Optimization of diarylpentadienones as chemotherapeutics for prostate cancer. Issue 16 (1st September 2018)

• Record Type: Journal Article
• Authors: Patanapongpibul, Manee; Zhang, Changde; Chen, Guanglin; Guo, Shanchun; Zhang, Qiang; Zheng, Shilong; Wang, Guangdi; Chen, Qiao-Hong
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 16(2018)
• Page Start: 4751
• Page End: 4760
• Publication Date: 2018-09-01
• Subjects: Diarylpentadienone -- Prostate cancer -- Antiproliferative activity -- Pharmacokinetic study; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.08.018
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: In vitro potency of 1, 5-bis(1 H -imidazol-2-yl)penta-1, 4-diene-3-one was evaluated. Thirteen 1-aryl derivatives were synthesized through a three-step transformation. Six bis(1-arylimidazol-2-yl)pentadienones exhibit superior potency than curcumin. Bis(1-(2-methoxyphenyl)-1 H -imidazol-2-yl)pentadienone has good bioavailability. Abstract: 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.