High in vitro and in vivo antitumor activities of Ln(III) complexes with mixed 5,7-dichloro-2-methyl-8-quinolinol and 4,4'-dimethyl-2,2'-bipyridyl chelating ligands.

Three novel Ln(III) complexes, namely, [Pm(dmbpy)(ClQ)2NO3] (1), [Yb(dmbpy)(ClQ)2NO3] (2), and [Lu(dmbpy)(ClQ)2NO3] (3), with mixed 5,7-dichloro-2-methyl-8-quinolinol (H-ClQ) and 4,4'-dimethyl-2,2'-bipyridyl (dmbpy) chelating ligands were first synthesized. The cytotoxic activity of Ln(III) complexes 1-3, H-ClQ, and dmbpy against a panel of human normal and cancer cell lines, namely, human non-small cell lung cancer cells (NCI-H460), human cervical adenocarcinoma cancer cells, human ovarian cancer cells, and human normal hepatocyte cells, were evaluated by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The three novel Ln(III) complexes showed a high in vitro antitumor activity toward the NCI-H460 with IC50 of 1.00 ±â€¯0.25 nM for 1, 5.13 ±â€¯0.44 µM for 2, and 11.87 ±â€¯0.79 µM for 3, respectively. In addition, Ln(III) complexes 1 and 2 exerted their in vitro antitumor activity/mechanism mainly via the mitochondrial death pathway and caused a G2/M phase arrest in the following order: 1 > 2. An NCI-H460 tumor xenograft mouse model was used to evaluate the Pm(III) complex 1in vivo antitumor activity. Pm(III) complex 1 showed a high in vivo antitumor activity, and the tumor growth inhibition rate (IR) was 56.0% (p < 0.05). In summary, our study on Pm(III) complex 1 revealed promising results in in vitro and in vivo antitumor activity assays.

A comparative study of novel spectrophotometric resolution techniques applied for pharmaceutical mixtures with partially or severely overlapped spectra.

Simultaneous determination of mixtures of lidocaine hydrochloride (LH), flucortolone pivalate (FCP), in presence of chlorquinaldol (CQ) without prior separation steps was applied using either successive or progressive resolution techniques. According to the concentration of CQ the extent of overlapping changed so it can be eliminated from the mixture to get the binary mixture of LH and FCP using ratio subtraction method for partially overlapped spectra or constant value via amplitude difference followed by ratio subtraction or constant center followed by spectrum subtraction spectrum subtraction for severely overlapped spectra. Successive ratio subtraction was coupled with extended ratio subtraction, constant multiplication, derivative subtraction coupled constant multiplication, and spectrum subtraction can be applied for the analysis of partially overlapped spectra. On the other hand severely overlapped spectra can be analyzed by constant center and the novel methods namely differential dual wavelength (D(1) DWL) for CQ, ratio difference and differential derivative ratio (D(1) DR) for FCP, while LH was determined by applying constant value via amplitude difference followed by successive ratio subtraction, and successive derivative subtraction. The spectra of the cited drugs can be resolved and their concentrations are determined progressively from the same ratio spectrum using amplitude modulation method. The specificity of the developed methods was investigated by analyzing laboratory prepared mixtures and were successfully applied for the analysis of pharmaceutical formulations containing the cited drugs with no interference from additives. The proposed methods were validated according to the ICH guidelines. The obtained results were statistically compared with those of the official or reported methods; using student t-test, F-test, and one way ANOVA, showing no significant difference with respect to accuracy and precision.

Effects of highly active novel artemisinin-chloroquinoline hybrid compounds on ß-hematin formation, parasite morphology and endocytosis in Plasmodium falciparum.

4-Aminoquinolines were hybridized with artemisinin and 1,4-naphthoquinone derivatives via the Ugi-four-component condensation reaction, and their biological activities investigated. The artemisinin-containing compounds 6a-c and its salt 6c-citrate were the most active target compounds in the antiplasmodial assays. However, despite the potent in vitro activities, they also displayed cytotoxicity against a mammalian cell-line, and had lower therapeutic indices than chloroquine. Morphological changes in parasites treated with these artemisinin-containing hybrid compounds were similar to those observed after addition of artemisinin. These hybrid compounds appeared to share mechanism(s) of action with both chloroquine and artemisinin: they exhibited potent ß-hematin inhibitory activities; they caused an increase in accumulation of hemoglobin within the parasites that was intermediate between the increase observed with artesunate and chloroquine; and they also appeared to inhibit endocytosis as suggested by the decrease in the number of transport vesicles in the parasites. No cross-resistance with chloroquine was observed for these hybrid compounds, despite the fact that they contained the chloroquinoline moiety. The hybridization strategy therefore appeared to be borrowing the best from both classes of antimalarials.