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Alternative splicing (AS) is a process that enables the generation of multiple protein isoforms with different biological properties from a single mRNA. Cancer cells often use the maneuverability conferred by AS to produce proteins that contribute to growth and survival. In our previous studies, we identified that amiloride modulates AS in cancer cells. However, the effective concentration of amiloride required to modulate AS is too high for use in cancer treatment. In this study, we used computational algorithms to screen potential amiloride derivatives for their ability to regulate AS in cancer cells. We found that 3,5‐diamino‐6‐chloro‐N‐(N‐(2,6‐dichlorobenzoyl)carbamimidoyl)pyrazine‐2‐carboxamide (BS008) can regulate AS of apoptotic gene transcripts, including HIPK3, SMAC, and BCL‐X, at a lower concentration than amiloride. This splicing regulation involved various splicing factors, and it was accompanied by a change in the phosphorylation state of serine/arginine‐rich proteins (SR proteins). RNA sequencing was performed to reveal that AS of many other apoptotic gene transcripts, such as AATF, ATM, AIFM1, NFKB1, and API5, was also modulated by BS008. In vivo experiments further indicated that treatment of tumor‐bearing mice with BS008 resulted in a marked decrease in tumor size. BS008 also had inhibitory effects in vitro, either alone or in a synergistic combination with the cytotoxic chemotherapeutic agents sorafenib and nilotinib. BS008 enabled sorafenib dose reduction without compromising antitumor activity. These findings suggest that BS008 may possess therapeutic potential for cancer treatment.

Sphingosine‐1‐phosphate (S1P) is a bioactive lipid that exerts various pathophysiological functions through binding to its receptor family (S1PRs). Since first report of the breast cancer (BCA) promoting function by S1P production (through the function of sphingosine kinases) and S1P/S1PR signaling, their antagonists have never been successfully progress to clinics after three decades. Taking advantage of bioinformatics linking to gene expression to disease prognosis, we examined the impact of associated genes in BCA patients. We found high gene expressions involved in S1P anabolism suppressed disease progression of patients who are basal cell type BCA or receiving adjuvant therapy. In addition, S1PRs expression also suppressed disease progress of multiple categories of BCA patient progression. This result is contradictory to tumor promoter role of S1P/S1PRs which revealed in the literature. Further examination by directly adding S1P in BCA cells found a cell growth suppression function, which act via the expression of S1PR1. In conclusion, our study is the first evidence claiming a survival benefit function of S1P/S1PR signaling in BCA patients, which might explain the obstacle of relative antagonist apply in clinics.

Reactive oxygen species (ROS) induction had been previously reported in 4β-hydroxywithanolide (4βHWE)-induced selective killing of oral cancer cells, but the mechanism involving ROS and the DNA damage effect remain unclear. This study explores the role of ROS and oxidative DNA damage of 4βHWE in the selective killing of oral cancer cells. Changes in cell viability, morphology, ROS, DNA double strand break (DSB) signaling (γH2AX foci in immunofluorescence and DSB signaling in western blotting), and oxidative DNA damage (8-oxo-2'deoxyguanosine [8-oxodG]) were detected in 4βHWE-treated oral cancer (Ca9-22) and/or normal (HGF-1) cells. 4βHWE decreased cell viability, changed cell morphology and induced ROS generation in oral cancer cells rather than oral normal cells, which were recovered by a free radical scavenger N-acetylcysteine (NAC). For immunofluorescence, 4βHWE also accumulated more of the DSB marker, γH2AX foci, in oral cancer cells than in oral normal cells. For western blotting, DSB signaling proteins such as γH2AX and MRN complex (MRE11, RAD50, and NBS1) were overexpressed in 4βHWE-treated oral cancer cells in different concentrations and treatment time. In the formamidopyrimidine-DNA glycolyase (Fpg)-based comet assay and 8-oxodG-based flow cytometry, the 8-oxodG expressions were higher in 4βHWE-treated oral cancer cells than in oral normal cells. All the 4βHWE-induced DSB and oxidative DNA damage to oral cancer cells were recovered by NAC pretreatment. Taken together, the 4βHWE selectively induced DSB and oxidative DNA damage for the ROS-mediated selective killing of oral cancer cells.

The selective synthesis of various dideuterochalcones as potentially bioactive deuterium-labeled products is presented, by means of the highly controlled partial deuteration of antidiabetic chalcone derivatives. The benefits of continuous-flow processing in combination with on-demand electrolytic D2 gas generation has been exploited to avoid over-reaction to undesired side products and to achieve selective deuterium addition to the carbon-carbon double bond of the starting enones without the need for unconventional catalysts or expensive special reagents. The roles of pressure, temperature, and residence time proved crucial for the fine-tuning of the sensitive balance between the product selectivity and the reaction rate. The presented flow-chemistry-based deuteration technique lacks most of the drawbacks of the classical batch methods, and is convenient, time- and cost-efficient, and safe.

As a part of our continuing search for anti-HCV agents from a medicinal plant, Flueggea virosa, we identified fourteen new ingredients, including 13-methyl-3,4-seco-ent-podocarpanes (1–13) and a new naphthalene derivative (14). Their structures were determined by analysis of 2D NMR spectroscopic data, while their absolute configurations were determined by comparison of specific optical rotations with related analogues in the literature. The therapeutic potential against hepatitis C virus (HCV) infection was evaluated for the isolates. Compound 8 showed the most potent anti-HCV activity with a therapeutic index (TI = IC50/EC50) of 100.5.

Copper catalysed oxidative coupling reaction of formamides with β-keto esters and 2-carbonyl-substituted phenols successfully proceeded through direct C–H bond activation of formamides. The corresponding carbamates were formed with high stereoselectivity under mild reaction conditions. This protocol was successfully applied to the synthesis of three novel halogenated carbamates and a carbaryl insecticide derivative. Our results suggest the use of 6.0 equiv. TBHP is crucial for this type of reaction.

An efficient method for the synthesis of flavones and γ-benzopyranones has been developed utilizing a mild Sonogashira coupling and 18-crown-6 ether mediated 6-endo cyclization of o-alkynoylphenyl acetates. By using this strategy, flavones and γ-benzopyranones bearing electron-donating groups, halogens, and simple alkyl substituents were synthesized in satisfactory yields.

Chronic hepatitis C virus (HCV) infection ultimately leads to chronic hepatitis, hepatic cirrhosis and hepatocellular carcinoma (HCC). As the standard treatment is not completely efficacious, a safer and more effective agent against HCV infection needs to be developed. In this report, we demonstrated that 3-hydroxy caruilignan C (3-HCL-C) isolated from Swietenia macrophylla stems exhibited high anti-HCV activity at both protein and RNA levels at nontoxic concentrations, with an EC(50) value of 10.5 ± 1.2 μm. Combinations of 3-HCL-C and interferon-α (IFN-α), an HCV NS5B polymerase inhibitor (2'-C-methylcytidine; NM-107) or an HCV NS3/4A protease inhibitor (Telaprevir; VX-950) increased the suppression of HCV RNA replication. The results suggested that 3-HCL-C may be a potential anti-viral agent. We then demonstrated that 3-HCL-C interfered with HCV replication by inducing IFN-stimulated response element transcription and IFN-dependent anti-viral gene expression.

Photodynamic therapy was found to be an effective therapy for local malignant tumors. This study demonstrated that 80 μg/ml Hedyotis corymbosa extracts with 0.8 J/cm2 fluence dose caused M21 skin cancer cell death. Photoactivated H. corymbosa-induced M21 cell death is a typical apoptosis that is accompanied by nuclear condensation, externalization of phosphatidylserine and the changes in protein expression of apoptosis-related proteins, such as Bcl-2 and caspase family members. This study applied 2D electrophoresis to analyse the proteins involved in the photoactivated H. corymbosa-induced M21 cell apoptosis. We found 12 proteins to be markedly changed. According to the results of protein sequence analysis of these altered protein spots, we identified that the expression of cytoskeletal proteins and chaperones were involved in the photoactivated H. corymbosa-induced M21 cell apoptosis. We further demonstrated that photoactivated H. corymbosa caused a significant effect on the cytoskeleton distribution and mitochondrial activity in M21 cells. Based on the above findings, this study characterized the effects and mechanisms of the photoactivated H. corymbosa-induced apoptosis in M21 skin cancer cells.

BACKGROUND AND PURPOSE Activation of human platelets by thrombin is mediated predominately through two proteinase-activated receptors (PARs), PAR1 and PAR4. Phosphatidylinositol 3-kinase (PI3K) inhibition leads to reversible PAR1-mediated platelet aggregation, but has no effect on the stability of platelet aggregation induced by thrombin. In the present study, the molecular mechanisms underlying this difference were investigated. EXPERIMENTAL APPROACH The functions of PI3K and PAR4 were assessed using specific inhibitors and aggregometry. The duration of platelet glycoprotein (GP) IIb/IIIa exposure was determined by flow cytometry with the antibody PAC-1. Western blotting and fluo-3 was used to evaluate the activation of Akt and protein kinase C (PKC) and intracellular Ca2+ mobilization respectively. KEY RESULTS When PAR4 function was inhibited either by the PAR4 antagonist YD-3 [1-benzyl-3-(ethoxycarbonylphenyl)-indazole] or by receptor desensitization, the PI3K inhibitor wortmannin turned thrombin-elicited platelet aggregation from an irreversible event to a reversible event. Moreover, wortmannin plus YD-3 markedly accelerated the inactivation of GPIIb/IIIa in thrombin-stimulated platelets. The aggregation-reversing activity mainly resulted from inhibition of both PI3K-dependent PKC activation and PAR4-mediated sustained intracellular Ca2+ rises. Blockade of ADP P2Y12 receptor with 2-methylthioadenosine 5′-monophosphate triethylammonium salt mimicked the inhibitory effect of wortmannin on PI3K-dependent PKC activation and its ability to reverse PAR1-activating peptide-induced platelet aggregation. Co-administration of 2-methylthioadenosine 5′-monophosphate triethylammonium salt with YD-3 also decreased the stability of thrombin-induced platelet aggregation. CONCLUSIONS AND IMPLICATIONS These results suggest that PAR4 acts in parallel with the P2Y12/PI3K pathway to stabilize platelet aggregates, and provide new insights into the mechanisms of thrombus stabilization and potential applications for antithrombotic therapy.

Calotropin is one of cardenolides isolated from milkweed used for medicinal purposes in many Asian countries. Whereas calotropin possesses cytotoxicity against several cancer cells, the mechanisms of action remain unclear. We set out to evaluate the cytotoxic mechanism of calotropin on human chronic myeloid leukemia K562 cells. Calotropin inhibited the growth of K562 cells in a time- and dose-dependent manner by G(2)/M phase arrest. It upregulated the expression of p27 leading to this arrest by downregulating the G2/M regulatory proteins, cyclins A and B, and by upregulating the cdk inhibitor, p27. Furthermore, it downregulated anti-apoptotic signaling (XIAP and survivin) and survival pathways (p-Akt and NFkappaB), leading to caspase-3 activation which resulted in the induction of apoptosis. In all, calotropin exerted its anticancer activity on K562 cells by modulating the pro-survival signaling that leads to induction of apoptosis.

(4R,15R,16R,21S)-Rollicosin (2) was synthesized by palladium-catalyzed coupling of two building blocks 4 and 5. Lactone 4 was synthesized from 1-heptyne and terminal acetylene 5 was prepared from lactone 6 and allyl iodide or (S)-epichlorohydrin. (4S,15R,16R,21S)-Rollicosin (3) was also synthesized from (R)-epichlorohydrin by the same synthetic pathway.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

A thorough investigation of the ethyl acetate soluble fraction from a methanol extract of the resin of Ferula foetida has resulted in the isolation of a new sesquiterpene coumarin namely epi-conferdione (1), along with four known compounds, colladonin (2), karatavicinol (3), 8-acetoxy-5-hydroxyumbelliprenin (4), and asacoumarin (5). These structures were elucidated on the basis of extensive spectroscopic techniques, including 1D and 2D NMR spectroscopy. The absolute configuration of the new compound was established by circular dichroism (CD).

isolation and structure of two new compounds, 1β,7α-dihydroxyeudesman-4-one (I) and 5αH-megastigm-7-ene-3α,4α,6.beta,9-tetrol (II), along with nine known terpenoids

The cytotoxic activities of (I) and (II) are evaluated showing that (II) has medium antiproliferative activity.

A chemical investigation of Zoanthus kuroshio has yielded two new alkaloids, kuroshines A (1) and B (2). The compounds possess a densely functionalized ring system on the basis of the zoanthamine frames. The structures of 1 and 2 were elucidated through interpretation of spectroscopic methods, especially 2D NMR techniques (COSY, HMQC, HMBC, and ROESY). The absolute stereochemistry of 1 was further confirmed by an X-ray single crystallographic analysis using a mirror Cu-Kα radiation.

The metabolites, (24S)-3β-acetoxyergost-5-en-21-oic acid (2), 5′-O-acetylthymidine (3), 3′-O-acetylthymidine (4), and p-vinylbenzyl alcohol (5), along with a known steroid (1) were isolated from the EtOAc extract of the Formosan soft coral Caldiella australis. The structures of new metabolites were determined on the basis of spectroscopic (including 1D and 2D NMR) analyses and by comparison of their NMR spectral data with those of related compounds. Except for 3, all compounds exhibited cytotoxic activity of various degrees of potency against a limited panel of human liver and breast cancer cell lines.

A simple and reliable high-performance liquid chromatographic method with ultraviolet detection (280 nm) has been developed for the simultaneous analysis of 12 bioactive components in San-huang-xie-xin-tang (SHXXT), a traditional Chinese medicine containing Rhei rhizome, Coptidis rhizome and Scutellariae radix. A relatively simple extraction procedure was employed and optimised, and separation of the components was obtained within 1 h using a reversed-phase column under gradient elution with acetonitrile and a buffer containing 0.01 M sodium 1-pentanesulphonate (pH 3). The lower limit of detection for the analytes ranged from 25 to 75 ng/mL. The correlation coefficients associated with each calibration curve were greater than 0.99. The precision and accuracy of the method ranged from 1.0 to 10.5% at low concentration levels, 0.8 to 8.7% at medium levels and 1.2 to 5.8% at high levels. In commercial products of SHXXT, baicalin and berberine were present in the highest amounts with levels up to 4.0 and 3.3%, respectively, in one sample. The HPLC method was able rapidly and efficiently to analyse constituents in crude herb and traditional Chinese medicinal preparations containing Rhei rhizome, Coptidis rhizome and Scutellariae radix.

The three new diterpenes, polylongifoliaic A (I) and polylongifoliaons A (II), are isolated together with nine known diterpenes.

Two new polar lignans, i.e., squadinorlignoside (= 4-[(1E)-1-(hydroxymethyl)-3-(4-hydroxyphenyl)prop-1-en-1-yl]phenyl β-D-glucopyranoside; 1) and (6R,7R,8S)-7a-[(β-D-glucopyranosyl)oxy]-1-methoxyisolariciresinol (2) were isolated from the stems of Annona squamosa, together with eight known lignans and five known neolignans (compounds 3–15; Fig. 1). All of these constituents are reported for the first time from the genus Annona. The structures, absolute configurations, and selected conformational aspects of the new compounds were elucidated spectroscopically. Compound 1 is the first example of a 7,9′-dinorlignan natural product.

Oxidation of a series of phenols with cerium(IV) ammonium nitrate (CAN) in acetonitrile under mild conditions yields the mixture of corresponding nitrophenols. In the cases of methylphenols and hydroxy -carboxylic acids, the steric effect may reduce the nitration reaction. Compounds 3a and 4b showed selective activities to Hep 3B and Hep G2 cancer cell lines, respectively. Compound 2c showed selective activities to Hep G2 and MDA-MB-231 cancer cell lines. Furthermore, compound 10b showed selective activities to Hep G2, Hep 3B, MCF-7 and MDA-MB-231 cancer cell lines.

From the stems of Fissistigma bracteolatum, a novel natural product with an unprecedented skeleton, bractelactone (1), was isolated, together with four known compounds: piperolactam A (2), aristololactam BIII (3), aristololactam BII (4), and fissilandione (5). The structure of 1 was established on the basis of spectroscopic data as (3Z)-6,7-dihydroxy-4-methoxy-3-(phenylmethylidene)-5-(3-phenylpropanoyl)-1-benzofuran-2(3H)-one. This compound may be derived from a hybrid of a chalcone and a cinnamic acid, or from a degradation product of a dichalcone. Compounds 1, 2, and 5 showed inhibitory effects on NO generation by RAW264.7 macrophages in response to lipopolysaccharide. Compounds 2 and 5 showed inhibitory effects on formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-induced superoxide anion (O) generation in human neutrophils.

A convenient and useful esterification was realized, and this reaction proceeded without a dehydrating reagent or water removal equipment. A series of ortho-hydroxyphenyl carboxylic acids and benzoic acids were transformed to their corresponding methyl esters under CAN/CH 3 OH reaction conditions. Whereas in an aprotic solvent, acetonitrile, sp 3 -C tethered ortho-hydroxyphenyl carboxylic acids undergo simultaneous o,p-dinitration and intramolecular esterification reactions in good yields. Also, 2-((lE)-2-nitrovinyl)-4-nitrophenol (3e) showed selective cytotoxicities toward MCF-7, HEP G2, and HEP 3B cell lines with IC 5 0 values of 23.50, 7.33, and 7.59 ug/mL, respectively.

Our previous work demonstrated that liriodenine, an isoquinoline alkaloid isolated from plant species of many genera, exhibits a potent cytotoxic effect on various types of human cancer cells. In this study, we investigated the effect of liriodenine on the growth and viability of human lung cancer cells and addressed the underlying mechanism of action. We found that liriodenine suppressed proliferation of A549 human lung adenocarcinoma cells in a dose- and time-dependent manner. Flow cytometric analysis showed that liriodenine blocked cell cycle progression at the G2/M phase. Induction of G2/M arrest by liriodenine was accompanied by reduction of G1 cyclin (D1) and accumulation of G2 cyclin (B1). In vitro kinase activity assay demonstrated that the enzymatic activity of the cyclin B1/cyclin-dependent kinase 1 complex was reduced in liriodenine-treated cells. More importantly, incubation with liriodenine led to activation of caspases and apoptosis in A549 cells. The apoptosis-inducing activity of liriodenine was more apparent when cells were cultured under serum-free conditions. Our results indicate that liriodenine exerts potent anti-proliferative and apoptosis-inducing effects on human lung cancer cells.

Annosqualine (=(10′bR)-1′,5′,6′,10′b-tetrahydro-9′-hydroxy-7′,8′-dimethoxyspiro[cyclohexa-2,5-diene-1,2′-pyrrolo[2,1-a]isoquinoline]-3′,4-dione; 1), a novel alkaloid with an unprecedented skeleton, and a new amide, dihydrosinapoyltyramine (=3-(4-hydroxy-3,5-dimethoxyphenyl)-N-[2-(4-hydroxyphenyl)ethyl]propanamide; 2), were isolated from the stems of Annona squamosa L., together with six known alkaloids. The structures of all compounds were elucidated spectroscopically by means of optical rotation, 1H-, 13C-, and 2D-NMR, and by EI-MS, or by comparison with the spectral data of authentic samples. A possible biogenetical pathway towards annosqualine (1) is proposed.

). For example, the pro-ton at 6.11 carried by the carbon atom at 85.3 was corre-lated through three bonds to the quaternary aromatic carbonsat 128.9 and 146.2 carrying the methoxyl group, appearingitself at 61.1. Likewise, one of the AB-system protons, i.e.theoneat 6.96,wasalsocorrelatedtothecarbonatomsat128.9 and 146.2, whilst the isolated proton at 6.01 showedlong-range couplings with the carbon atoms at 119.3 bear-ing the second AB-system proton. The above correlationssustained by the observed NOE effects between the proton at 6.01 and those at 7.17 (1H, s) and 6.89 (1H, d

Four cyclic peptides, diandrine A–D (1–4), were isolated from the MeOH extract of Formosan Drymaria diandra. Their structures were elucidated by chemical and spectroscopic analyses as cyclo(-Gly1-Pro2-Trp3-Pro4-Tyr5-Phe6-), cyclo(-Gly1-Pro2-Leu3-Pro4-Leu5-Trp6-Ser7-Ser8-), cyclo(Gly1-Gly2-Pro3-Tyr4-Trp5-Pro6-), and cyclo(Gly1-Gly2-Pro3-Tyr4-Trp5-Pro6-), respectively. Compounds 3 and 4 were stable conformational isomers. Cyclopeptide 1 showed a selective inhibitory effect on collagen-induced platelet aggregation with an IC50 value of 44.2 μM.

A new flavanone, euchrenone a 1 7 (1), along with eighteen known compounds, glabrol (2), euchrenone a 2 (3), formononetin (4), 7-methoxy-2',4'-dihydroxyisoflavone (5), 3-(3,4-dimethoxy-phenyl)-7,8-dihydroxy-chromon-4-one (6), 5,7,2'-trihydroxy-4'-methoxyisoflavone (7), 2'-hydroxygenistein (8), euchrenone b 1 (9), euchrenone b2 (10), euchrenone b 1 6 (11), vanillin (12), p-hydroxybenzoic acid (13), medicagol (14), octadecyl ferulate (15), (+)-syringaresinol (16), β-sitosteryl-D-glucoside (17), and a mixture of β-sitosterol (18) and stigmasterol (19), were isolated from the methanolic extracts of the roots of Euchresta formosana. The structures of these compounds were established by means of spectral analysis.

A diverse library of novel carbamates was synthesized utilizing copper-catalyzed oxidative C–O coupling of formamides and salicylaldehydes. Sensitive aldehyde groups remained intact in the presence of an oxidant and a transition-metal salt. Salicylaldehydes bearing electron-donating, electron-withdrawing, and halogen groups as well as 1-hydroxy-2-naphthaldehydes provided the desired carbamates in good to excellent yields.

A simple iron carbonyl catalyzed method for the α-selective aryloxylation of cyclic ethers is developed using a variety of salicylic aldehydes as phenol derivative and tBuOOH as the oxidant.

A four-component Ugi reaction (Ugi-4CR) utilizing formylphenyl boronic acids under mild condition was developed for the synthesis of arylboronic acid analogs. The reactions were performed in methanol and accelerated by microwave irradiation, which makes this strategy suitable for constructing boronic-containing chemical libraries. Two of the synthesized analogs were found to have cytotoxic activity against HepG2, MDA-MB231, and A549 cancer cell lines, demonstrating the potential application of this approach in developing novel boron-containing pharmaceuticals.

1,5-Diphenylpent-3-en-1-yne derivatives were isolated in minor quantities from terrestrial plants and exhibited strong anti-inflammatory activity. A cross coupling reaction between B -benzyl-9-BBN and chloroenynes under mild condition was developed resulting in the formation of different 1,5-diphenylpent-3-en-1-yne derivatives with a full control on the E / Z selectivity. Several substrates bearing electron-donating and electron-withdrawing substituents were tolerable under the reaction conditions affording the corresponding products in good yields. This is the first study to report the synthesis of a vast array of novel 1,5-diphenylpent-3-en-1-yne derivatives paving the way for the preparation of tailored derivatives on mass scale necessary for biological studies and drug development.

A new C-α hydroxy benzylisoquinoline, annocherine C (1), along with nine teen compounds including six alkaloids, liriodenine (2), oxoxylopine (3), oxonantenine (4), (-)-asimilobine (5), (-)-xylopine (6) and (-)-anolobine (7); four steroids, β-sitosterol, stigmasterol, β-sitosteryl-D-glucoside and stigmasteryl-D-glucoside and nine benzenoids, methylparabene, vanillin, trans-methyl p-coumarate, cis -methyl p-coumarate, p-hydroxybenzadehyde, p-hydroxybenzoic acid, 4-methoxybenzoic acid methylester, methyl vanillate and p-dihydrocoumaric acid, were isolated from the leaves of Annona cherimola. These compounds were identified by spectral analysis.

A new amide, N-cis-sinapoyltyramine (1), and twelve known compounds were isolated from the aerial parts of Lindera glauca. The structure of the new compound has been established by the study of extensive 2D NMR data.

In a recent in vivo study, liriodenine, an aporphine alkaloid, has been identified as a prominent anti-arrhythmic agent that can prevent rats' sudden deaths, even at the dose as low as 10−7 g kg−1. The aim of this study was to determine whether liriodenine at its effective anti-arrhythmic dose of 10−7 g kg−1 had effects on the left ventricular (LV)-arterial coupling in Wistar rats. LV pressure and ascending aortic flow signals were recorded to construct the ventricular and arterial end-systolic pressure-stroke volume relationships to calculate LV end-systolic elastance (Ees) and effective arterial volume elastance (Ea), respectively. The optimal afterload (Qload) determined by the ratio of Ea to Ees was used to measure the optimality of energy transmission from the left ventricle to the arterial system. Liriodenine at the dose of 10−7 g kg−1 showed no significant changes in basal heart rate (HR), cardiac output (CO), LV end-systolic pressure (Pes), Ea, Ees, and Qload. By contrast, liriodenine at the dose of 10−6 g kg−1 produced a significant fall of 2.0% in HR and a significant rise of 5.8% in CO, but no significant change in Pes. Moreover, liriodenine administration of 10−6 g kg−1 to rats significantly decreased Ees by 8.5% and Ea by 10.6%, but did not change Qload. We conclude that liriodenine at the dose of 10−7 g kg−1 has no effects on the mechanical properties of the heart and the vasculature and the matching condition for the left ventricle coupled to its vasculature in rats. Even at 10 times the effective anti-arrhythmic dose, liriodenine shows no effects on the efficiency of energy transferred from the left ventricle to the arterial system. British Journal of Pharmacology (2001) 133, 29–36; doi:10.1038/sj.bjp.0704036

Two new alkaloids, glaucenamide (1) and fissiceine (2), along with fifteen known ones, liriodenine (3), oxocrebanine (4), kuafumine (5), oxoxylopine (6), atherospermidine (7), (-)-xylopine (8), (-)-N-acetylxylopine (9), N-trans-feruloyltyramine (10), aristololactam BII (11), aristololactam BIII (12), aristololactam AII (13), piperolactam A (14), goniothalactam (15), norcepharadion B (16), and noraristolodione (17) were isolated from the methanolic extracts of the Fissistigma glaucescens. The structures of these compounds were established by means of spectral analysis.