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The selected nicotinamide-based HDACi displayed selectivity towards HDAC3 over pan HDAC and exhibited potent cytotoxicity against the used cell lines.

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Background: Pyrimidine-5-carbonitrile had a broad spectrum of biological activities such as antiviral, antioxidant and anticancer activity. Among similar compounds, monastrol being the most prominent due to cell-permeant inhibitor of mitosis therefore, we investigated the new Pyrimidine-5-carbonitrile as a cytotoxic agent for p53 pathway. Objective: Several new benzyloxyphenyl pyrimidine-5-carbonitrile derivatives were designed, synthesized, characterized, and their cytotoxicity was evaluated. The most active compounds were tested for their activity against p53 as a mechanistic target for antiproliferative action. Method: The key intermediate tetrahydropyrimidine-5-carbonitrile derivative 4 was prepared by a multicomponent reaction (MCR) of Biginelli type. S-alkylation of the key intermediate with the required alkyl or aralkyl halides or refluxing 4 with POCl3 followed by an amino acid yielded the target compounds. The cytotoxicity of 5c-e, 7a-c, 9, 10a, b and 11 was evaluated using A549 cell line of human lung adenocarcinoma, HepG2 liver cell line, and MDA-MB-231 cell line of breast cancer using the MTT assay. The transcription effects of 7a, 7c, and 11 on the p53 were assessed and compared with the reference doxorubicin. Results: Compounds 7a, 7c, and 11 have the highest cytotoxic effect when applied to most cancer cells. The tested compounds with 5-FU showed a significant increase in the anticancer activity more than 5-FU alone. Compounds 7a, 7c, and 11 increased the level of active caspase 3 by 4-6-fold, compared to untreated control cells in human liver cancer cell line (HepG2). Compounds 7a, 7c, and 11 increase the levels of caspase 8 and 9, indicating activation of both intrinsic and extrinsic pathways and showed potent induction of Bax, down-regulation of Bcl-2 protein levels and over-expression of Cytochrome C levels in HepG2 cell lines. Compound 11 exhibited cell cycle arrest at the Pre-G1 and G2/M phases in the cell cycle analysis of HepG2 cell line. The results revealed an increase of 12.40-19.10 in p53 level compared to the test cells and that p53 protein level of 7a, 7c, and 11 was significantly inductive (636, 861 and 987 pg/mL, respectively) in relation to doxorubicin (1263 pg/mL). Conclusion: Pyrimidine-5-carbonitrile derivatives have potent apoptotic and antiproliferative properties.

Carbenium ions generated from substituted benzhydryls using acid catalysis undergo smooth intramolecular trapping by pendant sulfonamide groups to provide excellent yields of 1aryltetrahydroisoquinolines.