Novel Pyrimidine-5-Carbonitriles as potential apoptotic and antiproliferative agents by dual inhibition of EGFRWT/T790M and PI3k enzymes; Design, Synthesis, biological Evaluation, and docking studies.

A new series of 6-(4-fluorophenyl)-2-(methylthio) pyrimidine-5-carbonitrile derivatives were designed and synthesized as EGFR/PI3K dual inhibitors, and potential antiproliferative agents. The new 22 compounds were screened by DTP-NCI against all NCI60 cell lines. Almost all compounds showed cytotoxic activity. Compound 7c showed a promising antitumour activity on CNS cancer (SNB-75), and ovarian cancer (OVAR-4) with IC50 < 0.01, and 0.64 µM, respectively. Fortunately, 7c exhibited a better safety profile on normal cells (WI-38) than doxorubicin by 2.2-fold. Compound 7c displayed selective inhibitory activity on EGFRt790m over EGFRWT with IC50 = 0.08, and 0.13 µM, respectively, wherefore it might overcome EGFR-TKIs resistance. In addition to its remarkable inhibitory activity on all PI3K isoforms, specifically PI3K-δ with IC50 = 0.64 µM Compared with LY294002 IC50 = 7.6 µM. Compound 7c arrested the cell cycle of SNB-75 & OVAR-4 at the G0-G1 phase coupled with apoptosis induction. The western blotting analysis approved decreasing the expression level of p-AKT coupled with an increase in Casp3, Casp9, and BAX proteins in the SNB-75 & OVAR-4 after being treated with 7c which may support the suggested mechanism of action of 7c as EGFR/PI3K dual inhibitor. Physicochemical parameters were forecasted using SwissADME online tool. MD showed the interaction of 7c with the crucial amino acids of the active domain of both EGFR/PI3K which may explain its potent inhibitory activities. In vivo study disclosed a significant decrease in tumor weight and the number of nodules in the group of mice treated with 7c compared with the control group.

Design, synthesis, and biological evaluation of new pyrimidine-5-carbonitrile derivatives as novel anti-cancer, dual EGFRWT/COX-2 inhibitors with docking studies.

A novel series of pyrimidine-5-carbonitrile derivatives was designed, synthesized, then evaluated for their cytotoxic activity as novel anti-cancer with dual EGFRWT/COX-2 inhibitors. Two compounds 4e and 4f disclosed the highest activity against all NCI60 panel cell lines. They were most potent against Colo 205 (IC50 = 1.66, and 1.83 µM), Sequentially. The most potent two compounds disturbed cell cycle of Colo-205 cells by blocking the G1 phase, coupled with increased annexin-Vstained cells which indicated the increasing in percentage of apoptosis. In addition, 4e and 4f increase the concentration of caspase-3 by 10, and 8-fold compared to control, respectively. Moreover, the two candidate compounds were screened for cytotoxicity on normal epithelial colon cells; fortunately, they were found to be safe. Molecular docking study displayed that these compounds bound to the active site as EGFRWT/COX-2 inhibitors. Furthermore, 3D pharmacophore mapping disclosed many shared features between the most potent candidates 4e and 4f and the standard EGFRWT/COX-2 inhibitors; erlotinib, and celecoxib, respectively. Finally, the physicochemical parameter was calculated for the most potent novel anticancer candidates and the SwissAdme parameter showed that the newly synthesized compounds have good drug-likeness properties.

Inhibition of aldehyde dehydrogenase-1 and p-glycoprotein-mediated multidrug resistance by curcumin and vitamin D3 increases sensitivity to paclitaxel in breast cancer.

Treatment of breast cancer by paclitaxel (PAX) often encounters therapeutic failure most likely caused by innate/acquired resistance. Cancer stem cells (CSCs) and multidrug resistance complex (MDR-1 or P-glycoprotein) overexpression are main mechanisms implicated in chemoresistance. Increased aldehyde dehrogenase-1 (ALDH-1) was previously correlated with the stemness features of CSCs and hence is used as a marker for identification and CSCs targeting. The present study, therefore, aimed at investigating the effect of both curcumin (CUR) and vitamin D3 (D3) on MDR-1 and ALDH-1 expression and consequently the resistance to PAX both in vitro and in vivo. CUR was isolated from Turmeric rhizomes and identified using UPLC-ESI-MS/MS. For in vitro studies, the antiproliferative effect of PAX, CUR, 1,25(OH)2D3 (the active form of D3, also known as calcitriol) was determined, each alone and combined (PAX+CUR, PAX+1,25(OH)2D3, and PAX+CUR+1,25(OH)2D3) on MCF-7 breast cancer cells. Ehrlich ascites carcinoma solid tumor animal model was also used for in vivo studies. Combining CUR and/or 1,25(OH)2D3 to PAX showed synergistic cytotoxic interaction on MCF-7 cells. The apoptotic potential was also enhanced, as evidenced by a significant increase in caspase-7 and -9 as well as the pro-apoptotic Bax whereas a decrease in Bcl-2 levels was reported. Combining CUR and 1,25(OH)2D3 to PAX caused a downregulation in both MDR-1 and ALDH-1 gene expression in MCF-7 besides a decrease in their protein levels. In vivo, the triple therapy group (PAX+CUR+D3) showed the least tumor size. It also showed the lowest levels of MDR-1 and ALDH-1. PAX alone, however, showed increased levels of MDR-1 and ALDH-1 compared to control. Overall, the present study showed that PAX, as a monotherapy, demonstrated acquired resistance possibly by increasing MDR-1 expression and enriching CSCs population, as evidenced by increased ALDH-1. However, using CUR and D3 enhanced tumor response to PAX.