Synthesis and evaluation of coumarin derivatives against human lung cancer cell lines

Series of novel coumarin derivatives [I (a-d) and II (a-d)] were successfully synthesized and their structures were determined based on infrared 1H-nuclear magnetic resonance (NMR), HRMS, and single crystal X-ray crystallography. Additionally, the new synthesized compounds were evaluated to identify the molecular characteristics that contribute to their cytotoxicity, which was tested against SK-LU-1, SPC-A-1 and 95D human lung cancer cell lines, using the MTT assay. The results of this study showed that compounds Ic, Id, IIc, and IId exhibited an efficient percentage of inhibition of cell proliferation.

Trypanocidal constituents in plants: 7. Mammea-type coumarins

Calophyllum brasiliense and Mammea americana (Clusiaceae) are two trees from the tropical rain forests of the American continent. A previous screening showed high trypanocidal activity in the extracts of these species. Several mammea-type coumarins, triterpenoids and biflavonoids were isolated from the leaves of C. brasiliense. Mammea A/AA was obtained from the fruit peels of M. americana. These compounds were tested in vitro against epimastigotes and trypomastigotes of Trypanosoma cruzi, the etiologic agent of Chagas disease. The most potent compounds were mammea A/BA, A/BB, A/AA, A/BD and B/BA, with MC100 values in the range of 15 to 90 g/ml. Coumarins with a cyclized ,-dimethylallyl substituent on C-6, such as mammea B/BA, cyclo F + B/BB cyclo F, and isomammeigin, showed MC100 values > 200 g/ml. Several active coumarins were also tested against normal human lymphocytes in vitro, which showed that mammea A/AA and A/BA were not toxic. Other compounds from C. brasiliense, such as the triterpenoids, friedelin, canophyllol, the biflavonoid amentoflavone, and protocatechuic and shikimic acids, were inactive against the epimastigotes. The isopropylidenedioxy derivative of shikimic acid was inactive, and its structure was confirmed by X-ray diffraction. Our results suggest that mammea-type coumarins could be a valuable source of trypanocidal compounds.

Antitumor activity of 4-arylcoumarins from endophytic Streptomyces aureofaciens CMUAc130.

In a search for antitumor agents, we carried out a screening of 4-arylcoumarins isolated from endophytic Streptomyces aureofaciens CMUAc130, by examining their possible inhibitory effect on the growth of s.c. transplanted Lewis lung carcinoma (LLC) in BDF-1 mice by intraperitoneal (i.p.) administration. The 4-arylcoumarins showed antitumor activity with T/C values of 80.8 and 50.0% at doses of 1 and 10 mg/kg of 5,7-dimethoxy-4-p-methoxylphenylcoumarin treatment, respectively and 81.5 and 44.9% at doses of 1 and 10 mg/kg of 5,7-dimethoxy-4-phenylcoumarin treatment, respectively, compared to adriamycin, which was used a positive control, with T/C value of 55.9% at 2 mg/kg. Furthermore, we investigated the possible effects of these compounds on expression of the bcl-2 and Bax oncoproteins in A427, a human lung cancer cell lines. The cells were cultured in vitro for 24 h in RPMI 1640 with 1.5% (v/v) ethanol, 100 microg/ml 5,7-dimethoxy-4-p-methoxylphenylcoumarin or 5,7-dimethoxy-4-phenylcoumarin. Viability was determined by an MTT assay. Total protein was extracted from cell lysates and the bcl-2 and Bax oncoproteins were identified. Western blotting showed a decrease in bcl-2 and an increase in Bax in A427 cell cultured with 5,7-dimethoxy-4-p-methoxylphenylcoumarin or 5,7-dimethoxy-4-phenylcoumarin. We conclude that 5,7-dimethoxy-4-phenylcoumarin is a more potent inhibitor of cell proliferation than 5,7-dimethoxy-4-p-methoxylphenylcoumarin and has more marked effects on oncoprotein expression.

Synthesis and antimicrobial activity of some nitrogen heterocycles incorporation into coumarin

Substituted 3-carbethoxycoumarin [Ia] was reacted with aromatic primary amines e.g. aniline and o-toludine to give N-substitntcd carbox amides [IIa.b][12], respectively. Also, when 3-carbethoxycoumarin derivatives [Ia-c] were reacted with aromatic hetercyclic amines such as 2-aminopyridine, 2-amino-thiazole, 2-aminobenzothiazole and 3-methyl-5-ethoxypyroyle the products are N-substituted carboxamidocoumarins, [IIIa-e] and [IV], respectively. Mass spectrum for the compound [IIId] shows ion peaks fragmentation at m/z 400/402 and other peaks at m/z 251/252 m/z 172 m/z 74. Alcoholic ferric chloride test doesn't give any definite colour of phenol[3], i.e. the alpha-pyrone ring is not cleavage

Natural compounds, fraxin and chemicals structurally related to fraxin protect cells from oxidative stress

Coumarins comprise a group of natural phenolic compounds found in a variety of plant sources. In view of the established low toxicity, relative cheapness, presence in the diet and occurrence in various herbal remedies of coumarins, it appears prudent to evaluate their properties and applications further. The purpose of this study is to investigate cellular protective activity of coumarin compound, fraxin extracted from Weigela florida var. glabbra, under oxidative stress, to identify genes expressed differentially by fraxin and to compare antioxidative effect of fraxin with its structurally related chemicals. Of the coumarins, protective effects of fraxin against cytotoxicity induced by H2O2 were examined in human umbilical vein endothelial cells (HUVECs). Fraxin showed free radical scavenging effect at high concentration (0.5 mM) and cell protective effect against H2O2-mediated oxidative stress. Fraxin recovered viability of HUVECs damaged by H2O2- treatment and reduced the lipid peroxidation and the internal reactive oxygen species level elevated by H2O2 treatment. Differential display reverse transcription-PCR revealed that fraxin upregulated antiapoptotic genes (clusterin and apoptosis inhibitor 5) and tumor suppressor gene (ST13). Based on structural similarity comparing with fraxin, seven chemicals, fraxidin methyl ether (29.4% enhancement of viability), prenyletin (26.4%), methoxsalen (20.8 %), diffratic acid (19.9%), rutoside (19.1%), xanthyletin (18.4%), and kuhlmannin (18.2%), enhanced more potent cell viability in the order in comparison with fraxin, which showed only 9.3% enhancement of cell viability. These results suggest that fraxin and fraxin-related chemicals protect HUVECs from oxidative stress.

Aurapten, a coumarin with growth inhibition against Leishmania major promastigotes

Several natural compounds have been identified for the treatment of leishmaniasis. Among them are some alkaloids, chalcones, lactones, tetralones, and saponins. The new compound reported here, 7-geranyloxycoumarin, called aurapten, belongs to the chemical class of the coumarins and has a molecular weight of 298.37. The compund was extracted from the Rutaceae species Esenbeckia febrifuga and was purified from a hexane extract starting from 407.7 g of dried leaves and followed by four silica gel chromatographic fractionation steps using different solvents as the mobile phase. The resulting compound (47 mg) of shows significant growth inhibition with an LD50 of 30 æM against the tropical parasite Leishmania major, which causes severe clinical manifestations in humans and is endemic in the tropical and subtropical regions. In the present study, we investigated the atomic structure of aurapten in order to determine the existence of common structural motifs that might be related to other coumarins and potentially to other identified inhibitors of Leishmania growth and viability. This compound has a comparable inhibitory activity of other isolated molecules. The aurapten is a planar molecule constituted of an aromatic system with electron delocalization. A hydrophobic side chain consisting of ten carbon atoms with two double bonds and negative density has been identified and may be relevant for further compound synthesis.

In vitro antiviral activity of bael (Aegle marmelos Corr) upon human coxsackieviruses B1-B6.

The in-vitro antiviral activity of a series of compounds in samples extracted from various parts of the Indian holy tree, Bael (Aegle marmelos corr.) were evaluated for their efficacy against human coxsackieviruses B1-B6. The inhibitory concentrations (IC50) for leaves (L1 and L2) stem and stem bark (S1, S2, S3 and S4) fruit (F1 and F2micro) root and root bark (R1 and R2) and pure compound, the marmelide were 1000 microg/ml (for L1 and L2), 1000 microg/ml (for S1, S2, S3 and S4), 1000 microg/ml (for F1) and 500 microg/ml (for F2) 250 microg/ml (for R1) and 500 microg/ml (for R2) and 62.5 microg/ml for marmelide respectively by plaque inhibition assay at 96 hrs. On the other hand, the corresponding value for Ribavirin, a standard antiviral drug, was 2000 microg/ml for the same viruses at the same time period. These concentrations did not exhibit any toxicity to Vero cells, the host subtoxic concentrations were 5000 microg/ml for leaf and stem fractions 2000 microg/ml for fruit fractions 500 and 1000 microg/ml for root fractions 250 microg/ml for marmelide and 2000 microg/ml for Ribavirin. The cytotoxic concentrations were 8000 microg/ml for leaf and stem compounds 4000 mg/ml for fruit; 1000 microg/ml and 2000 microg/ml for root 500 microg/ml for marmelide and 4000 microg/ml for ribavirin at 96 hrs. These were also confirmed by trypan blue dye exclusion test and further passaging of cells. Additionally pretreatment of host cells, virus inactivation, yield reduction and effect of time of addition assays against coxsackievirus B3 suggested that marmelide was most effective as a virucidal agent besides interfering at early events of its replicative cycle like adsorption, penetration, at various steps in single cycle growth curve and effect of time of addition.

Spectrophotometric determination of thulium [lll] and dioxouranium ions using 8- [arylazo] -6,7 dihydroxy - 4 - methylcoumarin derivatives

The complexes of Tm [III] and UO2 [VI] with 8-[arylazo] -6,7-dihydroxy-4-methylcoumarin derivatives were investigated spectrophotometrically. The optimum conditions for chelation, pH, sequence of addition, time, solvents and stoichiometry were critically evaluated. The studies revealed that 1: 1 and 1: 2 [M: L] complexes were formed. The higher stability constants for Tm [III] complexes compared to those of UO2+ 2 complexes were explained in terms of the hydrolysis, steric effect and nature of bonding of both metal ions. Beer's Law was valid up to 16.89 mug/cm3 for Tm3+ complexes and 23.28 mug/cm3 for UO2+ 2 complexes. Spectrophotometric methods for the determination of Tm [III] and UO2+ 2 were presented. The methods were precise as shown by low standard deviations ranging from 0.0011 to 0.0146 and high correlation coefficient [r] ranging from 0.9965 to 0.9994. The values of molar absorptivity, epsilon [LM-1 cm-1] specific absorptivity, a [ml g-1 cm-1] and Sandell sensitivity and S [mug cm-1] indicated the method to be quite sensitive compared to recommended methods using arsenazo I and thoron. A photometric titration method using EDTA as titrant was given

Expresión de moléculas de adhesión en el melanoma metastásico murino B16-F10 y su modificación farmacológica in vitro con el empleo de cumarina / Adhesion molecules expression in murine B16-F10 metastatic melanoma and its pharmacological modification in vitro by the use of coumarin

Recientemente se han demostrado correlaciones significativas entre la expresión de algunas moléculas de adhesión y la capacidad de células de producir metástasis. Por ejemplo, se ha observado una correlación entre la expresión de la integrina a6/ß1 en células cancerosas pulmonares y la producción de metástasis. También se ha observado correlación entre la expresión de algunas moléculas de adhesión en células de melanoma maligno y su capacidad de producir metástasis pulmonares. En este trabajo estudiamos la acción in vitro de la cumarina en el melanoma murino B16-F10, productor de metástasis pulmonares, sobre la expresión de dos moléculas de adhesión, ICAM-1 y LFA-1. No se observó disminución en la expresión de la molécula de adhesión LFA-1, y la expresión de ICAM-1 disminuyó de manera uniforme con todas las concentraciones de cumarina estudiadas. Estos resultados no explican los efectos antimetastásicos producidos por la cumarina en modelos animales de metástasis pulmonares experimentales y espontáneas, ni los efectos antimetastásicos en humanos. Es necesario, por tanto, estudiar el efecto de la cumarina en la expresión de otras integrinas. Este tipo de estudios permite el desarrollo de nuevas estrategias en la búsqueda de mejores agentes antineoplásicos que disminuyan en mayor grado el número y tamaño de metástasis, y retarden importantemente su producción; contribuye, adenomás, al conocimiento de la fisiopatogenia de estos tumores malignos

Synthesis of some coumarin derivatives of possible biological activity

A series of bromocoumarins incorporated with aromatic derivatives via amino and ether linkages were synthesized. Also, hydrazocoumarin incorporated with thiosemicarbazides were prepared. Azole ring systems as 1,3,4-thiadiazole and 1,2,4-triazole were synthesized. Schiff bases which were cyclized with thioglycolic acid were prepared. Isatin moiety attached to hydrazocoumarin was prepared. The biological activity of some newly prepared compounds were carried out

Synthesis and reactions of mannich bases of 3-hydroxycoumarins

Mannich bases of 3-hydroxycoumarin show some antibacterial activity and are effective against fungi[1] Aminocoumarins and their derivatives are effective against several bacterial strains[2-5]

Synthesis and biological evaluation of 1,2,4 triazole and 1,3,4-Oxa-and Thiadiazoles derivatives

The alkaline hydrolysis with dimethylsulfate and potassium hydroxide of coumarin-6-derivatives [Ia-d] yielded 3-propenoic acid derivatives [IIa-d] which in turn were reached with thionyl chloride in toluene to give carbonyl chloride derivatives [IIa-d]. The latter compounds condensed with thiosemicarbazide in dioxane to give carbonylthiosemicarbazide derivatives [IVa-d], respectively. Cyclization of IVa-d, using sodium hydroxide yielded 5-mercapto- 1,2,4-triazol-3-yl-derivatives [Va-d]. Cyclodehydration of IVa-d using ortho-phosphoric acid or dicyclohexylcarbodiimide [DCC] led to the formation of the corresponding 5-amino-1,3,4-thia and oxadiazol-2-derivatives [VIa-d] and [VIIa-d], respectively. The antimicrobial and antiaflatoxigenic activities of Va-d, VIa-d were also evaluated

Crocatone and coumarins from the roots of torilis arvensis

From the roots of Torilis arvensis [Huds.] Link, crocatone, bergapten, xanthotoxin, scopoletin and umbelliferone were isolated and their structures were established through spectroscopic analyses. The present isolation of crocatone represents the first report of this isomyristicin derivative in the Scandiceae and the Caucalideae

Synthesis and reactions of 6-acetyl-7-hydroxy-4-methyl coumarin

Perkin condensation of 2, 4 diacetyl resorcinol with acetic anhydride and sodium acetate gave 6-acetyl-7-hydroxy-4-methyl coumarin [I]. Nitration of coumarin [I], then reduction followed by diazotization and coupling gave 3-azocoumarin derivative [V]. Alkylation of I followed by cyclization with anthranilic acid gave 2-[7/[6/acetyl-4-methyl] coumarinoxy] methyl-[4H] 3, 1-benzoxazin-4-one [VII]. The behavior of coumarin I towards bromination in different solvents, Claisen and Grignard reaction were studied and gave compounds [VIII-XII]. The structures of the products were confirmed by elemental analysis, IR and 1H-NMR spectroscopy