C4-substituted isoquinolines: synthesis and cytotoxic action.

A facile synthesis of the C4-substituted isoquinolines 5a-c and 6a-c is described. Commercially available 4-bromoisoquinoline is converted to the alpha,beta-unsaturated esters 8 and 10 on treatment with the appropriate acrylate ester under Heck reaction conditions. The saturated amides 5a-c were obtained from the reaction of ester 9 with the requisite primary amine. Similarly the unsaturated analogues 6a-c were prepared by reacting ester 10 with the appropriate amine. The cytotoxicity of the target molecules was evaluated in two tumour cell lines in vitro. Two compounds, 6b and 6c, showed sufficient activity in the human non-small cell lung cancer line NSCLC-N16-L16 to be worthy of further study.

Synthesis of 7 alpha- and 7 beta-spermidinylcholesterol, squalamine analogues.

Stereoselective synthesis of squalamine dessulfates analogues, 7 alpha and 7 beta-N-[3N-(4-aminobutyl) aminopropyl]aminocholesterol are reported, using 7 alpha and 7 beta-aminocholesterol as a key intermediate. It's the first example in which the position of spermidine is modified at the steroid ring. These molecules showed a comparable antibacteria and fungi activities to squalamine. Then, they have a cytotoxic activity on a human non-small cell bronchopulmonary carcinoma line (NSCLC-N6).

Synthesis and cytotoxic activity against a non-small-cell bronchopulmonary carcinoma line (NSCLC-N6) of benzofuran enantiomeric derivatives.

The synthesis of 2-isopropenyl-2,3-dihydrobenzofuranic enantioisomers is described. Ortho-(2-hydroxy-3-methyl-but-3-enyl)phenol synthons are used as precursors to these structures. In vitro antitumor activity against a non-small-cell bronchopulmonary carcinoma line (NSCLC-N6) of these enantioisomers has been investigated.

Effect of four genes (ALDH1, NRF1, JAM and KBL) on proliferation arrest in a non-small cell bronchopulmonary cancer line.

Despite new protocols, non-small cell bronchopulmonary cancers are still difficult to treat by current chemotherapeutic procedures. Thus, it is essential to define new treatment strategies and detect new therapeutic targets. In order to define these new targets, this study applied the "differential display" (DD) technique to the NSCLC-N6 cell line treated with VT1 [methyl-4-methoxy-3-(3-methyl-2-butanoyl)benzoate]. VT1 induces arrest of the NSCLC-N6 cell cycle in the G1-phase, followed by cell death. DD enabled us to detect seven overexpressed mRNAs during treatment, four of which corresponded to identified genes: aldehyde dehydrogenase 1, nuclear transcription factor Nrfl, junctional adhesion molecule, and amino-ketobutyrate ligase. An antisense strategy showed that amino-ketobutyrate ligase is involved in the proliferation arrest of NSCLC-N6 cells in the G1-phase after VT1 treatment.

Up-regulation of a novel mRNA (NY-CO-1) involved in the methyl 4-methoxy-3-(3-methyl-2-butenoyl) benzoate (VT1)-induced proliferation arrest of a non-small-cell lung carcinoma cell line (NSCLC-N6).

It is now well known that treatment of tumors, especially non-small-cell lung cancer (NSCLC), remains limited and it is urgent to develop strategies that target tumor cells and their genetic features. In this regard, our work is about genetic modifications arising in an in vitro NSCLC cell line after treatment with a chemical substance, methyl 4-methoxy-3-(3-methyl-2-butenoyl) benzoate (VT1). First, we showed that VT1 induces arrest of proliferation by blocking cells in the G1 phase of the cell cycle. Second, we use "differential display" strategy to clarify the genetic mechanisms involved in this proliferation arrest. A novel mRNA, NY-CO-1 (New-York Colon 1), of unknown function showed up-regulated expression after treatment. Application of "antisense" strategy confirmed this novel mRNA induction was effectively linked to growth arrest. Therefore, these data provide new information about mechanisms participating in arrest of proliferation of tumor cells and open new ways of treatment to target tumor growth.

Effects of temperature on polyunsaturation in cytostatic lipids of Haslea ostrearia.

Unusual chemicals produced by the-'blue oyster' diatom, Haslea ostrearia, include the water-soluble blue pigment marennine and numerous polyunsaturated sesterterpene oils or haslenes. Aqueous extracts of the alga exhibit in vitro and in vivo activities against human lung cancer cells and anti-HIV effects. Here we report that three haslenes also demonstrate in vitro cytostatic action against a human lung cancer cell line. The most active haslene is the most unsaturated and unsaturation in the haslenes increases with increasing algal growth temperature.

Effects of triterpenes from the stem bark of Dysoxylum cauliflorum on a non-small-cell bronchopulmonary carcinoma cell line (NSCLC-N6).

Six triterpenoids and one sesquiterpene were isolated from the ethanolic extract of the stem bark of Dysoxylum cauliflorum. Their structures were determined from 1D and 2D NMR and mass spectral data. Only compound 1 was cytostatic. Kinetic studies with ethyl eichlerianoate 1 demonstrated that this growth arrest was irreversible and cytofluorimetric analysis with compound 1 showed a complete block of NSCLC-N6 cells in the G1 phase. These events were related to a terminal maturation induction.

Antiproliferative effects of a product isolated from the gorgonian Rumphella aggregata.

A fraction isolated from the gorgonian Rumphella aggregata (Plexauridae) was studied vitro on asynchronous cells of a human non-small-cell-bronchopulmonary-carcinoma line (NSCLC-N6). Cell growth appeared to be inhibited in the Gl phase of the cell cycle, and kinetic studies in pretreated cells showed that this growth arrest was irreversible. These events seem to show a terminal maturation induced by this new product.

Cytotoxicity against human leukemic cell lines, and the activity on the expression of resistance genes of flavonoids from Platanus orientalis.

The cytotoxic activity of three flavonoids, belonging to the kaempherol series, was evaluated against 15 human leukemic cell lines. Flavonoids bearing acyl substituants, 2 and 3, were found to be the most active compounds. A further compound, 1, was examined for its ability to modulate the expression of MDR-1 and GST-pi resistance genes and compounds 2 and 3 for their effect on the uptake of [3H]-thymidine as a marker of DNA synthesis.

Antibacterial and cytotoxic natural and synthesized hydroquinones from sponge Ircinia spinosula.

In order to check the structure-activity relationship and find more potent derivatives of the natural products 1 and 2 obtained from sponge Ircinia spinosula, a series of oxidation, hydrogenation, acetylation and methylation derivatives was prepared. All compounds (natural and synthetic ones) were screened for their cytotoxic and antibacterial activities. The biological studies showed a wide range of antibacterial activity even though only 2 and 2d showed a moderate cytotoxicity against the clone C98. The oxidation of the hydroquinone to quinone and the hydrogenation of the side-chain increased the antibacterial effect of the molecules.

Synthesis and cytotoxicity of aminosterols: activity studies on a non-small-cell bronchopulmonary carcinoma line (NSCLC-N6).

Various new aminosterols were synthesized. The antiproliferative activity of these compounds (I-IV) was studied in vitro on a continuous human non small-cell bronchopulmonary carcinoma line (NSCLC-N6) at the cell cycle level. The histograms indicate cell blockage in Phase Gl (compound I-III) associated with a reduction in the number of cells phases S and G2M and appearance of cellular debris derived from cells in Phase G1.

Antitumor and antiproliferative effects of an aqueous extract from the marine diatom Haslea ostrearia (Simonsen) against solid tumors: lung carcinoma (NSCLC-N6), kidney carcinoma (E39) and melanoma (M96) cell lines.

An aqueous extract of the marine diatom Haslea ostrearia (Simonsen) was studied for its antiproliferative properties against human solid tumors: lung carcinoma (NSCLC-N6), kidney carcinoma (E39) and melanoma (M96). These types of carcinoma are particularly chemoresistant. The extract has a potent cytostatic effect in vitro on the three cell lines and blocks the NSCLC-N6 line in the G1/S phase of the cell cycle. Moreover, the extract strongly inhibits tumor growth of NSCLC-N6 bearing nude mice. These preliminary results indicate that the aqueous extract of Haslea ostrearia exhibits inhibitory effects both in vitro and in vivo against solid carcinoma lines, suggesting the presence of a new potent antitumor agent in the aqueous algal homogenate.

New jaspamide derivatives from the marine sponge Jaspis splendans collected in Vanuatu.

Two new jaspamide derivatives (1 and 2) along with jaspamide have been isolated from the marine sponge Jaspis splendans collected in Vanuatu. Their chemical structures were determined from 1D and 2D NMR studies and MS data. These two compounds inhibited the in vitro growth of the NSCLC-N6 human tumor cell lines with IC50 values in the microg/mL range.

Subtractive hybridization and differential screening identified two genes differentially expressed after induction of in vitro (atypical) terminal differentiation in the NSCLC-N6 cell line by a marine substance (bistramide K).

Non-small-cell lung carcinoma is generally refractory to chemotherapy. The difficulties that arise in the treatment of this type of tumor make it necessary to develop new therapeutic strategies. Previous work done in our laboratory showed that a marine substance named bistramide K induced in vitro (atypical) terminal differentiation of NSCLC-N6 cell line. This activity is linked to a growth arrest of NSCLC-N6 cell line and an irreversible block at the G1 phase of the cell cycle (G1DT). In order to identify the genes that could be expressed after the treatment by the drug, we constructed a subtractive cDNA library with enriched mRNA extracted from BK-treated NSCLC-N6. After differential hybridization and DNA sequencing, we identified two sequences. The sequence identified for the clone 8 showed strong homology to the sequence of the ribosomal protein L35A. The sequence identified for the clone 4 did not show any homology with known sequences in official gene data banks.

Starfish saponins. 55. Isolation, structure elucidation, and biological activity of the steroid oligoglycosides from an Antarctic starfish of the family Asteriidae.

This paper reports an analysis of the chemical constituents from an Antarctic starfish of the family Asteriidae. Different steroid glycoside types are represented among its constituents, including the five hexaglycoside steroidal sulfates ("asterosaponins") asteriidosides A-E (1-5), differing in their oligosaccharide chain, and the two nonsulfated diglycosides asteriidoside F (6) and G (7), in which 6 is the 26-methyl analogue of 7. Also present are the two sulfated diglycosides asteriidoside H (8) and I (9) and one sulfated monoglycoside asteriidoside L (10). Eight of the compounds were tested against human nonsmall-cell lung carcinoma cells (NSCLC-L16) and found to be moderately cytotoxic.

Synthesis and in vitro cytotoxicity of lipidic alcohols and amines.

General methods for the conversion of unsaturated fatty acids into alcohols and amines and the preparation of lipidic 1,2-diamines were developed. The in vitro cytotoxicity of the synthetic lipidic compounds was tested against two different cell lines (P388 and NSCLCN6). Oleyl amine was the most active among the lipidic alcohols and monoamines. However, the saturated lipidic 1,2-hexadecanediamine exhibited the highest cytotoxicity (IC50 0.1 microgram/ml and 1.1 micrograms/ml).

Cloning of a human cancer cell line (NSCLC-N6) and comparative study of the clones in vitro.

Non-small-cell lung carcinoma (NSCLC) is a particularly serious disease because of its chemoresistance to current treatments. To investigate the nature of his generally innate resistance, we cloned an established cell line (NSCLC-N6) derived from a non-small cell bronchopulmonary carcinoma. Four cell subpopulations (C15, C65, C92 and C98) were isolated from the mother line. These four clones were studied in comparison with each other for cell doubling time in vitro, ploidy, chemosensitivity in vitro, cytogenetic, expression of the oncogene erb-B2 and other tumor markers (Kr, CEA and Chr A). Each clone shows a distinct biologic pattern for various biological parameters. Our results indicated hat cell doubling time (in vitro) increased when the hyperploid population was prevailing. The clones differ in their chemosensitivity to therapeutic agents. This cellular diversity might help to explain why these tumors are chemoresistant. This heterogeneity within NSCLC tumors should be taken into consideration in the choice of treatment.

Cytotoxic coumarins from the aerial parts of Tordylium apulum and their effects on a non-small-cell bronchial carcinoma line.

Seven coumarins were isolated from the aerial parts of Tordylium apulum; their structures were established by spectroscopic means. All compounds were tested in vitro for their cytotoxicity against two cell line systems. The antiproliferative effects for three of them were studied at the level of the cell cycle in asynchronous cells of the NSCLC-N6 line with a flow cytometry apparatus.

Synthesis and in vitro cytotoxicity of lipophilic platinum(II) complexes.

A number of lipophilic platinum(II) complexes of the general structures cis-[Pt(LA)2Cl2] and [Pt(LD)Cl2] were synthesised. Long chain amines (LA) and diamines (LD), prepared from lipidic amino acids, were used as ligands. The in vitro cytotoxicity of the complexes was evaluated against four cell lines (P388, NSCLC-N6, E39, M96). cis-Dichloro-bis(2-aminohexadecanol)platinum(II) was the most active against P388, NSCLC-N6 and E39 (IC50: 11 micrograms/ml, 25 micrograms/ml, 31 micrograms/ml), while dichloro(1,3-heptadecanediamine)platinum(II) presented the highest activity against M96 (IC50: 13 micrograms/ml).