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To discover new antiproliferative agents with high efficacy and selectivity, a new series of 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea derivatives (7a–7t) were designed, synthesized and evaluated for their antiproliferative activity against A549, HCT-116 and PC-3 cancer cell lines in vitro. Most of the target compounds demonstrated significant antiproliferative effects on all the selective cancer cell lines. Among them, the target compound, 1-[4-chloro-3-(trifluoromethyl)phenyl]-3-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}thio}phenyl}urea (7i) was identified to be the most active one against three cell lines, which was more potent than the positive control with an IC50 value of 1.53 ± 0.46, 1.11 ± 0.34 and 1.98 ± 1.27 μM, respectively. Further cellular mechanism studies confirmed that compound 7i could induce the apoptosis of A549 cells in a concentration-dependent manner and elucidated compound 7i arrests cell cycle at G1 phase by flow cytometry analysis. Herein, the studies suggested that the 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea skeleton might be regarded as new chemotypes for designing effective antiproliferative agents. [ABSTRACT FROM AUTHOR]

Our earlier studies indicate that (1 E ,4 E )-1,5-bis(1-alkyl-1 H -imidazol-2-yl)penta-1,4-diene-3-ones and (1 E ,4 E )-1,5-bis(1-alkyl-1 H -benzo[ d ]imidazol-2-yl)penta-1,4-diene-3-ones exhibit up to 121-fold greater antiproliferative potency than curcumin in human prostate cancer cell models, but only 2–10 fold increase in mouse plasma concentrations. The present study aims to further optimize them as anti-prostate cancer agents with both good potency and bioavailability. (1 E ,4 E )-1,5-Bis(1 H -imidazol-2-yl)penta-1,4-diene-3-one, the potential metabolic product of (1 E ,4 E )-1,5-bis(1-alkyl-1 H -imidazol-2-yl)penta-1,4-diene-3-ones, was synthesized and evaluated for its anti-proliferative activity. The promising potency of 1,5-bis(1-alkyl-1 H -imidazol-2-yl)penta-1,4-diene-3-ones was completely abolished by removing the 1-alkyl group, suggesting the critical role of an appropriate group on the N1 position. We then envisioned that N -aryl substitution to exclude the C–H bond on the carbon adjacent to the N 1 position ( α -H) may increase the metabolic stability. Consequently, seven (1 E ,4 E )-1,5-bis(1-aryl-1 H -imidazol-2-yl)penta-1,4-dien-3-ones and three (1 E ,4 E )-1,5-bis(1-aryl-1 H -benzo[ d ]imidazol-2-yl)penta-1,4-dien-3-ones, as well as three (1 E ,4 E )-1,5-bis(1-aryl-1 H -pyrrolo[3,2- b ]pyridine-2-yl)penta-1,4-dien-3-ones, were synthesized through a three-step transformation, including N -arylation via Ullmann condensation, formylation, and Horner-Wadsworth-Emmons reaction. Six optimal (1 E ,4 E )-1,5-bis(1-aryl-1 H -imidazol-2-yl)penta-1,4-dien-3-ones exhibit 24- to 375-fold improved potency as compared with curcumin. Replacement of the imidazole with bulkier benzoimidazole and 4-azaindole results in a substantial decrease in the potency. (1 E ,4 E )-1,5-Bis(1-(2-methoxyphenyl)-1 H -imidazol-2-yl)penta-1,4-dien-3-one ( 17d ) was established as an optimal compound with both superior potency and good bioavailability that is sufficient to provide the therapeutic efficacy necessary to suppress in vivo tumor growth. [ABSTRACT FROM AUTHOR]