5- or/and 20-O-alkyl-2,3-dehydrosilybins: Synthesis and biological profiles on prostate cancer cell models

Abstract

To investigate the effects of alkylation at 5-OH and 20-OH of 2,3-dehydrosilybin on prostate cancer cell proliferation, the synthetic approaches to 5- or/and 20-O-alkyl-2,3-dehydrosilybins, through a multi-step sequence from commercially available silybin, have been successfully developed. The first three reactions in the syntheses were completed through a one-pot procedure by managing anaerobic and aerobic conditions. With these synthetic methods in hand, twenty-one 2,3-dehydrosilybins, including seven 20-O-alkyl, seven 5,20-O-dialkyl, and seven 5-O-alkyl-2,3-dehydrosilybins, have been achieved for the evaluation of their biological profiles. Our WST-1 cell proliferation assay data indicate that nineteen out of the twenty-one 2,3-dehydrosilybins possess significantly improved antiproliferative potency as compared with silybin toward both androgen-sensitive (LNCaP) and androgen-insensitive prostate cancer cell lines (PC-3 and DU145). 5-O-Alkyl-2,3-dehydrosilybins were identified as the optimal subgroup that can consistently inhibit cell proliferation in three prostate cancer cell models with all IC50 values lower than 8 μM. Our flow cytometry-based assays also demonstrate that 5-O-heptyl-2,3-dehydrosilybin effectively arrests the cell cycle in the G0/G1 phase and activates PC-3 cell apoptosis.

Elevated phospholipase D activity in androgen-insensitive prostate cancer cells promotes both survival and metastatic phenotypes

“…Since prostate cancer, like breast cancer, is largely a hormonally driven cancer [2], we wanted to evaluate the level of PLD activity in androgen responsive and androgen non-responsive prostate cancer cells. We looked at three prostate cancer cell lines – DU145 and PC-3, which are androgen non-responsive; and LNCaP, which are androgen responsive [15]. We first examined the responsiveness of the three prostate cancer cell lines to androgen as observed by the ability to induce expression of PSA, which is induced by androgen [16].…”

O-Aminoalkyl-O-Trimethyl-2,3-Dehydrosilybins: Synthesis and In Vitro Effects Towards Prostate Cancer Cells

“…Note that a small amount of 3,5,7,20- O -tetramethyl-2,3-dehydrosilybin can be formed if anaerobic conditions are not well-controlled, which would complicate the purification process and decrease the yield. Even though 5,7,20- O -tribenzylsilybin was much easier to aerobically oxidize than that in silibinin [30], the oxidation of 5,7,20- O -trimethylsilybin ( 15 ) under the same conditions led to a mixture of products instead of the desired oxidation product. After several trials with different oxidation conditions, 5,7,20- O -trimethyl-2,3-dehydrosilybin ( 16 ) was eventually obtained by the oxidation of 15 with sodium hydroxide and hydrogen peroxide.…”

O-Aminoalkyl-O-Trimethyl-2,3-Dehydrosilybins: Synthesis and in vitro Effects towards Prostate Cancer Cells

“…Note that a small amount of 3,5,7,20-O-tetramethyl-2,3-dehydrosilybin can be formed if anaerobic conditions are not well-controlled, which would complicate the purification process and decrease the yield. Even though 5,7,20-O-tribenzylsilybin was much easier to aerobically oxidize than that in silibinin [30], the oxidation of 5,7,20-O-trimethylsilybin (15) under the same conditions led to a mixture of products instead of the desired oxidation product. After several trials with different oxidation conditions, 5,7,20-O-trimethyl-2,3-dehydrosilybin (16) was eventually obtained by the oxidation of 15 with sodium hydroxide and hydrogen peroxide.…”