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• 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 IC 50 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. [ABSTRACT FROM AUTHOR]