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Inspired by the synergistic effects of dietary natural products with different scaffolds on the inhibition of cancer cell proliferation, incorporation of central (1 E ,4 E )-1,4-penta-dien-3-one linker (an optimal substitute for the central metabolically unstable diketone linker of curcumin), 1-alkyl-1 H -imidazol-2-yl (a promising bioisostere of terminal aryl group in curcumin), and chromone (the common pharmacophore in genistein and quercetin) into one chemical entity resulted in ten new hybrid molecules, 3-((1 E ,4 E )-5-(1-alkyl-1 H -imidazol-2-yl)-3-oxopenta-1,4-dien-1-yl)-4 H -chromen-4-ones. They were synthesized through a three-step transformation using acid-catalyzed aldol condensation as key step. The WST-1 cell proliferation assay showed that they have greater anti-proliferative potency than curcumin, quercetin, and genistein on both androgen-dependent and androgen-independent human prostate cancer cells. [ABSTRACT FROM AUTHOR]

To further engineer dienones with optimal combinations of potency and bioavailability, thirty-four asymmetric 1,5-diarylpenta-1,4-dien-3-ones ( 25 – 58 ) have been designed and synthesized for the evaluation of their in vitro anti-proliferative activity in three human prostate cancer cell lines and one non-neoplastic prostate epithelial cell line. All these asymmetric dienones are sufficiently more potent than curcumin and their corresponding symmetric counterparts. The optimal dienone 58 , with IC 50 values in the range of 0.03–0.12 μM, is 636-, 219-, and 454-fold more potent than curcumin in three prostate cancer cell models. Dienones 28 and 49 emerged as the most promising asymmetric dienones that warrant further preclinical studies. The two lead compounds demonstrated substantially improved potency in cell models and superior bioavailability in rats, while exhibiting no acute toxicity in the animals at the dose of 10 mg/kg. Dienones 28 and 46 can induce PC-3 cell cycle regulation at the G 0 /G 1 phase. However, dienone 28 induces PC-3 cell death in a different way from 46 even though they share the same scaffold, indicating that terminal heteroaromatic rings are critical to the action of mechanism for each specific dienone. [ABSTRACT FROM AUTHOR]

Twenty-two 3- O -substituted-3′,4′,5′-trimethoxyflavonols have been designed and synthesized for their anti-proliferative activity towards three human prostate cancer cell lines. Our results indicate that most of them are significantly more potent than the parent 3′,4′,5′-trimethoxyflavonol in inhibiting the cell proliferation in PC-3 and LNCaP prostate cancer cell models. 3- O -Substituted-3′,4′,5′-trimethoxyflavonols have generally higher potency towards PC-3 and LNCaP cell lines than the DU145 cell line. Incorporation of an ethyl group to 3-OH of 3′,4′,5′-trimethoxyflavonol leads to 3- O -ethyl-3′,4′,5′-trimethoxyflavonol as the optimal derivative with up to 36-fold enhanced potency as compared with the corresponding lead compound 3′,4′,5′-trimethoxyflavonol, but with reversed PC-3 cell apoptotic response. Introduction of a dipentylaminopropyl group to 3-OH increases not only the antiproliferative potency but also the ability in activating PC-3 cell apoptosis. Our findings imply that modification on 3-OH of trimethoxyflavonol can further enhance its in vitro anti-proliferative potency and PC-3 cell apoptosis induction. [ABSTRACT FROM AUTHOR]

In search of more effective chemotherapeutics for the treatment of castration-resistant prostate cancer and inspired by curcumin analogues, twenty five (1 E ,3 E ,6 E ,8 E )-1,9-diarylnona-1,3,6,8-tetraen-5-ones bearing two identical terminal heteroaromatic rings have been successfully synthesized through Wittig reaction followed by Horner–Wadsworth–Emmons reaction. Twenty-three of them are new compounds. The WST-1 cell proliferation assay was employed to assess their anti-proliferative effects toward both androgen-sensitive and androgen-insensitive human prostate cancer cell lines. Eighteen out of twenty-five synthesized compounds possess significantly improved potency as compared with curcumin. The optimal compound, 78 , is 14- to 23-fold more potent than curcumin in inhibiting prostate cancer cell proliferation. It can be concluded from our data that 1,9-diarylnona-1,3,6,8-tetraen-5-one can serve as a new potential scaffold for the development of anti-prostate cancer agents and that pyridine-4-yls and quinolin-4-yl act as optimal heteroaromatic rings for the enhanced potency of this scaffold. Two of the most potent compounds, 68 and 75 , effectively suppress PC-3 cell proliferation by activating cell apoptosis and by arresting cell cycle in the G 0 /G 1 phase. [ABSTRACT FROM AUTHOR]

Flavonoids are a large class of polyphenolic compounds ubiquitously distributed in dietary plants with an array of biological activities. Flavonols are a major sub-class of flavonoids featuring a hydroxyl group at C-3. Certain natural flavonols, such as quercetin and fisetin, have been shown by in vitro cell-based and in vivo animal experiments to be potential anti-prostate cancer agents. However, the Achilles’ heel of flavonols as drug candidates is their moderate potency and poor pharmacokinetic profiles. This study aims to explore the substitution effect of 3-OH in flavonols on the in vitro anti-proliferative potency against both androgen-sensitive and androgen-insensitive human prostate cancer cell lines. Our first lead flavonol (3′,4′-dimethoxyflavonol), eight 3- O -alkyl-3′,4′-dimethoxyflavonols, and six 3- O -aminoalkyl-3′,4′-dimethoxyflavonols have been synthesized through aldol condensation and the Algar–Flynn–Oyamada (AFO) reaction. The WST-1 cell proliferation assay indicates (i) that all synthesized 3- O -alkyl-3′,4′-dimethoxyflavonols and 3- O -aminoalkyl-3′,4′-dimethoxyflavonols are more potent than the parent 3′,4′-dimethoxyflavonol and the natural flavonol quercetin in suppressing prostate cancer cell proliferation; and (ii) that incorporation of a dibutylamino group to the 3-OH group through a three- to five-carbon linker leads to the optimal derivatives with up to 292-fold enhanced potency as compared with the parent flavonol. Flow cytometry analysis showed that the most potent derivative 22 can activate PC-3 cell cycle arrest at the G 2 /M phase and induce PC-3 cell apoptosis. No inhibitory ability of 22 up to 50 μM concentration was observed against PWR-1E normal human epithelial prostate cells, suggesting its in vitro safety profile. The results indicate that chemical modulation at 3-OH is a vital strategy to optimize flavonols as anti-prostate cancer agents. [ABSTRACT FROM AUTHOR]

Eight 3- O -alkyl-2,3-dehydrosilibinins have been synthesized from commercially available silibinin through two synthetic approaches. A one-pot reaction, starting with aerobic oxidation of silibinin followed by direct alkylation of the phenolic hydroxyl group in the subsequent 2,3-dehydrosilibinin, furnishes the desired derivatives in 11–16% yields. The three-step procedure employing benzyl ether to protect 7-OH in silibinin generates the desired derivatives in 30–46% overall yields. The antiproliferative activity of the 2,3-dehydrosilibinin derivatives against both androgen-sensitive and androgen-insensitive prostate cancer cells have been assessed using a WST-1 cell proliferation assay. All derivatives exhibited greater antiproliferative potency than silibinin, with 2,3-dehydrosilibinins each possessing a three- to five-carbon linear alkyl group to 3-OH (IC 50 values in a range of 1.71–3.06 μM against PC-3 and LNCaP cells) as the optimal derivatives. The optimal potency was reached with three- to five-carbon alkyl groups. Our findings suggest that 3- O -propyl-2,3-dehydrosilibinin effectively inhibits the growth of PC-3 prostate cancer cells by arresting cell cycle in the G 0 / G 1 phase, but not by activating PC-3 cell apoptosis. [ABSTRACT FROM AUTHOR]

[Display omitted] • An amide mimic of desTHPdactylolide was synthesized via a 26-step transformation. • Antiproliferative activity was evaluated against five prostate cancer cell lines. • The lactam moiety can serve as a bioisostere for the lactone in desTHPdactylodide. (−)-Zampanolide is a unique microtubule stabilizing agent (MSA) with covalent-binding mechanism and low nanomolar anitproliferative potency towards multi-drug resistant cancer cells. MSAs have a special connection with prostate cancer by inhibiting androgen receptor nuclear translocation. Zampanolide and the structurally related dactylolide have thus been sought after by us as lead compounds for development of anti-prostate cancer agents. DesTHPdactylolide is a simplified mimic of dactylolide and has previously been synthesized by us in both configurations, with the (17 R) configuration being more potent in suppressing prostate cancer cell proliferation. The current study aims to synthesize an amide mimic of (17 R) desTHPdactylolide that was anticipated to be metabolically more stable than (17 R) desTHPdactylolide. To this end, the amide mimic has been successfully synthesized through a 26-step transformation from 2-butyn-1-ol. Our WST-1 cell proliferation assay in five human prostate cancer cell models indicated that the lactam moiety can serve as a bioisostere for the lactone in desTHPdactylolide. [ABSTRACT FROM AUTHOR]