3-Aryl-2-quinolone derivatives: synthesis and characterization of in vitro and in vivo antitumor effects with emphasis on a new therapeutical target connected with cell migration.

Among 25 3-aryl-2-quinolone derivatives synthesized, the antitumor activity of some of them was characterized both in vitro and in vivo. In this series, no compound appeared to be cytotoxic in vitro, as was known by the colorimetric MTT assay carried out on 12 distinct human cancer cell lines obtained from the American Type Culture Collection. Indeed, the concentration values decreasing the growth of the 12 cell lines by at least 50% (IC(50) index) were always higher than 10(-5) M. We then made use of a computer-assisted phase-contrast videomicroscopy system to quantitatively determine in vitro the level of migration of living MCF-7 human breast cancer cells. For example, at 10(-7) M, compounds 7, 13, 16, and 28 markedly decreased the migration level of these MCF-7 human breast cancer cells. The in vivo determination of the maximum tolerated dose showed that all compounds tested were definitively nontoxic. When the nontoxic, antimigratory compound 16 was combined with either doxorubicin or etoposide, two cytotoxic compounds routinely used in the clinic, this led to additive in vivo benefits from this treatment (as compared to individual administrations of the drugs) when the MXT mouse mammary adenocarcinoma was used. Thus, nontoxic antimigratory compounds, including the 2-quinolone derivatives synthesized here, can actually improve the efficiency of antitumor treatment when combined with conventional cytotoxic agents.

Synthesis and in vitro antitumor activity of phenanthrolin-7-one derivatives, analogues of the marine pyridoacridine alkaloids ascididemin and meridine: structure-activity relationship.

A series of substituted pyrido[4,3,2-de][1,7] or [1,10]-phenanthrolin-7-ones, analogues of the marine pyridoacridines meridine and ascididemin, have been synthesized on the basis of Diels-Alder reactions involving different quinoline-5,8-diones and N,N-aldehyde-dimethylhydrazones. All the compounds were evaluated for in vitro cytotoxic activity against 12 distinct human cancer cell lines. They all exhibit cytotoxic activity with IC(50) values at least of micromolar order.

Synthesis and in vitro antitumor activity of novel ring D analogues of the marine pyridoacridine ascididemin: structure-activity relationship.

Marine compounds with pyridoacridine skeletons are known to exhibit interesting antitumor activities. Ascididemin has already been reported as displaying significant antitumor activities in vitro and has also been found to have a relatively high global toxicity in vivo. We synthesized a series of 16 analogues (among which 11 compounds were different from previously described ones) with the aim of developing new anticancer agents with significantly improved efficacy/tolerability ratios. These compounds were obtained either by total synthesis from 5,8-quinolinedione and substituted 2-aminoacetophenones or by the direct substitution of ascididemin. The different compounds and ascididemin used as the control compound were tested at six different concentrations on 12 different human cancer cell lines of various histopathological types (glioblastomas and breast, colon, lung, prostate, and bladder cancers). The IC(50) value (i.e., the drug concentration inhibiting the mean growth value of the 12 cell lines by 50%) of these compounds ranged over five log concentrations, i.e., between 10 000 and 0.1 nM. For several new chemical entities, the antitumor activity (determined in vitro) and tolerability (determined in vivo) were superior to those of the parent alkaloids, i.e., ascididemin and 2-bromoleptoclinidone.

Synthesis and in vitro antitumor activity of ring C and D-substituted phenanthrolin-7-one derivatives, analogues of the marine pyridoacridine alkaloids ascididemin and meridine.

A series of cycle C and D-substituted phenanthrolin-7-ones, analogues of the marine pyridoacridines meridine and ascididemin have been synthesized on the basis of Diels-Alder reactions involving quinoline-5,8-dione and 2- (or un)-substituted-N,N-dimethylhydrazones. All the compounds were evaluated for in vitro cytotoxic activity against 12 distinct human cancer cell lines. They all exhibit cytotoxic activity with IC(50) values at least of micromolar order.