Excavating precursors from the traditional Chinese herb Polygala tenuifolia and Gastrodia elata: Synthesis, anticonvulsant activity evaluation of 3,4,5-trimethoxycinnamic acid (TMCA) ester derivatives.

Epilepsy is a group of neurological disorders characterized by recurrent seizures that disturbs about 60 million people worldwide. In this article, a novel series of 3,4,5-trimethoxycinnamic acid (TMCA) ester derivatives 1-35 were designed inspired from the traditional Chinese herb pair drugs Polygala tenuifolia and Gastrodia elata and synthesized followed by in vivo and in silico evaluation of their anticonvulsant potential. All the synthesized derivatives were biologically evaluated for their anticonvulsant potential using two acute model of seizures induced in mice, the maximal electroshock (MES) and sc-pentylenetetrazole (PTZ) models. Simultaneously, the motor impairment as a surrogate of acute neurotoxicity and in vitro screening of cytotoxicity against HepG-2 cells line were assessed through the rotarod performance test and CCK-8 assay, respectively. In addition, the physicochemical and pharmacokinetic parameters of the active compounds were determined. Our results showed that compounds 5, 7, 8, 13, 20, 25, 28, 30 and 32 exhibited preferable anticonvulsant activity in primary evaluation, with compounds 28 and 32 being the most promising anticonvulsant agents in according to results of subsequent pharmacology and toxicity evaluation. Additionally, the molecular modeling experiments predicted good binding interactions of part of the obtained active molecules with the gamma-aminobutyric acid (GABA) transferas. Therefore, it could be concluded that the synthesized derivatives 28 and 32 would represent useful lead compounds for further investigation in the development of anticonvulsant agents.

Synthesis and biological evaluation of picroside derivatives as hepatoprotective agents.

Picrorhizae Rhizoma as a hepatoprotective herb, has been applied for thousands of years, and picroside was proved to be its active constituent. In this study, twelve derivatives of picroside were synthesized and the hepatoprotective activity of the derivatives was evaluated on SMMC-7721 cells. Six out of the derivatives had shown a better protective effect on H2O2-induced SMMC-7221 cells than picroside, and the activity of two derivatives (2 and 4) was stronger than that of the reference compound, silybin. Compound 2 shown the strongest protective effect (EC50 = 6.064 ± 1.295 µM).

Styryl-cinnamate hybrid inhibits glioma by alleviating translation, bioenergetics and other key cellular responses leading to apoptosis.

Gliomas are lethal and aggressive form of brain tumors with resistance to conventional radiation and cytotoxic chemotherapies; inviting continuous efforts for drug discovery and drug delivery. Interestingly, small molecule hybrids are one such pharmacophore that continues to capture interest owing to their pluripotent medicinal effects. Accordingly, we earlier reported synthesis of potent Styryl-cinnamate hybrids (analogues of Salvianolic acid F) along with its plausible mode of action (MOA). We explored iTRAQ-LC/MS-MS technique to deduce differentially expressed landscape of native & phospho-proteins in treated glioma cells. Based on this, Protein-Protein Interactome (PPI) was looked into by employing computational tools and further validated in vitro. We hereby report that the Styryl-cinnamate hybrid, an analogue of natural Salvianolic acid F, alters key regulatory proteins involved in translation, cytoskeleton development, bioenergetics, DNA repair, angiogenesis and ubiquitination. Cell cycle analysis dictates arrest at G0/G1 stage along with reduced levels of cyclin D; involved in G1 progression. We discovered that Styryl-cinnamate hybrid targets glioma by intrinsically triggering metabolite-mediated stress. Various oncological circuits alleviated by the potential drug candidate strongly supports the role of such pharmacophores as anticancer drugs. Although, further analysis of SC hybrid in treating xenografts or solid tumors is yet to be explored but their candidature has gained huge impetus through this study. This study equips us better in understanding the shift in proteomic landscape after treating glioma cells with SC hybrid. It also allows us to elicit molecular targets of this potential drug before progressing to preclinical studies.

Synthesis, in silico and in vivo blood brain barrier permeability of ginkgolide B cinnamate.

Ginkgolide B, one of the important components of Ginkgo biloba extracts, has been revealed to exhibit great potential in therapy of cerebrovascular diseases. However the lack of permeability greatly limited it from further clinical application. Based on the prediction model for blood brain barrier (BBB) permeation, herein a potential brain-targeting analog ginkgolide B cinnamate (GBC) was successfully synthesized and characterized. After intravenous administration of GBC or GB, liquid chromatography tandem mass spectrometry (LC-MS/MS) was conducted to determine the analog in rat plasma and brain. The results showed that GBC had a significant increase in BBB permeability. A significant 1.61-times increase in half-life was observed for GBC and the drug targeting index (DTI) value was calculated to be 9.91. The experiment results matched well with the predicted one, which revealed that BBB permeability prediction model combined with in vivo study could be used as a quick, feasible and efficient tool for brain-targeting drug design.

SC-III3, a novel scopoletin derivative, induces autophagy of human hepatoma HepG2 cells through AMPK/mTOR signaling pathway by acting on mitochondria.

(E)-3-(4-chlorophenyl)-N-(7-hydroxy-6-methoxy-2-oxo-2H-chromen-3-yl) acrylamide (SC-III3), a newly synthesized derivative of scopoletin, was previously shown to reduce the viability of HepG2 cells and tumor growth of HepG2 xenograft mouse model. It induces the death of HepG2 cells by a way irrelevant to apoptosis and necrosis. To shed light on the cytotoxic mechanisms of SC-III3, the present study addresses whether and how it can induce autophagic cell death. When HepG2 cells were incubated with various concentrations of SC-III3, autophagic vacuoles could be observed by transmission electron microscopy and monodansylcadaverine staining. Increased expressions of LC3-II to LC3-I and Beclin-1, required for autophagosome formation, were accompanied. These characteristics integrally indicated that SC-III3 could initiate autophagy in HepG2 cells. N-acetyl-l-cysteine (NAC), a ROS scavenger, could reverse SC-III3-caused ROS accumulation, but it did not affect SC-III3-induced autophagy, suggesting that ROS was not involved in SC-III3-mediated autophagy in HepG2 cells. SC-III3 significantly depressed mitochondrial function, as evidenced by disruption of mitochondrial transmembrane potential and loss of the mitochondrial cristae structure, as well as decrease of Cox-I, Cox-III, Cox-IV, and ATP levels. The autophagy and activation of AMPK-TSC2-mTOR-p70s6k pathways induced by SC-III3 in HepG2 cells could be efficiently blocked by pre-treatments of compound C (an inhibitor of AMPK). Moreover, addition of extracellular ATP to the cell culture media could reverse SC-III3-caused activation of AMPK-TSC2-mTOR-p70s6k pathway, autophagy and cell viability decrease in HepG2 cells. Collectively, SC-III3 leads to autophagy through inducing mitochondrial dysfunction, depleting ATP, and activating AMPK-mTOR pathway, which thus reflects the cytotoxic effect of SC-III3 in HepG2 cells.

Sulfation mediates activity of zosteric acid against biofilm formation.

Zosteric acid (ZA), a metabolite from the marine sea grass Zostera marina, has attracted much attention due to its attributed antifouling (AF) activity. However, recent results on dynamic transformations of aromatic sulfates in marine phototrophic organisms suggest potential enzymatic desulfation of metabolites like ZA. The activity of ZA was thus re-investigated using biofilm assays and simultaneous analytical monitoring by liquid chromatography/mass spectrometry (LC/MS). Comparison of ZA and its non-sulfated form para-coumaric acid (CA) revealed that the active substance was in all cases the non-sulfated CA while ZA was virtually inactive. CA exhibited a strong biofilm inhibiting activity against Escherichia coli and Vibrio natriegens. The LC/MS data revealed that the apparent biofilm inhibiting effects of ZA on V. natriegens can be entirely attributed to CA released from ZA by sulfatase activity. In the light of various potential applications, the (a)biotic transformation of ZA to CA has thus to be considered in future AF formulations.

Synthesis of substituted 1,3-diesters of glycerol using wittig chemistry.

1,3-di-O-Cinnamoyl-glycerol is a natural compound isolated from a Jamaican medicinal plant commonly referred to as Ball moss (Tillandsia recurvata). The synthesis of this compound was achieved via a Wittig chemistry process. The synthetic approach started with acylation of a di-protected glycerol with cinnamoyl chloride, deprotection of the glycerol moiety, reaction of the primary alcohol with bromo acetylbromide followed by treatment with triphenyl phosphine to give the corresponding phosphonium bromide. The phosphonium bromide was then converted in situ to the Wittig reagent which is the basis for a novel route to 1,3-di-O-cinnamoyl glycerol. Four analogs were also synthesized, three of which are new and are being reported in this article for the first time. The new compounds include 3-(3,4-diemthoxy-phenyl)-acrylic acid 2-hydroxy-3-(3-ptolyl-acryloyloxy)-propyl ester (3), 2-acetoxy-5-((E)-3-(3-((E)-3-(3,4-dimethoxyphenyl)acryloyloxy)-2-hydropropoxy)-3-oxoprop- 1-enyl)benzoic acid (4) and 4-((E)-3-(3-((E)-3-(3,4-dimethoxyphenyl)acryloyloxy)-2-hydropropoxy)-3-oxoprop-1-enyl)benzoic acid (5). The compounds showed no activity in our anticancer assay.

The effect of caffeic acid phenethyl ester analogues in a modified resistant hepatocyte model.

We present a study of the chemoprotective effects of two caffeic acid phenethyl ester (CAPE)-related structures: LQM717 and LQM706. The modified resistant hepatocyte model in rats was used to study the chemoprevention of these CAPE analogues, which are inexpensive and easily obtained. In the liver cancer model used, we detected extensive necrosis and lipid peroxidation after 24 h, many altered hepatic foci, putatively preneoplastic lesions with γ-glutamyl transpeptidase staining after 30 days, and liver tumors at 12 months. We tested the effect of the CAPE analogues on necrosis, lipid peroxidation, proliferation, p65 activation, altered hepatic foci, and tumors. Both compounds exerted protective effects on lipid peroxidation, necrosis, cell proliferation, p65 activation, and preneoplastic lesions. Rats under a carcinogenic protocol showed a 52, 71.74, and 51.6% decrease in the number of preneoplastic nodules when pretreated with CAPE, LQM706, and LQM717, respectively. At 12 months after carcinogenic treatment, eight of eight rats developed liver cancer, whereas in the group of rats that received pretreatment with CAPE, LQM706, or LQM717, 62.5, 83.3, or 42.85%, respectively, had tumors. In conclusion, LQM717 has the potential to enhance chemoprotection activity much better than CAPE by markedly reducing the formation of liver cancers in this model, and this is a compound that is easy to obtain.

Isolation and synthesis of melodamide A, a new anti-inflammatory phenolic amide from the leaves of Melodorum fruticosum.

Together with twelve known compounds (2-13), melodamide A (1), a new phenolic amide possessing p-quinol moiety, was purified and characterized from the methanolic extracts of the leaves of Melodorum fruticosum. The structure of melodamide A (1) was established with a combination of 2D NMR experiments, HR-ESI-MS and X-ray analyses. The other known compounds were identified by comparison of their spectroscopic and physical data with those reported in the literature. Moreover, some isolated compounds were examined for their inhibitory activity towards superoxide anion generation and elastase release in human neutrophils. Among the tested compounds, 1, 3, and 5 exhibited strong inhibition of superoxide anion generation with IC50 values ranging from 5.25 to 8.65 µM. Furthermore, synthesis and biological evaluation of melodamide A (1) and its analogs (14a-p) were described.

Synthesis and evaluation of a series of 3,4,5-trimethoxycinnamic acid derivatives as potential antinarcotic agents.

A series of 3,4,5-trimethoxycinnamic acid derivatives was prepared and evaluated for antinarcotic effects on morphine dependence in mice and binding affinities on serotonergic receptors. The key synthetic strategies involve generation of ketones 6-7, esters 9-12 through condensation reaction, and amides 13-19 via coupling reaction using 1-hydroxybenzotriazole/ethyl(dimethylaminopropryl)carbodiimide system in high yield. We found that the naloxone-induced morphine withdrawal syndrome was significantly suppressed by new synthetic 3,4,5-trimethoxycinnamic acid derivatives (20 mg/kg/day). Most of 3,4,5-trimethoxycinnamic acid derivatives were found to have high affinity to 5-HT(1A) receptor. The naloxone-induced morphine withdrawal syndrome was attenuated by (+)8-OH-DPAT (0.1 mg/kg/day, i.p.), a 5-HT(1A) receptor agonist. In cortical neuronal cells, (+)8-OH-DPAT (1 µM) produced an elevation of the pERK 1/2 expression, and the elevated pERK levels were inhibited by WAY 100635, a 5-HT(1A) receptor-specific antagonist. Interestingly, the pERK levels were increased by the 3,4,5-trimethoxycinnamic acid derivatives and the derivatives-mediated changes in pERK levels were blocked by the WAY 100635. These results suggested that new synthetic 3,4,5-trimethoxycinnamic acid derivatives have a potential antinarcotic effect through acting as a 5-HT(1A) receptor agonist in mice.

Structure-anti-leukemic activity relationship study of ortho-dihydroxycoumarins in U-937 cells: key role of the δ-lactone ring in determining differentiation-inducing potency and selective pro-apoptotic action.

Previous studies indicated the need of at least one phenolic hydroxyl group in the coumarin core for induction of cytotoxicity in different cell lines. Herein, we present an exhaustive structure-activity relationship study including ortho-dihydroxycoumarins (o-DHC) derivatives, cinnamic acid derivatives (as open-chain coumarin analogues) and 1,2-pyrones (representative of the δ-lactone ring of the coumarin core), carried out to further identify the structural features of o-DHC required to induce leukemic cell differentiation and apoptosis in U-937 cells. Our results show for the first time that the δ-lactone ring positively influences the aforementioned biological effects, by conferring greater potency to compounds with an intact coumarin nucleus. Most tellingly, we reveal herein the crucial role of this molecular portion in determining the selective toxicity that o-DHC show for leukemic cells over normal blood cells. From a pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents.

[Antimicrobial activity of some cinnamic acid derivatives]. / Evaluarea actiunii antimicrobiene a unor derivati de acid cinamic.

Due to drug-resistance phenomenon, there is a constant need for discovering new antiinfectious agents. A series of cinnamic acid derivatives was synthesized and then brominated with bromine in the presence of chloroform or acetic acid. The structure of the new compounds was confirmed by elemental and spectral data. Their antimicrobial activity was tested by disc-diffusion method. The tested compounds had mainly antifungal activity and were moderately active against Gram-positive bacteria. Bromination of the double bond determined the enhancement of the antimicrobial activity for all the tested compounds.

Synthesis and preliminary biological evaluation of novel N-(3-aryl-1,2,4-triazol-5-yl) cinnamamide derivatives as potential antimycobacterial agents: an operational Topliss Tree approach.

A series of novel N-(3-aryl-1,2,4-triazol-5-yl) cinnamamide derivatives were designed on basis of structural similarity to the known FAS II inhibitors. Topliss operational method was used to optimize the potency of molecules. The minimum inhibitory concentration (MIC) of all synthesized compounds was determined against Mycobacterium tuberculosis H(37)R(v) using resazurin microtitre assay (REMA) plate method. The synthesized compounds exhibit antimycobacterial activity in the range of 5-95µM with a good safety profile.

[Preparation and anti-oxidant activity of cinnamic acid derivatives-g-CTS].

OBJECTIVE: To prepare cinnamic acid derivatives-g-CTS and to study its antioxidation activity. METHOD: The ability of catching oxygen of the products and raw material were determined through two methods, Marklund method and trace pyrogallic acid method, with autoxidation reaction of pyrogallol as the oxygen anion source. RESULT: The antioxidation activities of all products were better than the raw material. CONCLUSION: Cinnamic acid derivatives-g-CTS is suitable as the O2-* -capture agent.

Phenylethyl cinnamides: a new series of alpha-glucosidase inhibitors from the leaves of Aegle marmelos.

A series of phenylethyl cinnamides, which included new compounds named anhydromarmeline, aegelinosides A and B, were isolated from Aegle marmelos leaves as alpha-glucosidase inhibitors. The structures of new compounds were characterized by spectroscopic data and chemical degradation. Of compounds isolated, anhydroaegeline revealed the most potent inhibitory effect against alpha-glucosidase with IC(50) value of 35.8 microM. The present result also supports ethnopharmacological use of A. marmelos as a remedy for diabetes mellitus.

N-caffeoylphenalkylamide derivatives as bacterial efflux pump inhibitors.

As part of an ongoing project to identify plant natural products as efflux pump inhibitors (EPIs), bioassay-guided fractionation of the methanolic extract of Mirabilis jalapa Linn. (Nyctaginaceae) led to the isolation of an active polyphenolic amide: N-trans-feruloyl 4'-O-methyldopamine. This compound showed moderate activity as an EPI against multidrug-resistant (MDR) Staphylococcus aureus overexpressing the multidrug efflux transporter NorA, causing an 8-fold reduction of norfloxacin MIC at 292 microM (100 microg/mL). This prompted us to synthesize derivatives in order to provide structure-activity relationships and to access more potent inhibitors. Among the synthetic compounds, some were more active than the natural compound and N-trans-3,4-O-dimethylcaffeoyl tryptamine showed potentiation of norfloxacin in MDR S. aureus comparable to that of the standard reserpine.

Prenyloxyphenylpropanoids as novel lead compounds for the selective inhibition of geranylgeranyl transferase I.

In this study, we synthesized some natural and semisynthetic prenyloxyphenylpropanoids (e.g., coumarins and cinnamic acid derivatives) and we assessed their in vitro inhibitory activity against farnesyl transferase (FTase) and geranylgeranyl transferase I (GGTase I). No compound was an effective inhibitor of FTase, while farnesyloxycinnamic acids were shown to selectively inhibit GGTase I with IC(50) values ranging from 28 to 39 microM.

Biosynthesis of podophyllotoxin in Linum album cell cultures.

Cell cultures of Linum album Kotschy ex Boiss. (Linaceae) showing high accumulation of the lignan podophyllotoxin (PTOX) were established. Enzymological studies revealed highest activities of phenylalanine ammonia-lyase, cinnamyl alcohol dehydrogenase, 4-hydroxycinnamate:CoA ligase and cinnamoyl-CoA:NADP oxidoreductase immediately prior to PTOX accumulation. To investigate PTOX biosynthesis, feeding experiments were performed with [2-(13)C]3',4'-dimethoxycinnamic acid, [2-(13)C]3',4'-methylenedioxycinnamic acid (MDCA), [2-(13)C]3',4',5'-trimethoxycinnamic acid, [2-(13)C]sinapic acid, [2-(13)C]- and [2,3-(13)C(2)]ferulic acid. Analysis of the metabolites by HPLC coupled to tandem mass spectrometry revealed incorporation of label from ferulic acid into PTOX and deoxypodophyllotoxin (DOP). In addition, MDCA was also unambiguously incorporated intact into PTOX. These observations suggest that in L. album both ferulic acid and methylenedioxy-substituted cinnamic acid can be incorporated into lignans. Furthermore, it appears that, in this species, the hydroxylation of DOP is a rate-limiting point in the pathway leading to PTOX. Electronic supplementary material to this paper can be obtained by using the Springer LINK server located at http://dx.doi.org/wo.1007/s00425-002-0834-1.

Carboxy-substituted cinnamides: a novel series of potent, orally active LTB4 receptor antagonists.

A series of carboxy-substituted cinnamides were investigated as antagonists of the human cell surface leukotriene B4 (LTB4) receptor. Binding was determined through measurement of [3H]LTB4 displacement from human neutrophils. Receptor antagonism was confirmed through a functional assay, which measures inhibition of Ca2+ release in human neutrophils. Potent antagonists were discovered through optimization of a random screening hit, a p-(alpha-methylbenzyloxy)cinnamide, having low-micromolar activity. Substantial improvement of in vitro potency was realized by the attachment of a carboxylic acid moiety to the cinnamide phenyl ring through a flexible tether, leading to identification of compounds with low-nanomolar potency. Modification of the benzyloxy substituent, either through ortho-substitution on the benzyloxy phenyl group or through replacement of the ether oxygen with a methylene or sulfur atom, produced achiral antagonists of equal or greater potency. The most potent compounds in vitro were assayed for oral activity using the arachidonic acid-induced mouse ear edema model of inflammation. Several compounds in this series were found to significantly inhibit edema formation and myeloperoxidase activity in this model up to 17 h after oral administration. Representatives of this series have been shown to be potent and long-acting orally active inhibitors of the LTB4 receptor.

Synthesis and antifungal activity of cinnamic acid esters.

Cinnamic, p-coumaric and ferulic acids were isolated from pineapple stems (Ananas comosus var. Cayenne). Twenty-four kinds of esters were prepared from these acids, alcohols and the components of Alpinia. Isopropyl 4-hydroxycinnamate (11) and butyl 4-hydroxycinnamate (12) were found to have almost the same effectiveness in antifungal activity against Pythium sp. at 10 ppm as that of the commercial fungicide iprobenfos (kitazin P).