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[Display omitted] • Novel uracil derivatives synthesized as potential anticancer agents. • Compounds 5, 11, and 15 showed potent activity against HepG-2, HCT-116, and MCF-7 cell lines. • Compound 15 induced apoptosis by modulating Bax, BCL-2, PI3K, and STAT1 proteins. • Molecular docking and dynamics confirmed stable binding to thymidylate synthase. • Uracil derivative 15 is a promising candidate for cancer therapy development. An efficient synthesis of a series of uracil analogous was performed to obtain new potential anticancer agents. The cytotoxic effect of the synthesized derivatives was assessed in vitro against three cancer cell lines, namely hepatic cancer (HepG-2), colon cancer (HCT-116), and breast cancer (MCF-7). Among the tested compounds, 5 , 11 and 15 stood as potent uracil derivatives with pan cytotoxicity against the 3 cell lines out-performing the reference compound 5-FU. Furthermore, selected compounds underwent thymidylate synthase (TS) enzyme inhibition assay and demonstrated effective inhibition of the enzyme's catalytic activity. Thereafter, flow cytometric apoptosis and protein expression of pro- and anti-apoptotic markers Bax, BCL-2, PI3K, and STAT1 proteins assays were performed employing the most active compound on the respective most responsive cell line and compounds demonstrated effectiveness in inducing apoptosis in the treated cell lines. Finally, in silico studies encompassing molecular docking and molecular dynamics studies were also conducted to predict the interaction mechanisms and stability of the active compounds within the active site of their biological target TS. [ABSTRACT FROM AUTHOR]

• Design and synthesis of new 3-cyano-6-naphthylpyridine scaffold-based selective VEGFR-2 cytotoxic agents. • Sub-micromolar IC 50 values against VEGFR-2. • Nanomolar in vitro cytotoxicity against PC3, DU145, MCF-7, MDA-MB435 and BT549. • Potent anticancer effect in in vivo xenograft animal models. • Apoptosis and G1 phase cell cycle arrest of 11b treated breast cancer cells. • Promising ADME and drug-like profiles. VEGFR-2 is a key regulator in cancer angiogenesis. This research displays the design and synthesis of novel 3-cyano-6-naphthylpyridine scaffold-based derivatives as selective VEGFR-2 inhibitors and cytotoxic agents. In vitro percent kinase activity inhibition screening against a panel of 23 kinases at a single high dose (30 nM) affirmed that VEGFR-2 was selectively the most responsive to inhibition by the investigated chemotypes. IC 50 values determination demonstrated kinase inhibitory activities of the test compounds at the sub-nanomolar level. In vitro testing of the new compounds against two prostate cancer cell lines namely PC3 and DU145 and two breast cancer cell lines namely MCF-7 and MDA-MB435 confirmed their potent cytotoxic activity with IC 50 s at the nanomolar level. The most active compound against MCF-7 viz. 11d was subjected to an in vivo examination against a xenograft mouse model and was found effective. Studying the tissue mRNA expression levels of various cell cycle controlling biomolecules in 11d -treated MCF-7 cells demonstrated (i) upregulation of p53, p21 and p27, (ii) cleavage of PARP protein, (iii) activation of caspase-3, −8 and −9, (iv) downregulation of the anti-apoptotic protein Bcl, (v) upregulation of the pro-apoptotic protein Bax, and (vi) decreased expression of Cdks 2, 4, 6 and cyclin D1. Additionally, 11d affected a cell cycle arrest at the G1 phase in treated MCF-7 cells and an S phase arrest in MCF-7 p53 knockdown cells. Additionally, molecular docking was performed to predict how 11d might bind to its biological target VEGFR-2. Finally, in-silico ADME and drug-likeness profiling of these derivatives demonstrated favorable properties thereof. [ABSTRACT FROM AUTHOR]

• New thiazolidinone, thiazinone and dithiazepinone-benzenesulfonamides as cytotoxic agents. • Effect of 5a-d on MCF-7 and HepG2 cell cycle phase distribution. • Caspase 8 and 9 levels determination in MCF-7 and HepG2 after test agents' treatment. • In vivo biodistribution study of radioiodinated-5c. A new series of thiazolidinone (5a-g), thiazinone (9a-g) and dithiazepinone (9a-g) heterocycles bearing a benzenesulfonamide scaffold was synthesized. Cytotoxicity of these derivatives was assessed against MCF-7, HepG2, HCT-116 and A549 cancer cell lines and activity was compared to the known cytotoxic agents doxorubicin and 5-FU where the most active compounds displayed better to nearly similar IC 50 values to the reference compounds. For assessing selectivity, the most active derivatives against MCF-7, 5b , 5c and 5e , were also assessed against the normal breast cell line MCF-10 A where they demonstrated high selective cytotoxicity to cancerous cells over that to normal cells. Further, the effect of the most active compounds 5b-e on MCF-7 and HepG2 cell cycle phase distribution was assessed and the tested sulfonamide derivatives were found to induce accumulation of cells in the <2n phase. To further confirm apoptosis induction, caspase 8 and 9 levels in MCF-7 and HepG2 were evaluated before and after treatment with compounds 5b-e and were found to be significantly higher after exposure to the test agents. Since 5c was the most active, its effect on the cell cycle regulation was confirmed where it showed inhibition of the CDK2/cyclin E1. Finally, in vivo biodistribution study using radioiodinated-5c revealed a significant uptake and targeting ability into solid tumor in a xenograft mouse model. [ABSTRACT FROM AUTHOR]

• A series of novel pyrimidines have been synthesized and tested for their in vitro cytotoxic activity against 60 tumor cell lines by NCI. • 5d and 7c derivatives were found to be the most potent derivatives against KM12 cell line with a high selectivity index. • Derivatives 5d and 7c showed the up-regulation of caspase-3/9 and the pro-apoptotic factor Bax in KM12 cells. • The expression of Bcl-2, was down-regulated and inhibited at a nanomolar concentration. • The apoptotic effect for derivatives 5d and 7c in KM12 cells was detected using annexin V-FITC staining method. A series of novel derivatives of hydrazinylpyrimidines, pyrazolylpyrimidines and 3-amino[3,4- d ]pyrazolopyrimidines have been synthesized and tested for their in vitro cytotoxic activity against 60 tumor cell lines by NCI. The in vitro cytotoxic IC 50 values for the most active compounds were determined against the colon-KM12 cell line (5d , 7c and 7d), breast-MCF-7 (6a) and melanoma-MDA-MB-435 (6h) using 5-fluorouracil (5-FU) as a positive control. Derivatives 5d and 7c were found to be the most potent derivatives against KM12 cell line (IC 50 = 1.73 and 1.21 µM, respectively) with a high selectivity index (SI) (18.82 and 35.49, respectively) compared to 5-FU (IC 50 = 12.26 µM, SI = 1.93). Compounds 5d and 7c were further investigated for their apoptotic behavior in KM12 cell line. The investigations showed the up-regulation of caspase 3/9 and the pro-apoptotic factor Bax. On the other hand, the expression of the anti-apoptotic factor Bcl-2, was down-regulated, as well as its inhibition at a nanomolar concentration. Furthermore, the apoptotic effect for derivatives 5d and 7c in KM12 cells was detected using annexin V-FITC staining method. [ABSTRACT FROM AUTHOR]