinositol 3-kinase ß (PI3Kß) with a binding free energy of -13.265 kcal/mol. In addition, Psm2 did not cause toxicity in EA.hy926 cells and produced only slight bleeding in a mouse tail cutting model. CONCLUSION: Psm2 inhibits platelet aggregation and thrombus formation by affecting PI3K/Akt signaling. Psm2 may be a lead compound or drug candidate that could be developed for the prevention or treatment of thrombotic diseases.

[Medicinal values and their chemical bases of Paris].

Medicinal values and their chemical bases of Paris (Trilliaceae) are reviewed. Paris plants include 40 species and varieties. Among them, 18 ones are medicinal plants with similarity in traditional uses. Fourteen species have been studied phytochemically, which led to isolation of 207 compounds including 121 steroidal saponins. These saponins are major active constituents from Paris plants, which can explain the traditional uses of the plants to treat cancer, malignant boil, bleeding, gastritis, and so on. The similarity in medicinal uses and chemical constituents of Paris plants implies the possibility of resource substitution among these species. It is worth to further investigate Paris plants in chemical constituents, pharmacological activity, biological property, and toxicology.

Multidrug resistance-selective antiproliferative activity of Piper amide alkaloids and synthetic analogues.

Twenty-five amide alkaloids (1-25) from Piper boehmeriifolium and 10 synthetic amide alkaloid derivatives (39-48) were evaluated for antiproliferative activity against eight human tumor cell lines, including chemosensitive and multidrug-resistant (MDR) cell lines. The results suggested tumor type-selectivity. 1-[7-(3,4,5-Trimethoxyphenyl)heptanoyl]piperidine (46) exhibited the best inhibitory activity (IC50=4.94 µM) against the P-glycoprotein (P-gp)-overexpressing KBvin MDR sub-line, while it and all other tested compounds, except 9, were inactive (IC50 >40 µM) against MDA-MB-231 and SK-BR-3. Structure-activity relationships (SARs) indicated that (i) 3,4,5-trimethoxy phenyl substitution is critical for selectivity against KBvin, (ii) the 4-methoxy group in this pattern is crucial for antiproliferative activity, (iii) double bonds in the side chain are not needed for activity, and (iv), in arylalkenylacyl amide alkaloids, replacement of an isobutylamino group with pyrrolidin-1-yl or piperidin-1-yl significantly improved activity. Further study on Piper amides is warranted, particularly whether side chain length affects the ability to overcome the MDR cancer phenotype.

Anticancer principles from medicinal piper ( hú jiao) plants.

The ethnomedical uses of Piper ( Hú Jiao) plants as anticancer agents, in vitro cytotoxic activity of both extracts and compounds from Piper plants, and in vivo antitumor activity and mechanism of action of selected compounds are reviewed in the present paper. The genus Piper (Piperaceae) contains approximately 2000 species, of which 10 species have been used in traditional medicines to treat cancer or cancer-like symptoms. Studies have shown that 35 extracts from 24 Piper species and 32 compounds from Piper plants possess cytotoxic activity. Amide alkaloids account for 53% of the major active principles. Among them, piplartine (piperlongumine) shows the most promise, being toxic to dozens of cancer cell lines and having excellent in vivo activity. It is worthwhile to conduct further anticancer studies both in vitro and in vivo on Piper plants and their active principles.

Diarylheptanoids and phenylphenalenones from Musa itinerans fruits.

Two diarylheptanoids, musaitinerins A and B, one heterodimeric phenylphenalenone musaitinerone and four known phenylphenalenones, identified as 4-hydroxy-2-methoxy-9-phenyl-1H-phenalen-1-one, musanolone E, hydroxyanigorufone and irenolone were isolated from the fruits of Musa itinerans Cheesm. Their structures were elucidated using spectroscopic analyses. The antimicrobial activity of these compounds was evaluated against Escherichia coli, Staphylococcus aureus and Candida albicans; the cytotoxic activity of these compounds was also evaluated against human erythromyeloblastoid leukemia (K562) and human alveolar carcinoma epithelial (A549) cell lines, respectively. Musaitinerone and musanolone E exhibited weak effects against the A549 cell line, as compared with adriamycin. However, these two compounds did not exhibit any growth inhibition against K562 cells, S. aureus, E. coli or C. albicans. The other compounds were inactive against all of the tested cell lines and microorganisms, even at concentrations as high as 50 µM.

Total synthesis of plagiochin G and derivatives as potential cancer chemopreventive agents.

A new and efficient total synthesis has been developed to obtain plagiochin G (22), a macrocyclic bisbibenzyl, and four derivatives. The key 16-membered ring containing biphenyl ether and biaryl units was closed via an intramolecular SNAr reaction. All synthesized macrocyclic bisbibenzyls inhibited Epstein-Barr virus early antigen (EBVEA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells and, thus, are potential cancer chemopreventive agents.

Sarmentosumols A to F, new mono- and dimeric alkenylphenols from Piper sarmentosum.

Two new mono- and four new dimeric alkenylphenols, namely sarmentosumols A to F (1-6), were isolated from the aerial parts of Piper sarmentosum. The structures of these compounds were determined through a detailed analysis of NMR and MS data. Their antimicrobial activity against Escherichia coli, Staphyloccocus aureus, and Candida albicans, and their cytotoxic activity against human myeloid leukemia (K562) and human lung adenocarcinoma (A549) cell lines were also evaluated. Except for sarmentosumol A (1), whose MIC on S. aureus was reported to be 7.0 µg/mL, none of the other newly discovered compounds exhibited antimicrobial property. The studied compounds did not possess any cytotoxic property.

Nudibaccatumone, a trimer comprising a phenylpropanoid and two sesquiterpene moieties from Piper nudibaccatum.

A new complex natural product with a C39 skeleton, named nudibaccatumone, and the known sesquiterpenes (+)-spathulenol, (-)-4ß,10α-aromadendranediol, and ent-T-muurolol, as well as the phenylpropanoid hydroxychavicol, were isolated from the aerial parts of Piper nudibaccatum. The structure and absolute configuration of nudibaccatumone were elucidated using spectroscopic methods and ECD calculations. A 1,8-Michael addition reaction and an intermolecular, inverse electron demand Diels-Alder reaction are proposed as the key steps in the biosynthesis of nudibaccatumone.