Cytotoxic effect and electrophysiological activity of S-irniine, a synthesised isomer of the natural R-irniine, on human MRC-5 fibroblasts

Numerous original alkaloids are present in tubers of Arisarum vulgare Targ. a species belonging to the Araceae family known in Morocco for its toxicity. Some previous works deal with the activity of these natural compounds as R-irniine. As the enantioselective total synthesis of irniine has been realised, the R- and S-forms were obtained and this last one could be tested. Thus, a study of the cytotoxicity and the electrophysiological activity of S-irniine was carried out on human MRC-5 fibroblasts. A cytotoxic effect of S-irniine at 40 microg/mL was detected on MRC-5 fibroblasts. An electrophysiological study was also carried out on the MRC-5 cells by using the patch-clamp technique and no effect of this compound at this concentration on the outward potassium current of MRC-5 fibroblasts was observed. Thus, this study showed, as it was for R-irniine, that the cytotoxicity of S-irniine was not explained by an effect on the potassium currents.     

Synthesis, gastroprotective effect and cytotoxicity of new amino acid diterpene monoamides and diamides

Following our studies on the gastroprotective effect and cytotoxicity of terpene derivatives, new amides were prepared from the diterpene 8(17)-labden-15,19-dioic acid (junicedric acid) and its 8(9)-en isomer with C-protected amino acids (amino acid esters). The new compounds were evaluated for their gastroprotective effect in the ethanol/HCl-induced gastric lesions model in mice, as well as for cytotoxicity using the following human cell lines: normal lung fibroblasts (MRC-5), gastric adenocarcinoma cells (AGS) and liver hepatocellular carcinoma (Hep G2). A dose-response experiment showed that at 25 mg/kg the C-15 leucyl and C-15,19-dileucylester amides of junicedric acid reduced gastric lesions by about 65.6 and 49.6%, respectively, with an effect comparable to lansoprazole at 20 mg/kg (79.3% lesion reduction). The comparison of the gastroprotective effect of 18 new amino acid ester amides was carried out at a single oral dose of 25 mg/kg. Several compounds presented a strong gastroprotective effect, reducing gastric lesions in the 70.9-87.8% range. The diprolyl derivative of junicedric acid, the most active product of this study (87.8% lesion reduction at 25 mg/kg) presented a cytotoxicity value comparable with that of the reference compound lansoprazole. The structure-activity relationships are discussed.     

Studies on constituents with cytotoxic activity from the stem bark of Syringa velutina.

Cytotoxic compounds, oleuropein (1) and a phenylethanoid glycoside (2) were isolated from the stem bark of Syringa velutina KOM. along with coniferylaldehyde 4-O-glucoside, syringin, ligstroside, (+)-syringaresinol 4-O-glucoside, (+)-medioresinol 4"-O-glucoside and (-)-olivil 4"-O-glucoside. Phenylethanoid glycoside (2) was identified to be 3,4-dihydroxyphenylethyl alcohol 8-O-beta-D-glucopyranoside. This compound showed the most potent cytotoxic effect on several tumor cell lines (P-388, L-1210, SNU-5 and HL-60) among eight compounds isolated in the present study. We suggest that the 3,4-dihydroxyphenylethoxy moiety of this compound contributes to cytotoxicity.     

New 1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.13,11]tetradecane-4,8,12-trione derivative as an allosteric modulator of the glutamatergic system

An optimized synthesis of N-{5-[(1,11-dimethyl-4,8,12-trioxo-3,6,9-triazatricyclo[7.3.1.1^3,11]tetradec-6-yl)methyl]-indan-2-yl}-1,3-benzodioxole-5-carboxamide has been carried out from indan-2-one oxime in seven steps. In vitro studies using electrophysiological patch clamp technique have revealed a positive modulation effect of this compound on kainate induced currents in Purkinje neurons in a wide range of concentrations from 10^–12 to 10^–8 m.     

New Imidazo[1,2‐c]pyrimidin‐5(6H)‐Ones Derived from Cytosine: Synthesis,Structure, and Cytotoxic Activity

This work describes the synthesis of 8‐iodoimidazo[1,2‐c]pyrimidin‐5(6H)‐one 2 from 5‐iodocytosine 1 . This compound was subjected to Suzuki cross‐coupling reaction with aryl and heteroarylboronic acids. After optimization, 10 products 3a , 3b , 3c , 3d , 3e , 3f , 3g , 3h , 3i , 3j were obtained in good yields 61‐90%. Cytotoxic activity of all new products was evaluated on seven tumor cell lines including resistant variants and on normal human fibroblasts. Two derivatives showed promising biological activity and good therapeutic index in the case of 3h .     

Synthesis and Cytotoxicity Testing of New Amido-Substituted Triazolopyrrolo[2,1-<em>c</em>][1,4]benzodiazepine (PBDT) Derivatives

A series of amido-substituted triazolopyrrolo[2,1-c][1,4]benzodiazepine (PBDT) derivatives was synthesized from isatoic anhydride, and their cytotoxicity against the MRC-5 and Mahlavu cell lines was evaluated. The results suggest that compound PBDT-7i with the meta-trifluoromethylbenzoyl substituent can selectively inhibit the growth of Mahlavu cells and has low toxicity towards MRC-5 cells.     

Synthesis and in vitro cytotoxic evaluation of aminoquinones structurally related to marine isoquinolinequinones

The synthesis of 4-methoxycarbonyl-3-methylisoquinolinequinone (1) and a variety of its substitution products with amino-, alkylamino and halogen groups on the quinone nucleus is reported. The series of 6-, 7- and 6,7-subtituted isoquinolinequinones were evaluated in vitro for their cytotoxic activity using the MTT colorimetric method. All the newly synthesized compounds showed moderate to high potency against MRC-5 healthy lung fibroblasts and four human tumor cell lines: AGS gastric adenocarcinoma, SK-MES-1 lung, J82 bladder carcinoma, and HL-60 leukemia cells. Among the series, compounds 4b, 12 and 13 exhibited interesting antitumor activity against human gastric adenocarcinoma, human lung and human bladder carcinoma cancer cells. 7-Amino-6-bromoisoquinoline-5,8-quinone (13) was found to be the most promising active compound against the tested cancer cell lines, with IC?? values in the 0.21-0.49 μM range, lower than the anti-cancer agent etoposide used as reference.     

Studies on quinones. Part 40: Synthesis and cytotoxicity evaluation of anthraquinone epoxides and isomerization products

Aerobic oxidation of 1,4,4a,10a-tetrahydro-1,4-alkano-5,10-anthraquinones and thiophene-analogues in dichloromethane-DBU yielded the corresponding dihydroalkanoquinones which, depending on their structures, react with in situ generated hydroperoxide anion to give quinone epoxides and/or hydroperoxides. The calcium hydroxide-induced rearrangement of quinone epoxides yielded furan-containing angular quinones. The cytotoxic activities of quinone epoxides and their isomerization products were evaluated in vitro against normal human lung fibroblasts (MRC-5) and human cancer gastric epithelial cells (AGS).     

In vitro evaluation of cytotoxic and mutagenic activity of avarol

The cytotoxicity of avarol, a main secondary metabolite of the Mediterranean sponge Dysidea avara, was in vitro screened by MTT assay against four human tumour cell lines. The colon HT-29 tumour cells practically showed to be the only sensitive ones towards this organic compound. No toxicity was found against the fetal lung fibroblast MRC-5 cells at the concentrations tested. In comparison with doxorubicin, used as a positive control, avarol actually exhibited at least 588-fold less toxicity towards normal MRC-5 cells. Finally, comet assay indicated that DNA fragmentation was almost fivefold higher upon the treatment with doxorubicin, compared to avarol. The obtained results have actually confirmed that avarol scaffold may contribute to development of new cytostatics inspired by nature.     

Synthesis and pharmacological activity of diterpenylnaphthoquinone derivatives

New diterpenylquinones, combining a diterpene diacid and a naphthoquinone, were prepared from junicedric acid and lapachol. The new derivatives were assessed as gastroprotective agents by the HCl-EtOH-induced gastric lesions model in mice as well as for basal cytotoxicity on the following human cell lines: Normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), and hepatocellular carcinoma (Hep G2). Several of the new compounds were significantly active as antiulcer agents and showed selective cytotoxicity against AGS cells.     

Synthesis, X-ray structural analysis, and cytotoxic activity of some new androstane d-homo lactone derivatives

A series of d-homo lactones 4?C10 from dehydroepiandrosterone 1 via 16-hydroximino derivatives 2 and 3 were synthesized. The d-homo lactone 4 was transformed by the Oppenauer oxidation to obtain compound 5. The (Z)-2-hydroxymethylene-4-en-3-one compound 6, was obtained through reaction of 4-en-3-one compound 5 with ethyl formate and sodium hydride. The epoxides 8 and 9 were prepared from compound 7 by oxidation with m-chloroperbenzoic acid. Compound 10 was obtained by treating epoxides 8 and 9 with chromium(VI)-oxide. The structure of compounds 6 and 10 were confirmed by X-ray structural analysis. These derivatives were screened for antitumor activity against three tumor cell lines (human breast adenocarcinoma ER+, MCF-7, human breast adenocarcinoma ER?, MDA-MB-231, prostate cancer AR?, PC-3), and one human non-tumor cell line, MRC-5. Compounds 4, 7, 8, and 10 exhibited significant antitumor activity against MDA-MB-231 cells, while compound 5 showed strong cytotoxicity against MDA-MB-231. No compounds displayed toxicity against MRC-5 cells.     

A new xanthone from the bark extract of Rheedia acuminata and antiplasmodial activity of its major compounds

Bioassay-guided fractionation of the ethyl acetate bark extract of Rheedia acuminata led to the isolation of the new compound 1,5,6-trihydroxy-3-methoxy-7-geranyl-xanthone, together with four known compounds. These compounds were tested in vitro for their antiplasmodial activity on a chloroquine-resistant strain of Plasmodium falciparum (FcB1) and for their cytotoxicity against the human diploid embryonic lung cell line MRC-5.     

Phytochemical and cytotoxic investigations of Curcuma mangga rhizomes

Investigations on the cytotoxic effects of the crude methanol and fractionated extracts (hexane, ethyl acetate) C. mangga against six human cancer cell lines, namely the hormone-dependent breast cell line (MCF-7), nasopharyngeal epidermoid cell line (KB), lung cell line (A549), cervical cell line (Ca Ski), colon cell lines (HCT 116 and HT-29), and one non-cancer human fibroblast cell line (MRC-5) were conducted using an in-vitro neutral red cytotoxicity assay. The crude methanol and fractionated extracts (hexane and ethyl acetate) displayed good cytotoxic effects against MCF-7, KB, A549, Ca Ski and HT-29 cell lines, but exerted no damage on the MRC-5 line. Chemical investigation from the hexane and ethyl acetate fractions resulted in the isolation of seven pure compounds, namely (E)-labda-8(17),12-dien-15,16-dial (1), (E)-15,16-bisnor-labda-8(17),11-dien-13-on (2), zerumin A (3), β-sitosterol, curcumin, demethoxycurcumin and bis-demethoxycurcumin. Compounds 1 and 3 exhibited high cytotoxic effects against all six selected cancer cell lines, while compounds 2 showed no anti-proliferative activity on the tested cell lines. Compound 1 also demonstrated strong cytotoxicity against the normal cell line MRC-5. This paper reports for the first time the cytotoxic activities of C. mangga extracts on KB, A549, Ca Ski, HT-29 and MRC-5, and the occurrence of compound 2 and 3 in C. mangga.     

Efficient Synthesis of New Thieno[2,3‐d]pyrimidin‐4(3H)‐one Derivatives for Evaluation as Anticancer Agents

Thieno[2,3‐d]pyrimidinones were reported to act as potent anticancer agents; in this work, a series of new substituted thieno[2,3‐d]pyrimidinone ( 6 ) were synthesized via the aza‐Wittig reaction in satisfactory yields. The structures of these compounds were confirmed by elemental analysis, IR, ¹H‐NMR, and mass spectral data, and compound 6h was further analyzed by single crystal X‐ray diffraction. Cytotoxic effect of all the compounds was carried out on human breast and lung cancer cell lines (MCF‐7 and SPC‐A‐1, A459). Compound 6f exhibited the best inhibition activities against A459 with IC₅₀ 4.1 μM.     

Synthesis,characterization and cytotoxic activity of ferrocenyl hydrazone complexes containing a furan moiety

A ferrocenyl ligand 1 was prepared from condensation of 5-methyl-2-furaldehyde with l,l′-diacetylferrocene dihydrazone. This ligand forms 1:1 complexes with cobalt(II), nickel(II), copper(II) and zinc(II) 2–5 in good yield. Characterization of the ligand and complexes was carried out using infrared, nuclear magnetic resonance, mass spectra, electronic absorption, magnetic susceptibility, molar conductivity, and elemental analysis. Cytotoxic activity of the prepared ligand and its complexes were tested against different human cancer cell lines. The results suggested that the synthesized compounds were more potent than the comparative standards drugs used in most cases, whereas they had less activity in the others.     

Computerized, comprehensive databases of cellular and secreted proteins from normal human embryonic lung MRC-5 fibroblasts: identification of transformation and/or proliferation sensitive proteins

Databases of protein information from human embryonal lung fibroblasts (MRC-5) have been established using computer analyzed two-dimensional gel electrophoresis. One thousand four hundred and eighty-two cellular proteins (1060 with isoelectric focusing and 422 with nonequilibrium pH gradient electrophoresis, in the first dimension) ranging in molecular mass between 8 and 234 kDa were separated and numbered. Information entered in the database (in most cases for major proteins) includes: protein name, HeLa protein catalog number, mouse protein catalog number, proteins matched in transformed human epithelial amnion cells (AMA) and peripheral blood mononuclear cells (PBMC), transformation and/or proliferation sensitive proteins, synthesis in quiescent cells, cell cycle regulated proteins, mitochondrial and heat shock proteins, cytoskeletal proteins and proteins whose synthesis is affected by interferons. Additional information entered for a few transformation-sensitive proteins that have been selected for future studies includes levels of synthesis and amounts in fetal human tissues. A total of four hundred and seventy-six [35S]methionine labeled polypeptides (258 isoelectric focusing; 218, nonequilibrium pH gradient electrophoresis) secreted by MRC-5 fibroblasts were separated and recorded (J. E. Celis et al., Leukemia 1987, 1, 707-717). Information entered in this database includes molecular weight and transformation sensitive proteins. These databases, as well as those of epithelial and lymphoid cell proteins (J. E. Celis et al., Leukemia 1988, 9, 561-601), represent the initial stages of a systematic effort to establish comprehensive databases of human protein information. In the long run, these databases are expected to offer a useful framework in which to focus the human genome sequencing effort.     

A specific probe for two-photon fluorescence lysosomal imaging

Lysosomes are vital organelles in physiological processes, as they receive and degrade macromolecules from the secretory and endocytic procedures. Evidences have shown that lysosomes were related to oncogenic activation and cancer progression, so lysosomes targeting and imaging probes make them convenient to be observed. In this study, a lysosome specific probe W-7 was designed and synthesized via convenient one-pot reaction and Heck reaction. This probe was derived from Tröger's base with a dimethylaminomethyl end group. The optical properties of this compound were measured. W-7 also showed two-photon absorption (TPA) effect by using laser excitation at the wavelength of infrared light. In vivo experiment, W-7 showed high specificity and selectivity for lysosomes in living cells (HeLa cells, MRC-5 cells and NRK cells), compared with LT Red, GT Red and MT Red (R = 0.96). Two-photon fluorescence images of HeLa cells stained by W-7 were obtained. And high resolution 3D reconstruction of lysosomes in one HeLa cell was provided by using two-photon confocal microscopy. The anantioseparation of racemic W-7 was carried out by chiral-HPLC, and the two enantiomers showed no significant difference in lysosomes imaging.     

Novel seco-dibenzopyrrocoline alkaloid from Cryptocarya oubatchensis

[structure: see text] A novel seco-dibenzopyrrocoline alkaloid, named oubatchensine 6, and five phenanthroindolizidines (1-5) were isolated from Cryptocarya oubatchensis, and their structures were elucidated. Displacement centrifugal partition chromatography was used to purify compounds 1 and 6. Structure determination of the latter was carried out by mass spectrometry, NMR spectroscopy, quantum chemistry, and computer-assisted structure determination. Cytotoxic activity against KB cells was then investigated.     

The redox couple avarol/avarone in the fight with malignant gliomas: the case study of U-251 MG cells

This study aimed to screen in vitro antitumour activity of the redox couple avarol/avarone against the human malignant glioma cell line U-251 MG for the first time. Compared both with avarol and positive controls used (temozolomide and doxorubicin), avarone was found to be the most active compound with IC₅₀ value below 1 μM (IC₅₀ 0.68 ± 0.04 μM, 96 h). Considerable less DNA damage in the cells treated with avarol and avarone vs. doxorubicin (105 & 123% vs. 299%, respectively; untreated U-251 MG cells were used as a control, 100%), coupled with no sign of cytotoxicity against the normal human foetal lung fibroblast MRC-5 cells (IC₅₀ > 100 μM), has actually pointed out the importance of this marine sesquiterpenoid quinone structure as a promising lead compound in development of novel brain chemotherapeutics.