Dibenzoate esters of cis-tetralin-2,3-diol as analogs of (-)-epigallocatechin gallate: synthesis and crystal structure of anticancer drug candidates.

(-)-Epigallocatechin gallate (EGCG), the main component of green tea extract, displays multiple biological activities. However, it cannot be used as a drug due to its low cellular absorption, instability and metabolic degradation. Therefore, there is a need to provide analogs that can overcome the limitations of EGCG. In this work, six synthetic analogs of EGCG sharing a common tetralindiol dibenzoate core were synthesized and fully characterized by 1H NMR, 13C NMR, HRMS and IR spectroscopies, and X-ray crystallography. These are (2R,3S)-1,2,3,4-tetrahydronaphthalene-2,3-diyl bis[3,4,5-tris(benzyloxy)benzoate], C66H56O10, and the analogous esters bis(3,4,5-trimethoxybenzoate), C30H32O10, bis(3,4,5-trifluorobenzoate), C24H14F6O4, bis[4-(benzyloxy)benzoate], C38H32O6, bis(4-methoxybenzoate), C26H24O6, and bis(2,4,6-trifluorobenzoate), C24H14F6O4. Structural analysis revealed that the molecular shapes of these dibenzoate esters of tetralindiol are significantly different from that of previously reported dimandelate esters or monobenzoate esters, as the acid moieties extend far from the bicyclic system without folding back over the tetralin fragment. Compounds with small fluorine substituents take a V-shape, whereas larger methoxy and benzyloxy groups determine the formation of an L-shape or a cavity. Intermolecular interactions are dominated by π-π stacking and C-H...π interactions involving the arene rings in the benzoate fragment and the arene ring in the tetrahydronaphthalene moiety. All six crystal structures are determined in centrosymmetric space groups (either P-1, P21/n, C2/c or I2/a).

Potential anti-neuroblastoma agents from Juniperus oblonga.

Neuroblastoma (NB) is a neuroendocrine tumor derived from neural crest cells. Approximately 90% of cases occur in children less than 5 years old. The amplification of MYCN correlates with high-risk neuroblastoma and patients with MYCN amplified showed poorer prognosis than those without MYCN amplification. In this study, three compounds isolated from Juniperus oblonga showed anti-proliferative activity against NB cell lines with and without tetracycline inducible MYCN over-expression which were identified as (-)-deoxypodophyllotoxin (1), (-)-matairesinol (2) and (+)-isocupressic acid (3). The effects of compounds 2 and 3 in NB cells included a decrease in NB cell viability and induction of apoptosis. Compound 1 was more effective in NB cells over-expressing MycN. Compound 1 also showed almost 2-fold induction of intracellular free calcium levels in M2(+) cells, which may indicate a different mechanism of action for this compound. Cytotoxicity studies against the human embryonic kidney cell (HEK-293) showed compounds 1, 2 and 3 were ineffective in the non-cancer cells at concentrations approximating their IC50 against the NB cell lines. These results may lead to safer and more effective treatment options for NB patients especially for those with high-risk NB.

New Bis-Alkenoic Acid Derivatives from a Marine-Derived Fungus Fusarium solani H915.

Fusarium solani H915 is a fungus derived from mangrove sediments. From its ethyl acetate extract, a new alkenoic acid, fusaridioic acid A (1), three new bis-alkenoic acid esters, namely, fusariumester A1 (2), A2 (3) and B (4), together with three known compounds (5⁻7), were isolated. The structures of the new compounds were comprehensively characterized by high resolution electrospray ionization-mass spectrometry (HR-ESI-MS), 1D and 2D nuclear magnetic resonance (NMR). Additionally, the antifungal activities against tea pathogenic fungi Pestalotiopsis theae and Colletotrichum gloeosporioides were studied. The new compound, 4, containing a ß-lactone ring, exhibited moderate inhibitory activity against P. theae, with an MIC of 50 µg/disc. Hymeglusin (6), a typical ß-lactone antibiotic and a terpenoid alkaloid, equisetin (7), exhibited potent inhibitory activities against both fungal species. The isolated compounds were evaluated for their effects on zebrafish embryo development. Equisetin clearly imparted toxic effect on zebrafish even at low concentrations. However, none of the alkenoic acid derivatives exhibited significant toxicity to zebrafish eggs, embryos, or larvae. Thus, the ß-lactone containing alkenoic acid derivatives from F. solani H915 are low in toxicity and are potent antifungal agents against tea pathogenic fungi.

Tetrazolone as an acid bioisostere: application to marketed drugs containing a carboxylic acid.

Matched molecular pair analysis was used to evaluate the ability of a tetrazolone group to act as a bioisostere of a carboxylic acid. Compound 7, a tetrazolone of the anti-hypertensive drug, telmisartan 6, was shown to be a potent AT1 antagonist (Kb = 0.14 nM), with activity comparable to telmisartan itself (Kb = 0.44 nM). Additionally, compound 9, a tetrazolone congener of the marketed anti-cancer agent, bexarotene 8, was shown to be an agonist at the retinoid X receptor alpha (EC50 = 64 nM). Compounds containing a tetrazolone group showed similar microsomal stability and plasma protein binding to marketed acid counterparts, while also reducing the value for clog P. Furthermore, compound 7 displayed an improved rat pharmacokinetic profile cf. telmisartan 6. Taken together, the results demonstrate that a tetrazolone group may serve as a bioisostere for a carboxylic acid.

RIFM fragrance ingredient safety assessment, 1-(1,2,3,4-tetrahydro-4,4-dimethyl-1-naphthyl)propan-1-one, CAS Registry Number 74499-60-8.

The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data from the target material and the suitable read across analog 6-acetyl-1,1,2,4,4,7-hexamethyltetraline (CAS # 21145-77-7) show that this material is not genotoxic. Data from the suitable read across analog 6-acetyl-1,1,2,4,4,7-hexamethyltetraline (CAS # 21145-77-7) provided a MOE > 100 for the repeat dose and developmental toxicity endpoints. The reproductive and local respiratory toxicity endpoints were completed using the TTC (Threshold of Toxicological Concern) for a Cramer Class II material (0.009 mg/kg/day and 0.47 mg/day, respectively). Data on the target material showed that this material is below the non-reactive DST for skin sensitization and did not have the potential for phototoxicity or photoallergenicity. The environmental endpoint was completed as described in the RIFM Framework.

Simultaneous determination of andrographolide, dehydroandrographolide and neoandrographolide in dog plasma by LC-MS/MS and its application to a dog pharmacokinetic study of Andrographis paniculata tablet.

In this study, a sensitive and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to simultaneously determinate andrographolide (AP), dehydroandrographolide (DP), and neoandrographolide (NP) in plasma of beagle dogs after oral administration of Andrographis paniculata tablet (A. paniculata). The analytes and bilobalide (internal standard) were separated on an Agilent ZORBAX XDB-C18 column (50mm×2.1mm, 3.5µm) by using gradient elution consisting of methanol and water at a flow rate of 0.50mL/min in 7min. Multiple reaction monitoring (MRM) mode was performed to quantify data under monitoring precursor-product ion transitions of m/z 348.8→286.9, 330.9→107.9, 479.1→160.8 and 325.0→163.0 for AP, DP, NP and internal standard (IS) at negative ion mode, respectively. This method was developed at linearity ranging from 0.50 to 250ng/mL for AP, 1.00 to 500ng/mL for DP and 0.20 to 100ng/mL for NP. The accuracy of each analyte ranged between 94.8% and 107.1% and the precision was within 14.6%. No significant matrix effect was observed. AP, DP and NP were stable during sample storage, preparation and analytic procedures. Furthermore, this method was successfully applied in the investigation of the pharmacokinetic profile of AP, DP and NP in beagle dogs after oral administration of A. paniculata tablet (49.5mg for AP, 7.0mg for DP, 22.0mg for NP). Biological half-life (t1/2) was 2.08±0.99, 3.13±1.19 and 1.07±0.38h for AP, DP and NP, respectively. The areas under curves (AUC0-t) of AP, DP and NP was 494.50±150.64, 26.01±8.72 and 78.78±18.29ngh/mL, respectively.

Novel PEG-grafted nanostructured lipid carrier for systematic delivery of a poorly soluble anti-leukemia agent Tamibarotene: characterization and evaluation.

Tamibarotene (Am80), a poorly water-soluble drug for the treatment of acute promyelocytic leukemia (APL), loaded nanostructured lipid carrier (Am80-NLC) was developed and characterized previously. The purpose of the present work was to develop PEGylated nanostructured lipid carrier (PEG-NLC) for intravenous delivery of Am80, with the aim to further extend the circulation in blood and decrease the adverse events. Am80-loaded PEG-NLC (Am80-PEG-NLC) modified with PEG-40 stearate (PEG40-SA, molecular weight 2000 Da) was formulated by the method of melt-emulsification and low temperature-solidification technique. Am80-NLC was developed as well as control. Based on the optimized results of single-factor screening experiment, the average drug entrapment efficiency, the mean particle size, and zeta potential of Am80-NLC and Am80-PEG-NLC were found to be 89.8-94.3%, 178.9-201.6 nm, and -37.74 to -20.1 mV, respectively. In vitro drug release of Am80-NLC and Am80-PEG-NLC possessed a sustained release characteristic and their release behavior was in accordance with the Ritger-Peppas equation. In vivo, after intravenous (i.v.) injection to rats, the mean residence time (MRT) of Am80-PEG-NLC group was significantly prolonged and the AUC value was improved as well compared with the Am80-NLC group. Furthermore, the biodistribution in mice showed that Am80-PEG-NLC preferentially decreased the accumulation of Am80 in kidney and increased the drug concentration in brain after i.v. injection. In conclusion, Am80-PEG-NLC may be a potential delivery system for Am80 in the treatment of APL.

Effect of confertifolin from Polygonum hydropiper L. against dengue vector mosquitoes Aedes aegypti L.

The essential oil from the leaves of Polygonum hydropiper L. (Polygonaceae) was tested against Aedes aegypti L. The LC50 values were 190.72 and 234.37 ppm against second and fourth instar larvae of A. aegypti, respectively. Confertifolin (6,6,9a-trimethy l-4,5,5a,6,7,8,9,9a-octahydronaphtho [1,2-c] furan-3 (1H)-one) was isolated from the essential oil of P. hydropiper leaves using silica gel column chromatography. The LC50 values were 2.90 and 2.96 ppm for second and fourth instar larvae of A. aegypti, respectively. At 10 ppm, the concentration of confertifolin showed ovicidal activity of 100, 100, and 77.6 % on 0-6, 6-12, and 12-18 h old eggs; the repellent activity was 323.2 min; and oviposition deterrent activity was 97.52 % and adulticidal activity was 100 % against A. aegypti. The results were statistically significant at P < 0.05 level. The results suggested that confertifolin as an effective major constituent against A. aegypti and might be considered as a potent source for the production of superior natural mosquitocides.

Isolation and biological activity of a novel cadinane-type sesquiterpenoid from the essential oil of Alangium salviifolium.

The components of the essential oil from the roots of Alangium salviifolium were analyzed by capillary gas chromatography-mass spectrometry (GC-MS). Ninety compounds, representing 74.5% of the total oil, were identified; the main components of the oil were epi-α-cadinol, followed by trans-2-hydroxycalamenene, cadalene, and cadina-4,10(15)-dien-3-one. A further unknown component comprised 5.5% of the oil. Therefore, the essential oil was purified by flash column chromatography to isolate this component. Its structure was established using extensive spectroscopic data analyses, including NMR, HR-EI-MS, and IR. The results showed that this isolated compound was (-)-7, 8-dihydroxycalamenal, which is a novel cadinane-type sesquiterpenoid. This compound was tested for its antioxidant activity and inhibition of tyrosinase, and showed particularly strong inhibition effects.

[HPTLC fingerprint analysis of andrographolides from Andrographis paniculata].

OBJECTIVE: To establish the high-performance thin layer chromatography (HPTLC) fingerprint of andrographolides from Andrographis paniculata, and to valuate the fingerprint similarity of samples from different habitats, markets, used parts and so on. METHODS: Chromatographic conditions were as follows: stationary phase: precoated HPTLC GF254 silica-gel plate (20 cm x 10 cm); developing solvent system: chloroform-toluene-methanol (80:10:15); Relative humidity: 42%; Color development reagent: 5% H2SO4 ethanolic solution, heating at 105 degrees C and observing the fluorescent chromatogram in a UV cabinet at 366 nm. The common patterns of HPTLC fingerprint were obtained through CHROMAP 1.5 solution software. RESULTS: The HPTLC fingerprint of andrographolides was consisted of 9 characteristic peaks (fluorescent bands) including andrographolide, neoandrographolide and dehydroandrographolide which were chemical reference substances. The investigation and analysis of 51 batches of Andrographis paniculata showed that there were remarkable differences among different samples, so was the content of andrographolide and total lactones. CONCLUSION: This method is simple and rapid, which can serve as an effective identification and quality assessment method for Andrographis paniculata.

Cytotoxic aryltetralin lignans from fruits of Cleistanthus indochinensis.

Eight new aryltetralin lignans, cleisindosides A-F (1-6), picroburseranin (7), and 7-hydroxypicropolygamain (8), were isolated from the fruits of Cleistanthus indochinensis (Euphorbiaceae). The structures of the isolates were established on the basis of their one- and two-dimensional NMR spectral data, as well as their mass spectrometric data. Compound 7 was found to have potent cytotoxicity against oral epidermoid carcinoma cells with an IC50 value of 0.062 µM, whereas glycosylation to 3 (IC50 7.5 µM) and stereochemical changes to 8 (IC50 10.8 µM) led to marked decreases in biological activity. Thus, it was determined that the C-7 and C-8' positions are critical for the biological activity of the lignans from this plant.

[Advances in studies on aryltetralin lactone lignans].

Natural aryltetralin lactone lignans existed in the plants of family Berberidaceae, Acanthaceae, Burseraceae, Verbenaceae, Euphorbiaceae, etc. Due to the antineoplastic and antiviral properties, it has become a hot research topic in medicinal chemistry. This review covers extraction and isolation, biosynthesis, plant origin, and structure and spectral characteristics of natural aryltetralin lactone lignans. It will provide a useful reference for the intensive studies and rational utilization of aryltetralin lactone lignans.

Qualitative and quantitative analysis of Andrographis paniculata by rapid resolution liquid chromatography/time-of-flight mass spectrometry.

A rapid resolution liquid chromatography/time-of-flight tandem mass spectrometry (RRLC-TOF/MS) method was developed for qualitative and quantitative analysis of the major chemical constituents in Andrographis paniculata. Fifteen compounds, including flavonoids and diterpenoid lactones, were unambiguously or tentatively identified in 10 min by comparing their retention times and accurate masses with standards or literature data. The characteristic fragmentation patterns of flavonoids and diterpenoid lactones were summarized, and the structures of the unknown compounds were predicted. Andrographolide, dehydroandrographolide and neoandrographolide were further quantified as marker substances. It was found that the calibration curves for all analytes showed good linearity (R² > 0.9995) within the test ranges. The overall limits of detection (LODs) and limits of quantification (LOQs) were 0.02 µg/mL to 0.06 µg/mL and 0.06 µg/mL to 0.2 µg/mL, respectively. The relative standard deviations (RSDs) for intra- and inter-day precisions were below 3.3% and 4.2%, respectively. The mean recovery rates ranged from 96.7% to 104.5% with the relative standard deviations (RSDs) less than 2.72%. It is concluded that RRLC-TOF/MS is powerful and practical in qualitative and quantitative analysis of complex plant samples due to time savings, sensitivity, precision, accuracy and lowering solvent consumption.

Molecular docking and ADME studies of natural compounds of Agarwood oil for topical anti-inflammatory activity.

Aquilaria agallocha Roxb. family, Thymelaeaceae, is an evergreen plant of South-East Asia, commonly described as aloe wood or agarwood. Traditionally, the bark, root and heartwood are used for their medicinal properties as a folk medicine for hundreds of years. Chemical analyses revealed that the bulk of the oil is constituted by agarospirol (12.5%), jinkoh-eremol (11.8%) and hinesol (8.9%) as major contributor. In the present work, a QSAR model for antiinflammatory activity of 10-epi-γ-Eudesmol, jinkoh-eremol, agarospirol and other compounds has been developed by multiple linear regression method. The r(2) and rCV(2) of a model were 0.89 and 0.81 respectively. In silico molecular docking study suggests that compound 10-epi-γ-Eudesmol, jinkoh-eremol and agarospirol are preferentially more active than other identified compounds with strong binding affinity to major anti-inflammatory and immunomodulatory receptors. The oil displayed a significant and dose dependent reduction of 12-O-tetradecanoylphorobol-13 acetate (TPA)- induced ear edema and MDA activity when compared with vehicle treated mice. Pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) were also reduced significantly in a dose dependent manner in all the TPA treated groups as compared to control. The present study indicates that agarwood oil significantly reduced the skin thickness, ear weight, oxidative stress and pro-inflammatory cytokines production in TPA-induced mouse ear inflammation model and contributed towards validation of its traditional use to treat inflammation related ailments.

Two novel phenolic compounds from the rhizomes of Cyperus rotundus L.

Two novel compounds, 1α-methoxy-3ß-hydroxy-4α-(3',4'-dihydroxyphenyl)-1, 2,3,4-tetrahydronaphthalin (1) and 1α,3ß-dihydroxy-4α-(3',4'-dihydroxyphenyl)-1,2,3,4-tetrahydronaphthalin (2), were isolated along with six known compounds 3-8 from the rhizomes of Cyperus rotundus. This paper reports the isolation and full spectroscopic characterization of these new compounds by NMR, UV, IR and MS data.

Mechanism of tetralin ring opening and contraction over bifunctional Ir/SiO2-Al2O3 Catalysts.

The development of cleaner fuels from conventional resources requires the finding of new hydrotreatment processes able to improve the combustion performances of fuels and limit undesirable emissions. In the context of gas oil upgrading by selective ring opening, we have investigated the hydroconversion of tetralin over iridium nanoparticles supported on amorphous silica-alumina. The conversion of tetralin leads to hydrogenation, ring-contraction, and ring-opening products. The selectivity to ring-opening/-contraction products (ROCPs) increases linearly with the acid-metal site ratio and can be tuned by modifying the metal loading, the metal nanoparticle size, or the support composition. From the combination of catalytic tests at variable conversion and the products identification by two-dimensional gas chromatography, a mechanistic reaction scheme has been established. Aromatic ROCPs are formed through purely acidic steps, whereas the formation of saturated ROCPs mostly involves bifunctional reaction steps. Iridium-catalyzed hydrogenolysis appears to be a minor pathway with respect to iridium-catalyzed hydrogenation and Brønsted acid catalyzed isomerization.

[Study on chemical constituents from petroleum ether-soluble parts of cones of Platycladus orientalis].

OBJECTIVE: To study chemical constituents from petroleum ether-soluble parts of cones of Platycladus orientalis. METHODS: The compound were isolaeed by repeated column chromatography of silica gel and Sephadex LH-20. The structures were elucidated by physicochemical properties and spectrum analysis. RESULTS: Seven constituents were isolated and identified as sandaracopimaric acid (1), 6alpha-hydroxy sandaracopimaric acid (2), ent-isopimara-8 (14), 15-dien-3beta, 19-diol (3), ent-isopimara-8 (9), 15-dien-3beta-ol (4), ent-isopimara-8 (14),15- dien-3beta-ol (5), isocupressic acid (6) and 15-acetylisocupressic acid (7). CONCLUSION: Compounds 2 and 7 are isolated from this genus for the first time.

Silicon analogues of the nonpeptidic GnRH antagonist AG-045572: syntheses, crystal structure analyses, and pharmacological characterization.

AG-045572 (CMPD1, 1 a) is a nonpeptidic gonadotropin-releasing hormone (GnRH) antagonist that has been investigated for the treatment of sex hormone-related diseases. In the context of systematic studies on sila-substituted drugs, the silicon analogue disila-AG-045572 (1 b) and its derivative 2 were prepared in multi-step syntheses and characterized by elemental analyses (C, H, N), NMR spectroscopic studies (1H, 13C, 29Si), and single-crystal X-ray diffraction. The pharmacological properties of compounds 1 a, 1 b, and 2 were compared in terms of their in vitro potency at cloned human and rat GnRH receptors. Compounds 1 a and 2 were also examined in regard to their pharmacokinetics and in vivo efficacy in both castrated rat (luteinizing hormone (LH) suppression) and intact rat (testosterone suppression) models. The efficacy and pharmacokinetic profiles of 1 a and its silicon-containing analogue 2 appear similar, indicating that replacement of the 5,6,7,8-tetrahydronaphthalene ring system by the 1,3-disilaindane skeleton led to retention of efficacy. Therefore, the silicon compound 2 represents a novel drug prototype for the design of potent, orally available GnRH antagonists suitable for once-daily dosing.

Antimicrobial activities of neo- and 1-epineo-isoshinanolones from Plumbago zeylanica roots.

CONTEXT: The roots of Plumbago zeylanica Linn. (Plumbaginaceae) are reputed to have a wide spectrum of therapeutic properties in the Ayurvedic system of medicine. They are useful in curing many ailments such as skin diseases, diarrhea, plague and leprosy. OBJECTIVE: The study was aimed at isolating, separating and evaluating the antimicrobial properties of compounds such as neoisoshinanolone and 1-epineo-isoshinanolone from the roots of P. zeylanica. MATERIALS AND METHODS: The crude petroleum ether extract of roots of P. zeylanica was subjected to repeated chromatographic techniques to separate compounds 2 and 3 along with plumbagin. Structure elucidation was carried out using nuclear magnetic resonance (NMR), infra red (IR) and mass spectroscopy. The serial dilution method was used to test antimicrobial activities and their minimum inhibitory concentration (MIC) expressed in microg/mL. RESULTS: 1-Epineo-isoshinanolone is more active with a MIC of 12.5-25 microg/mL whereas neoisoshinanolone has recorded a MIC of 50-100 microg/mL. The activities are compared with plumbagin (0.78-3.13 microg/mL) and standards streptomycin for bacteria and nystatin for fungi. DISCUSSION: Earlier researchers have established the presence of plumbagin in the roots of P. zeylanica and its antimicrobial activities. The structure elucidation of two more biologically active biogenetic precursors along with their activities in the root extracts has been established for the first time in the present study. CONCLUSION: The root extract of P. zeylanica possesses good antimicrobial activity, which suggests its therapeutic use in the Ayurvedic system of medicine to cure skin diseases.

Identification of a naturally occurring rexinoid, honokiol, that activates the retinoid X receptor.

Screening of a total of 86 crude drugs for retinoid X receptor (RXR) ligands demonstrated that the methanol extract of the bark of Magnolia obovata markedly activated the transcriptional activity of RXRalpha in luciferase reporter assays. Thereafter, honokiol (1) was isolated as a constituent able to activate RXR selectively as a natural rexinoid, but not RARalpha. The activity of 1 was more potent than those of phytanic acid and docosahexaenoic acid, both of which are known to be natural RXR agonists. Honokiol (1) is capable of activating a RXR/LXR heterodimer, resulting in the induction of ATP-binding cassette transporter A1 mRNA and protein expression in RAW264.7 cells, as well as an increase in [(3)H]cholesterol efflux from peritoneal macrophages. These effects of 1 were enhanced synergistically in the presence of an LXR agonist, 22(R)-hydroxycholesterol. The results obtained demonstrate that 1, a newly identified natural rexinoid, regulates the functions of RXR/LXR heterodimer and abrogates foam cell formation by the induction of ABCA1 via activation of the RXR/LXR heterodimer.