Synthesis of an unusual quinazoline alkaloid: theoretical and experimental investigations of its structural, electronic, molecular and biological properties.

An unusual quinazoline alkaloid (1) was obtained when 2-aminobenzaldehyde was refluxed with pyrrolidine in ethanol for 12 h. The synthesized compound was characterized using spectral data analysis augmented with X-ray and literature precedent. Single crystal analysis depicted four conformations differing slightly in bond angles and bond lengths. Compound 1 crystallizes in a triclinic crystal system with a P1̄ space group having two molecules within the unit cell. The experimentally obtained parameters were compared to those obtained theoretically, which depicted a good agreement. Using the DFT/B3LYP/6-31G (d,p) level of theory, HOMO-LUMO energy gap, molecular electrostatic potential (MEP), vibrational (IR) and NMR analyses were carried out. The HOMO-LUMO energy gap allowed the calculation of chemical hardness, chemical inertness, electronegativity and the electrophilicity index of the molecule, which depicted its potential kinetic stability and reactivity. Prediction of activity spectra of the target compound revealed that compound 1 possesses notable antineoplastic activity with P a = 0.884. The molecule was therefore evaluated against various cancerous cell lines in an in vitro SRB assay which depicted that compound 1 possesses the highest growth inhibition activity against THP-1 cell lines with an IC50 of 7 µM.

Synthesis of Gallic-Acid-1-Phenyl-1H-[1,2,3]Triazol-4-yl Methyl Esters as Effective Antioxidants.

Using a click chemistry approach, a series of gallic-acid-1-phenyl-1H-[1,2,3]triazol-4-ylmethyl esters was synthesized to develop more effective antioxidants. The results of DPPH screening indicate that few of the synthesized analogs display better antioxidant effect compared to the standards. Among all, compounds, 9 and 20 displayed highest DPPH radical scavenging effect with IC50 values as low as 6.4±0.2 and 7.9±0.4 µM respectively, compared to the standard ascorbic acid (IC50=12±0.8 µM) and gallic acid (IC50=9.0±0.6 µM). Compound 10 also displayed a potent antioxidant effect with IC50 of 10.80±0.4 µM. This study provides an important aspect with regard to the use of these gallic-acid based synthetic antioxidants in food industry as dietary supplements.

Arglabin: From isolation to antitumor evaluation.

Arglabin belongs to guaianolide class of sesquiterpene lactones, isolated from Artemisia species. The molecule bears a 5,7,5-tricyclic ring system having five contiguous stereo centers in which the two five membered rings are trans-annulated. Arglabin shows promising antitumor activity against different tumor cell lines. The antitumor activity of arglabin proceeds through its inhibition of farnesyl transferase which leads to the activation of RAS proto-oncogene, a process that is believed to play a pivotal role in 20-30% of all human tumors. It actually inhibits the incorporation of farnesyl pyrophosphate into human H-ras proteins by the enzyme farnesyl transferase (FTase). The present review is an attempt to summarize the chemistry and biology of this molecule since its isolation in 1982. It embodies the isolation, structure elucidation, stereo chemical description, structural classification, chemical synthesis, structural modifications and antitumor evaluation reported till date.

LC-MS guided isolation, quantification and antioxidant evaluation of bioactive principles from Epimedium elatum.

This article presents the isolation, quantification and antioxidant evaluation of bioactive principles from Epimedium elatum. LC-MS guided isolation technique was applied for the separation of target constituents. Three isolates; magnoflorine, chrysin and dibenzylideneacetone (DBA) were isolated for the first time from E. elatum using LC-MS guided isolation method. Nine natural products, viz. icariin, epimedoside A, epimedin A, epimedin B, epimedin C, ikarisoside C, baohuoside II, magnoflorine and chrysin were simultaneously quantified by reverse phase HPLC-UV-DAD method. The HPLC method was validated in terms of precision and accuracy. Excellent specificity and linearity within test ranges for all standard calibration curves having regression coefficient of different linear equations in the range of 0.9966-0.9999 were observed. Relative recovery rates varied between 98.09±0.44 and 105.34±1.89% with relative standard deviation of less than 3%. This modified HPLC method is in accordance with yinyanghuo. All the 10 isolated constituents were screened for DPPH radical scavenging activity. Dibenzylideneacetone (DBA) turned out to be the most potent isolate with IC(50) of 4.32 µM.

Phytosterols as precursors for the synthesis of aromatase inhibitors: Hemisynthesis of testololactone and testolactone.

Using ß-sitosterol and stigmasterol as precursor materials, a concise and efficient hemisynthesis of aromatase inhibitors: testololactone and testolactone was accomplished in a well-established reaction scheme. It involves highly effective Oppaneur oxidation of both ß-sitosterol as well as stigmasterol to generate the required enone moiety in ring 'A' of the desired steroid system. The Oppaneur oxidation products of both ß-sitosterol and stigmasterol were then subjected to oxidative cleavage of the side chain to produce 4-androstene-3,17-dione. Baeyer-Villiger oxidation of 4-androstene-3,17-dione using m-CPBA yielded testololactone. Dehydrogenation of 4-androstene-3,17-dione using phenylselenyl chloride in ethyl acetate followed by selenoxide elimination with H2O2 in dichloromethane furnished androstenedienone. Baeyer-Villiger oxidation of the resulting androstenedienone yielded the desired testolactone (overall yield 33%). This expeditious reaction scheme may be exploited for the bulk production of aromatase inhibitors (especially testolactone marketed under the brand name Teslac) from the most abundant and naturally occurring phytosterols like ß-sitosterol.

Essential oil composition of Senecio graciliflorus DC: comparative analysis of different parts and evaluation of antioxidant and cytotoxic activities.

The essential oil of different parts of Senecio graciliflorus DC was obtained by hydrodistillation and analysed by GC-FID and GC-MS for the first time. A total of 17, 20, 19 and 17 constituents were identified comprising 99.90, 95.50, 98.93 and 95.96% of the essential oil of flower, leaf, stem and root parts of Senecio graciliflorus respectively. Monoterpene hydrocarbons predominated in the essential oil with 85.28% in flower, 57.53% in leaf, 67.74% in stem and 64.98% in root oil. α-pinene, cis-ocimene, 1,2,3-trimethylcyclohexane and ß-pinene were the major constituents of the essential oil. The flower essential oil exhibited a strong antioxidant potential displaying IC50 values of 21.6±0.6 and 26.0±1.0µg/ml in DPPH and hydroxyl radical assays respectively. On the other hand the essential oil of flower and root displayed highest cytotoxicity against lung (A-549) cancer cell lines (IC50=19.1±0.9 and 21.3±1.1µg/ml respectively. This study which represents the first report of the essential oil composition and bioevaluation of Senecio graciliflorus, can serve as a new source of cytotoxic and antioxidant activity.

Click chemistry inspired facile synthesis and bioevaluation of novel triazolyl analogs of Ludartin.

A convenient and modular synthesis involving diastereoselective Michael addition followed by regioselective Huisgen 1,3-dipolar cycloaddition reaction was carried out to furnish 1,4-disubstituted-1,2,3-triazoles of Ludartin. This reaction scheme involving Michael addition followed by regioselective Huisgen 1,3-dipolar cycloaddition reaction leading to the formation of triazolyl analogs is being reported for the first time. All the triazolyl products were characterised using spectral data analysis. Sulphorhodamine B cytotoxicity screening of the resulting products against a panel of five human cancerous cell-lines revealed that few of the analogs display promising broad spectrum cytotoxic effect. Among all the synthesized compounds, only 3q displayed the best cytotoxic effect with IC50 values of 12, 11, 38, 39 and 8.5 µM but less than the standard Ludartin (1) with IC50 values of 6.3, 7.4, 7.5, 6.9 and 0.5 µM against human neuroblastoma (T98G), lung (A-549), prostate (PC-3), colon (HCT-116) and breast (MCF-7) cancer cell lines, respectively. The present synthesis was designed based on the previous literature reports of Ludartin as an aromatase inhibitor. Our work provides an initial study on structure-activity relationship of triazolyl analogs of sesquiterpene lactones in general and Ludartin (1) in particular.

Isolation, cytotoxicity evaluation and HPLC-quantification of the chemical constituents from Artemisia amygdalina Decne.

The hexane extracts of both shoot and root parts of Artemisia amygdalina Decne displayed potent cytotoxic effects. Phytochemical analysis of these active extracts led to the isolation of six cytotoxic constituents, viz., Ergostadien-3ß-ol (1), ludartin (2), 5-hydroxy-6,7,3',4'-tetramethoxyflavone (3) (from shoot) and trans-matricaria ester (4), diacetylenic spiroenol ether (5) and cis-matricaria ester (6) (from root) for the first time from this plant. The constituents were identified using spectral techniques in the light of literature. Sulphorhodamine B cytotoxicity screening of the isolated constituents was carried out against four human cancer cell lines including Lung (A-549), Leukaemia (THP-1), Prostate (PC-3) and Colon (HCT-116) cell lines. Ludartin (2) exhibited the highest cytotoxicity with IC50 values of 7.4µM, 3.1µM, 7.5µM and 6.9µM against Lung (A-549), Leukaemia (THP-1), Prostate (PC-3), Colon (HCT-116) cancer cell lines respectively. To test against in vitro skin cancer models [human dermal fibroblasts (CRL-1635)] all the isolates were further subjected to 3-(4,5-Dimethylthiazol-yl)-diphenyl tetrazolium bromide (MTT) cytotoxicity screening. Ludartin (2) being highly cytotoxic was again evaluated against mouse melanoma (B16F10) and human epidermoid carcinoma (A-431) cells by MTT assay displaying IC50 values of 6.6µM and 19.0µM respectively. Finally a simple and reliable HPLC method was developed (RP-HPLC-DAD) and validated for the simultaneous quantification of these cytotoxic constituents in A. amygdalina Decne. Excellent specificity and high linearity for all the standard calibration curves having regression coefficients of the respective linear equations in the range of 0.9962-0.9999 was observed. Relative recovery rates varied between 98.37±0.90 and 105.15±1.74 with relative standard deviation less than 4%. Based on our results, the developed method features good quantification parameters, accuracy, precision and can serve as effective quality control method for standardisation of A. amygdalina Decne.

Synthesis and biological evaluation of amino analogs of Ludartin: potent and selective cytotoxic agents.

Diverse amino analogs of Ludartin, a cytotoxic guaianolide and a position isomer of an anticancer drug, Arglabin were prepared through Michael type addition at its highly active α-methylene-γ-lactone motif. The semisynthetic derivatives were subjected to sulphorhodamine B cytotoxicity assay against a panel of four different human cancer cell lines viz. lung (A-549), leukemia (THP-1), prostate (PC-3) and colon (HCT-116) to look into structure-activity relationship. Few of the analogs displayed potent selective cytotoxicity compared to the parent molecule-Ludartin (1). (11R)-13-(Diethyl amine)-11,13-dihydroludartin (6) and (11R)-13-(piperidine)-11,13-dihydroludartin (10) showed almost same cytotoxicity against leukemia cell lines (THP-1) as that of parent molecule-Ludartin, but were more active against colon (HCT-116) cancer cells. (11R)-13-(Morpholine)-11,13-dihydroludartin (11) displayed selectively better cytotoxicity against Leukemia cancer cells (THP-1) exhibiting IC50 of 2.8 µM. (11R)-13-(6-Nitroindazole)-11,13-dihydroludartin (17) was four times more potent than Ludartin with selective cytotoxic effects against prostate cancer cells (2.2 µM) while as (11R)-13-(6-nitroindazole)-11,13-dihydroludartin (18) exhibited three-fold selective cytotoxicity for Lung (A-549) cancer cell lines exhibiting IC50 of 2.6 µM.

Chemical composition, antioxidant and antibacterial activities of the leaf essential oil of Juglans regia L. and its constituents.

The essential oil from the leaves of Juglans regia L. (Juglandaceae) growing wild in Kashmir (India) was obtained by hydrodistillation and analysed by a combination of capillary GC-FID and GC-MS. A total of 38 compounds, representing 92.7% of the oil, were identified and the major components were found to be α-pinene (15.1%), ß-pinene (30.5%), ß-caryophyllene (15.5%) germacrene D (14.4%) and limonene (3.6%). The essential oil and the main individual constituents were screened for antibacterial activity and the essential oil evaluated for antioxidant activity. Antibacterial activity was evaluated using the disc diffusion and microdilution methods against a group of clinically significant Gram-positive (Staphylococcus epidermidis MTCC-435, Bacillus subtilis MTCC-441, Staphylococcus aureus) and Gram-negative bacteria (Proteus vulgaris MTCC-321, Pseudomonas aeruginosa MTCC-1688, Salmonella typhi, Shigella dyssenteriae, Klebsiella pneumonia and Escherichia coli). The essential oil and its major components exhibited broad spectrum inhibition against all the bacterial strains with Gram-positive being more susceptible to the oil than Gram-negative bacteria. Antioxidant activity of the oil was evaluated by the scavenging effect on DPPH (2,2-diphenyl-1-picrylhydrazyl) and hydroxyl radicals. In general, the essential oil exhibited high antioxidant activity which was comparable to the reference standards at the same dose (ascorbic acid and butylated hydroxyl toluene, BHT) with IC(50) values of 34.5 and 56.4µg/ml calculated by DPPH and hydroxyl radical scavenging assays respectively.

Isolation, characterisation and antibacterial activity studies of coumarins from Rhododendron lepidotum Wall. ex G. Don, Ericaceae / Estudos de isolamento, caracterização e atividade antibacteriana de cumarinas de Rhododendron lepidotum Wall. ex G. Don, Ericaceae

Six coumarins daphnin (1), daphnetin (2), daphnetin glucoside (3), rhodonetin (4), rhodonin (5) and umbelliferone (6) were isolated from the methanolic extract of Rhododendron lepidotum Wall. ex G. Don, Ericaceae (aerial part). The compounds and their acetyl derivatives were screened for antibacterial activity against Staphylococcus aureus ATCC-29213, methicillin resistant Staphylococcus aureus ATCC-15187, Escherichia coli ATCC-8739, Pseudomonas aeruginosa ATCC-9027 by microdilution method as compared to the reference ciprofloxacin. Compound 2 displayed the best antibacterial activity with MIC 125 μg/mL against S. aureus ATCC-29213 and MRSA ATCC-15187 followed by 4 which exhibited the MIC value of 250 μg/mL against all the four tested strains. All molecules showed better antibacterial activity than their acyl derivatives.

Seis cumarinas dafinina (1), dafinetina (2), dafinetina glicosídeo (3), rodonetina (4), rodonina (5) e umbeliferona (6) foram isoladas do extrato metanólico das partes aéreas de Rhododendron lepidotum Wall. ex G. Don, Ericaceae. Os compostos e seus derivados acetilados foram testados para verificar sua atividade antibacteriana contra Staphylococcus aureus ATCC-29213, Escherichia coli resistente à meticilina, Staphylococcus aureus ATCC-15187, ATCC-8739, Pseudomonas aeruginosa ATCC-9027, pelo método de microdiluição, usando ciprofloxacina como referência. A substância 2 apresentou a melhor atividade antibacteriana com o MIC 125 μg/mL contra S. aureus ATCC-29213 e MRSA ATCC-15187 seguido pela substância 4, que apresentou o valor de CIM de 250 μg/mL contra as quatro cepas testadas. Todas as moléculas apresentaram melhor atividade antibacteriana do que seus derivados acetilados.