Quinazolin-4(3H)-one based agents bearing thiadiazole-urea: Synthesis and evaluation of anti-proliferative and antiangiogenic activity.

A series of quinazolin-4(3H)-one based agents containing thiadiazole-urea were designed, synthesized, and biologically evaluated. The proliferation rate of PC3 cells was moderately reduced by compound 9f (IC50 = 17.7 µM)which was comparable with sorafenib (IC50 = 17.3 µM). There was also a significant reduction in the number of HUVEC cells, when they were exposed to compound 9y (IC50 = 6.1 µM). To test the potential of compounds in inducing apoptosis, Annexin V-FITC/propidium iodide double staining assay was used. After the treatment of HUVEC cells with 9f, they underwent apoptotic effects. A substantial effort was dedicated to gathering comprehensive data across CAM assay. These data showed that 9f moderately inhibits the growth of corresponding blood vessels. Finally, the outcomes of Western blotting proposed a mechanism of action, by which the phosphorylation of VEGFR-2 is inhibited by compounds 9f and 9y.

Comparison of QSAR models based on combinations of genetic algorithm, stepwise multiple linear regression, and artificial neural network methods to predict Kd of some derivatives of aromatic sulfonamides as carbonic anhydrase II inhibitors.

Four stepwise multiple linear regressions (SMLR) and a genetic algorithm (GA) based multiple linear regressions (MLR), together with artificial neural network (ANN) models, were applied for quantitative structure-activity relationship (QSAR) modeling of dissociation constants (Kd) of 62 arylsulfonamide (ArSA) derivatives as human carbonic anhydrase II (HCA II) inhibitors. The best subsets of molecular descriptors were selected by SMLR and GA-MLR methods. These selected variables were used to generate MLR and ANN models. The predictability power of models was examined by an external test set and cross validation. In addition, some tests were done to examine other aspects of the models. The results show that for certain purposes GA-MLR is better than SMLR and for others, ANN overcomes MLR models.

Design, synthesis and evaluation of novel thienopyrimidine-based agents bearing diaryl urea functionality as potential inhibitors of angiogenesis.

Inhibition of angiogenesis is a promising strategy for the treatment of cancer. Herein, we describe the design and synthesis of thieno[2,3-d]pyrimidine-1,3,4-thiadiazole-aryl urea derivatives 11a-m to evaluate their efficacy in the chick chorioallantoic membrane (CAM) assay. Among target agents, 11i had a considerable activity against prostate cancer cell line, PC3 (IC50 = 3.6 µM). Moreover, induction of apoptosis, good inhibitory activity against the growth of capillary blood vessels, and inhibition of VEGFR-2 phosphorylation were noticeable parameters which convinced us that 11i could be considered as a promising candidate for the discovery of novel drugs to treat tumors, particularly prostate cancer.