A thiazolidine-2,4-dione nucleus was molecularly hybridised with the effective antitumor moieties; 2-oxo-1,2-dihydroquinoline and 2-oxoindoline to obtain new hybrids with potential activity against VEGFR-2. The cytotoxic effects of the synthesised derivatives against Caco-2, HepG-2, and MDA-MB-231 cell lines were investigated. Compound
12a
was found to be the most potent candidate against the investigated cell lines with IC
50
values of 2, 10, and 40 µM, respectively. Furthermore, the synthesised derivatives were tested
in vitro
for their VEGFR-2 inhibitory activity showing strong inhibition. Moreover, an
in vitro
viability study against Vero non-cancerous cell line was investigated and the results reflected a high safety profile of all tested compounds. Compound
12a
was further investigated for its apoptotic behaviour by assessing the gene expression of four genes (Bcl2, Bcl-xl, TGF, and Survivin). Molecular dynamic simulations authenticated the high affinity, accurate binding, and perfect dynamics of compound
12a
against VEGFR-2.
New quinoline and isatin derivatives having the main characteristics of VEGFR-2 inhibitors was synthesised. The antiproliferative effects of these compounds were estimated against A549, Caco-2, HepG2, and MDA-MB-231. Compounds
13
and
14
showed comparable activities with doxorubicin against the Caco-2 cells. These compounds strongly inhibited VEGFR-2 kinase activity. The cytotoxic activities were evaluated against Vero cells. Compound
7
showed the highest value of safety and selectivity. Cell migration assay displayed the ability of compound
7
to prevent healing and migration abilities in the cancer cells. Furthermore, compound
7
induced apoptosis in Caco-2 through the expressive down-regulation of the apoptotic genes, Bcl2, Bcl-xl, and Survivin, and the upregulation of the TGF gene. Molecular docking against VEGFR-2 emerged the interactions of the synthesised compounds in a similar way to sorafenib. Additionally, seven molecular dynamics simulations studies were applied and confirmed the stability of compound
13
in the active pocket of VEGFR-2 over 100 ns.
. Pedigree and mating system analyses in a western larch (Larix occidentalis Nutt.) experimental population. Annals of Forest Science, Springer Verlag/EDP Sciences, 2008, 65 (7), pp.1. Ann. For. Sci. 65 (2008)
Abstract•The mating pattern and gene flow in a western larch (Larix occidentalis Nutt.) experimental population was studied with the aid of microsatellite markers and a combination of paternity-mating system analysis. The commonly difficult to assess, male gametic contribution was determined with 95% confidence and its impact on genetic gain and diversity was determined.• Male fertility success rate ranged between 0 and 11%. Male reproductive output parental imbalance was observed with 50% of the pollen being produced by the top 5% of males while the lower 39% males only produced 10% of the pollen.• A significant difference was observed between male effective population size (genetic diversity) estimates from paternity assignment compared to those based on population's census number (21 vs. 41); however, this difference did not affect estimates of genetic gain.• A total of 221 full-fib families were identified (sample size range: 1-8) and were nested among the studied 14 seed-donors.• A combination of paternity-mating system analysis is recommended to provide a better insight into seed orchards' mating dynamics. While pollen flow tends to inflate mating system's outcrossing rate, the paternity analysis effectively determined the rate and magnitude of contamination across receptive females. • Le taux de succès reproductif mâle était compris entre 0 et 11 %. Un déséquilibre dans la contribution des parents mâles a été observé avec la production de 50 % du pollen par 5 % des pères alors que 39 % d'entre eux ne contribuaient que pour seulement 10 % du pollen.
Mots-clés• Une différence significative a été observée entre la taille efficace de la population mâle (diversité génétique) estimée par la recherche de paternité et celle basée sur les effectifs recensés de la population (21 vs. 41) ; cependant, cette différence n'affecte pas l'estimation du gain génétique.• 221 familles de plein-frères ont été identifiées (effectifs entre 1 et 8), regroupées parmi les 14 arbresmères étudiés.• La combinaison d'une analyse de paternité et du système de reproduction est recommandée pour étudier de manière approfondie la dynamique de croisement en vergers à graines. Tandis que les flux de pollen tendent à augmenter le taux d'inter-croisements, l'analyse de paternité détermine de manière effective le taux et l'amplitude de contamination des arbres-mères.
We report herein, the design and synthesis of thiazolidine-2,4-diones derivatives as new inhibitors for VEGFR-2. The designed members were assessed for their in vitro anticancer activity against four cancer cell lines; A549, Caco-2, HepG-2 and MDA-MB-231. Compound 14a showed the most potent effects against Caco-2, and HepG-2 cell lines (IC50 = of 1.5 and 31.5 μM, respectively). Next, the in vitro VEGFR-2 inhibitory activity, safety profiles and selectivity indices were examined for all the synthesized members against the normal Vero cell line. Compound 14a (the safest member against Caco-2 cell line) was further investigated for its ability to inhibit Caco-2 cells migration and healing. Moreover, the apoptotic induction of compound 14a against Caco-2 cell line was investigated by assessing against four apoptotic genes (Bcl2, Bcl-xl, TGF, and Survivin). The results revealed that compound 14a can exert apoptosis through significant reduction of Bcl2, Survivin, and TGF gene expression levels. Finally, deep computational studies including molecular docking, ADMET, toxicity studies, and MD simulation were carried out. Also, the DFT calculations were performed and discussed, and the results confirmed the inhibitory reactivity of 14a against VEGFR-2. Compound 14a is expected to be used as a potential lead in the development of new VEGFR-2 inhibitors with increased potency.
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