Nitrogen-containing derivatives of O-tetramethylquercetin: Synthesis and biological profiles in prostate cancer cell models

• Published in: Bioorganic chemistry 2019-06, Vol.87, p.227-239
• Main Authors: Rajaram, Pravien, Jiang, Ziran, Chen, Guanglin, Rivera, Alyssa, Phasakda, Alison, Zhang, Qiang, Zheng, Shilong, Wang, Guangdi, Chen, Qiao-Hong
• Format: Article
• Language: English
• Subjects: Antiproliferative activity; Cell apoptosis; Prostate cancer; Quercetin derivative; Synthesis
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.03.047

[Display omitted] •48 New N-containing derivatives of O-tetramethylquercetin were synthesized.•Most of them are more potent than quercetin in three prostate cancer cell models.•5-O-(N,N-Dibutylamino)propyl-3,3′,4′,7-O-tetramethylquercetin is the optimal one.•The optimal derivative is over 35- to 182-fold more potent than quercetin.•The optimal derivative activates PC-3 cell apoptosis. Forty-eight nitrogen-containing quercetin derivatives were synthesized from readily available rutin or quercetin for the in vitro evaluation of their biological profiles. The WST-1 cell proliferation assay data indicate that thirty-nine out of the forty-eight derivatives possess significantly improved antiproliferative potency as compared with quercetin and fisetin, as well as the parent 3,3′,4′,7-O-tetramethylquercetin toward both androgen-sensitive (LNCaP) and androgen-insensitive (PC-3 and DU145) human prostate cancer cell lines. 5-O-Aminoalkyl-3,3′,4′,7-O-tetramethylquercetins were established as a better scaffold for further development as anti-prostate cancer agents. Among them, 5-O-(N,N-dibutylamino)propyl-3,3′,4′,7-O-tetramethylquercetin (44) was identified as the optimal derivative with IC50 values of 0.55–2.82 µM, being over 35–182 times more potent than quercetin. The flow cytometry-based assays further demonstrate that 44 effectively activates PC-3 cell apoptosis.