Isoflavones from the leaves of Nicotiana tabacum and their anti-tobacco mosaic virus activities

Three new isoflavones, 4′,8-dihydroxy-6,7-dimethoxyisoflavone (1), 4′,6-dihydroxy-8-methoxycarbonyl-7-methoxyisoflavone (2), 4′,7-dimethoxy-8-hydroxymethyl-6-hydroxyisoflavone (3), together with three known flavones (4–6), were isolated from the leaves of Nicotiana tabacum. Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D NMR techniques. Compounds 1–3 were evaluated for their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that compounds 1–3 (at the concentration of 20 μM) exhibited anti-TMV activities with inhibition rates of 25.2, 22.6, and 27.4%, respectively.     

Synthesis and cytotoxicity evaluation of oleanolic acid derivatives

Twelve derivatives of oleanolic acid (1) have been synthesized and evaluated for their inhibitory activities against the growth of prostate PC3, breast MCF-7, lung A549, and gastric BGC-823 cancer cells by MTT assays. Within these series of derivatives, compound 17 exhibited the most potent cytotoxicity against PC3 cell line (IC₅₀ = 0.39 μM) and compound 28 displayed the best activity against A549 cell line (IC₅₀ = 0.22 μM). SAR analysis indicates that H-donor substitution at C-3 position of oleanolic acid may be advantageous for improvement of cytotoxicity against PC3, A549 and MCF-7 cell lines.     

Three new flavonoids from the leaves of oriental tobacco and their cytotoxicity

Three new flavonoids, 6,7-dimethoxy-4′-hydroxy-8-formylflavon (1), 8-formyl-4′,6,7-trimethoxyflavon (2), 4′,7-dihydroxy-8-formyl-6-methoxyflavon (3), together with fifteen known flavonoids (4–18) were isolated from the leaves of oriental tobacco (a variety of Nicotiana tabacum L). Their structures were determined by means of HRESIMS, extensive 1D and 2D NMR spectroscopic studies and chemical evidences. The cytotoxicity against five human tumor (NB4, A549, SHSY5Y, PC3, and MCF7) cell lines of compounds 1–3 were also evaluated. The results showed that compounds 1 and 3 showed high cytotoxicity against PC3 and A549 cell lines with IC₅₀ values of 2.6 and 1.6 μM, respectively.     

Sesquiterpenes from the roots of Illicium dunnianum

Six allo-cedrane sesquiterpenes, four seco-prezizaane-type sesquiterpenes, two monocyclofarnesane sesquiterpenes, together with four known sesquiterpenes, were isolated from the roots of Illicium dunnianum. The structures were elucidated by spectroscopic methods including 1D and 2D NMR. The absolute configuration of 10 was determined by a CD experiment. Compounds 11 and 13 showed potent activities against the release of β-glucuronidase in rat polymorphonuclear leukocytes induced by platelet-activating factor in vitro, with IC₅₀ values of 2.10 ± 0.40 and 1.93 ± 0.57 μM, respectively. All compounds were evaluated for cytotoxicities against five human cancer cell lines (A549, Bel-7402, BGC-823, HCT-8, and A2780) in the MTT assay, but none of them exhibited activity at concentrations tested (10⁻⁵–10⁻⁷ M).     

Topoisomerase II inhibitors from the roots of Stellera chamaejasme L.

Three new compounds, including one daphnane diterpene (1), one sesquiterpene (6), and one lignan (7) have been isolated from the Stellera chamaejasme L., together with five other known compounds, including four daphnane diterpenenoids (2–5) and one lignan (8). The structures of the new compounds were elucidated by spectroscopic analysis. The cytotoxicities of compounds 1–8 towards human lung adenocarcinoma cells (A549 cells) were evaluated using a sulforhodamine B assay. All of the compounds displayed significant cytotoxicity, with IC₅₀ values in the ranging of 0.2 nM to 2.0 μM. Mechanistic studies revealed that the antitumor activities of compounds 1–3 and 7 were derived from their inhibition of topoisomerase II (Topo II). Furthermore, as a Topo II inhibitor, compound 1 was found to effectively induced G2-M phase cell cycle arrest and apoptosis in cancer cells.     

Benzylisoquinoline alkaloids from the tubers of Corydalis ternata and their cytotoxicity

Chemical investigation of the tubers of Corydalis ternata resulted in the isolation and characterization of four new benzylisoquinoline alkaloids, epi-coryximine (1) and coryternatines A–C (2–4), along with 10 known alkaloids (5–14). Their structures were established on the basis of extensive spectroscopic data analyses and comparison with spectroscopic data reported. In addition, the cytotoxicities of the alkaloids (1–14) were evaluated by determining their inhibitory effects on several human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and HCT-15) using the SRB assay. Compound 8 showed significant cytotoxicity against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines (IC₅₀ = 8.34, 5.14, 7.87, and 2.86 μM, respectively). The four new compounds (1–4) exhibited selective cytotoxicity against the HCT-15 cell line.     

Cytotoxic constituents from the leaves of Jerusalem artichoke (Helianthus tuberosus L.) and their structure–activity relationships

Bioassay-directed phytochemical study of the Jerusalem artichoke (Helianthus tuberosus L.) leaves led to the isolation of a new sesquiterpene lactone of 3-Hydroxy-8β-tigloyloxy-1,10-dehydroariglovin (1), ten known sesquiterpene lactones (2–11) and two known flavones (12–13). Their chemical structures were elucidated on the basis of NMR (1D and 2D) and mass spectroscopic analysis. The cytotoxic activities of those compounds were subsequently tested against the MCF-7, A549 and HeLa cancer cells lines. The results indicated that sesquiterpene lactones 1–11 exhibited consistent cytotoxicity against all three cancer cell lines, while flavones 12 and 13 showed selective inhibitory activity against HeLa cell lines. Among them, compound 3 exhibited significant growth inhibitory activity against all three cell lines. The IC₅₀ values of compound 3 against MCF-7, A549 and HeLa were 1.97 ± 0.04, 7.79 ± 0.44, 9.87 ± 0.20 μg/ml, respectively. In addition, some structure–activity relationships of these sesquiterpene lactones for cytotoxicity were explored and summarized in this study.     

Aethusifolins A–D: Four new components from a traditional Mongolian medicinal herb Clematis aethusifolia Turcz

Four new components named aethusifolins A–D (1–4), together with ten known (5–14) were isolated from the dried aerial parts of a traditional Mongolian medicinal herb Clematis aethusifolia Turcz. The planar structures were established based on extensive spectroscopic analysis (HRMS, 1D and 2D NMR), and the absolute configurations were determined by modified Mosher’s method, hydrolysis method. The cytotoxicities of isolated compounds against a panel of five human solid tumor cell lines were assayed. Compounds 5, 8, and 13 showed moderate cytotoxicity against A-375 with IC₅₀ values of 15–18 μM, while compound 8 also showed cytotoxicity against SH-SY5Y with IC₅₀ values of 20 μM.     

Design,synthesis and biological evaluation of novel 3,4,5-trisubstituted aminothiophenes as inhibitors of p53–MDM2 interaction. Part 2

Five series of novel 3,4,5-trisubstituted aminothiophene derivatives and analogs were designed and synthesized based on our previous studies. All target compounds were evaluated for their p53–MDM2 binding inhibitory activities and anti-proliferation activities against A549 and PC3 tumor cell lines. Twelve compounds displayed comparable p53–MDM2 binding inhibitory activities to that of Nutlin-3. Among them, compound 7a exhibited marked binding affinity (IC₅₀ = 0.086 μM). In addition, most target compounds showed potent anti-proliferation activities with IC₅₀ values at low micromolar level. A good selective profile for wild-type p53 expression cell line was also observed. Molecular docking analysis was performed as well to predict possible binding modes of target compounds with MDM2.     

Chromones from the stems of Cassia fistula and their anti-tobacco mosaic virus activities

Three new chromones, 5-methoxy-2,2-dimethyl-7-(2-oxopropyl)-2,3-dihydrochromen-4-one (1), 5-methoxy-2,2-dimethyl-8-(2-oxopropyl)-2,3-dihydrochromen-4-one (2), and 1-(3,4-dihydro-5-methoxy-2,2-dimethyl-2H-chromen-7-yl)propan-2-one (3), together with four known chromones (4–7) were isolated from the stems of Cassia fistula. Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D-NMR techniques. Compounds 1–5 were evaluated for their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that compound 5 exhibited high anti-TMV activity with inhibition rate of 30.8% at a concentration of 20 μM. The other compounds also exhibited potential anti-TMV activities with inhibition rates in the range of 15.6–22.1% at the same concentration.     

Methanolysis of triterpenoid saponin from Ardisia gigantifolia stapf. and structure–activity relationship study against cancer cells

Thirteen 13,28-epoxy triterpenoid saponins were isolated from Ardisia gigantifolia stapf. and one potential anti-tumor saponin was methanolysised by H₂SO₄ to afford four new compounds. The seventeen compounds were evaluated for their anti-proliferative activity on A549, HCT-8 and Bel-7402 cells. The structure–activity relationship analysis indicated that the incorporation of O group at C-16, l-rhamnose at R⁵ and acetyl group at OH-6 of the d-glucose lead to a significant increase of the cytotoxic activity on A549 and HCT-8 but significant reduction of the cytotoxic activity on Bel-7402 cells. The synthesized saponins losing 13,28-epoxy and CHO at C-30, losed their cytotoxicities on A549 and HCT-8 cells, suggesting that the two moieties play an essential role for activity. 3β-O-α-l-rhamnopyranosyl-(1 → 3)-[β-d-xylopyranosyl-(1 → 2)]-β-d-glucopyranosyl-(1 → 4)-[β-d-glucopyranosyl-(1 → 2)]-α-l-arabinopyranoside-16α-hydroxy-13,28-epoxy-oleanane (2) showed better inhibitory activity to Bel-7402 (IC₅₀ 0.86 μM) than that of 5-FU (IC₅₀ 8.30 μM), which indicate that five saccharide and methyl moiety at C-30 are important for anti-proliferative activity. The activities of saponins 15 > 14, 17 > 16, suggested that the configuration of 28,30-epoxy is preferable to be 30(R) rather than 30(S) on Bel-7402 cells. Further molecular mechanism studies of saponins 1 and 2 were carried out on the cell cycle distribution of Bel-7402 cells.     

Cytotoxic xanthene derivatives from Homalium paniculiflorum

Two new xanthene derivatives, homapanicones A (1) and B (2), along with 11 known compounds (3–13), were isolated from the stems of Homalium paniculiflorum. Among them, homapanicones A (1) and B (2) represent the first example of naturally occurring xanthene derivatives with an oxidized aromatic B unit, and the known compounds (3–13) were isolated from this plant for the first time. These structures were established on the basis of extensive spectroscopic methods. Compounds 1 and 2 were tested for their cytotoxicities on HL-60, SMMC-7721, A-549, MCF-7, and SW480 human tumor cell lines. Homapanicones A (1) and B (2) showed cytotoxicities against various human cancer cell lines in the range of IC₅₀ at 4.08–24.14 μM.     

A biphenyl derivative from the twigs of Chaenomeles speciosa

In our continuing search for bioactive constituents of Korean medicinal sources, we investigated an 80% MeOH extract of the twigs of Chaenomeles speciosa. Column chromatographic purification of the CHCl₃ fraction resulted in the isolation of a new biphenyl derivative (1), along with four known biphenyl compounds (2–5) and six triterpenes (6–11). The chemical structure of the new compound was determined on the basis of spectroscopic analyses including 1D and 2D NMR data. Among isolates, compound 3 exhibited potent cytotoxic activities against SK-OV-3, SK-MEL-2, and XF498 cell lines (IC₅₀ = 5.91, 4.22, and 6.28 μM, respectively). Also, Compounds 9 and 10 showed strong anti-neuroinflammatory activities (IC₅₀ 2.38, and 6.70 μM, respectively).     

Cytotoxic cassaine diterpenoid–diterpenoid amide dimers and diterpenoid amides from the leaves of Erythrophleum fordii

Detailed phytochemical investigation from the leaves of Erythrophleum fordii resulted in the isolation of 13 compounds, including three cassaine diterpenoid–diterpenoid amide dimers (1, 3 and 5), and seven cassaine diterpenoid amides (6 and 8–13), together with three previously reported ones, erythrophlesins D (2), C (4) and 3β-hydroxynorerythrosuamide (7). Compounds 1, 3 and 5 are further additions to the small group of cassaine diterpenoid dimers represented by erythrophlesins A–D. Their structures were determined by analysis of extensive one- and two-dimensional NMR experiments and ESIMS methods. Cytotoxic activities of the isolated compounds were tested against HCT-8, Bel-7402, BGC-823, A549 and A2780 human cancer cell lines in the MTT test. Results showed that compounds 1 and 3–5 exhibited significantly selective cytotoxic activities (IC₅₀ < 10 μM) against these cells, respectively.     

Synthesis and biological evaluation of 2′,5′-dimethoxychalcone derivatives as microtubule-targeted anticancer agents

A series of novel 2′,5′-dimethoxylchalcone derivatives including 18 new compounds were synthesized and evaluated for cytotoxicities against two human cancer cell lines, NTUB1 (human bladder cancer cell line) and PC3 (human prostate cancer cell line). All these derivatives except for 21 exhibited significant cytotoxic effect against NTUB1 and PC3 cell lines. Compounds 13 and 17 with 4-carbamoyl moiety showed potent inhibitory effect on growth of NTUB1 and PC3 cells. Flow cytometric analysis demonstrated that treatment of NTUB1 cells with 1 μM 13 and 17 induced G1 phase arrest accompanied by an increase in apoptotic cell death of NTUB1 cells after 24 h. Treatment of PC3 cells with 1 μM and 3 μM 13, and 1 μM and 3 μM 17 induced S and G1, and G1 and G2/M phase arrests, respectively, accompanied by an increase in apoptotic cell death. These data suggested that 13 and 17 with different 4-carbamoyl moiety displayed same cell cycle arrest in NTUB1 cells while different doses of 13 and 17 revealed different cell cycle arrest in PC3 cells. Cell morphological study of 17 indicated that more cells rounding up or dead associated with tubulin polymerization. Compound 17 showed an increased α-tubulin level in polymerized microtubule fraction in a dose-dependent manner while 500 nM paclitaxel also showed similar effect in NTUB1 cells by Western blot analysis. The result suggested that 17 may be used as microtubule-targeted agents.     

New cassane diterpenes from the fruits of Caesalpinia mimosoides Lam.

Six new cassane diterpenes, caesmimosins A-F (1–6) were isolated from the fruits of Caesalpinia mimosoides Lam. Their structures were identified by 1D and 2D NMR spectral data. Compounds 1–6 were evaluated for their cytotoxicity on HL-60, SMMC-7721, A-549, MCF-7 and SW-480 human cancer cell lines, they did not show inhibitory cytotoxic activities at a concentration of 40 μM against the five cell lines.     

Synthesis and anticancer activity of novel 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety

Herein, we designed and synthesized of a novel series of 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety (10a–j, 13a–j). All the compounds were evaluated for the IC₅₀ values against five cancer cell lines (A549, PC-3, MCF-7, Hela and HepG2). Seven of the target compounds exhibited moderate to excellent cytotoxicity. For these compounds, we tested their inhibitory activities against mTOR kinase, and four of them were tested their inhibitory activities against PI3Kα kinase in further. The results indicated that the optimized compound 10j showed excellent inhibitory activity and cytotoxicity against mTOR kinase, PI3Kα kinase and five cancer cell lines with IC₅₀ values of 1.1 μM, 0.92 μM and 8.77–14.3 μM. Structure–activity relationships (SARs) and docking studies indicated that the thiopyrano[4,3-d]pyrimidine scaffolds exerted little effect on antitumor activities of target compounds. Substitutions of chromone moiety at C-6 position with carboxyl were benefit to the antitumor activities.     

C ring may be dispensable for β-carboline: Design,synthesis, and bioactivities evaluation of tryptophan analog derivatives based on the biosynthesis of β-carboline alkaloids

According to our previous work and the latest research on the biosynthesis of β-carboline, and using the reverse thinking strategy, tryptophan, the biosynthesis precursor of β-carboline alkaloids, and their derivatives were synthesized, and their biological activities and structure–activity relationships were studied. This bioassay showed that these compounds exhibited good inhibitory activities against tobacco mosaic virus (TMV); especially (S)-2-amino-3-(1H-indol-3-yl)-N-octylpropanamide (4) (63.3 ± 2.1%, 67.1 ± 1.9%, 68.7 ± 1.3%, and 64.5 ± 3.1%, 500 μg/mL) exhibited the best antiviral activity both in vitro and in vivo. Compound 4 was chosen for the field trials and the acute oral toxicity test, the results showed that the compound exhibited good anti-TMV activity in the field and low acute oral toxicity. We also found that these compounds showed antifungal activities and insecticidal activities.     

Cytotoxicity and inhibition of DNA topoisomerase I of polyhydroxylated triterpenoids and triterpenoid glycosides

Cytotoxicity and inhibition on human DNA topoisomerase I (TOP1) and II (TOP2) of 74 plant-originated triterpenoids and triterpenoid glycosides were investigated. The cytotoxic compounds are primarily polyhydroxylated oleananes (GI₅₀ of A549: 1.0–10.19 μM). Sixteen cytotoxic aesculiosides isolated from Aesculus pavia inhibited TOP1 catalytic activity by interacting directly with the free enzyme and preventing the formation of the DNA–TOP1 complex. Interestingly, hydrolysis of six active aesculiosides (1, 4, 6, 8, 10, and 23) lost their TOP1 activities but enhanced their cytotoxicities. None of the test compounds showed any activity against TOP2. Structure–activity relationship (SAR) investigations indicated that cytotoxic oleananes required at least one angeloyl moiety at either C-21 or C-22 but the sugar moiety at C-3 may decrease their cytotoxicities. An angeloyl or tigeloyl group at C-21 is required for oleananes to bind the free TOP1 enzyme although the type and length of acyl moiety at C-22 also affects their activity. However, sugar moiety at C-3 is necessary for their TOP1 activities.     

Three new alkaloids from the twigs of Cassia siamea and their bioactivities

Three new tricyclic alkaloid, siamalkaloids A–C (1–3), together with three known alkaloids (3–6) were isolated from the twigs of Cassia siamea. Their structures were determined by means of HRESIMS and extensive 1D and 2D NMR spectroscopic studies. Compounds 1–6 were tested for their anti-tobacco mosaic virus (anti-TMV) activity, and compound 3 exhibited high anti-TMV activity with inhibition rate of 34.5%. This rate is higher than that of positive control. In addition, the cytotoxicity of compounds 1–6 were also tested, and compounds 2–6 showed weak activity with IC₅₀ values ranging from 2.8 to 9.4 μM for some tested human tumor cell lines.