Abstract
As part of our ongoing silybin project, this study aims to introduce a basic nitrogen-containing group to 7-OH of 3,5,20-O-trimethyl-2,3-dehydrosilybin or 3-OH of 5,7,20-O-trimethyl-2,3-dehydrosilybin via an appropriate linker for in vitro evaluation as potential anti-prostate cancer agents. The synthetic approaches to 7-O-substituted-3,5,20-O-trimethyl-2,3-dehydrosilybins through a five-step procedure and to 3-O-substituted-5,7,20-O-trimethyl-2,3- dehydrosilybins via a four-step transformation have been developed. Thirty-two nitrogen-containing derivatives of silybin have been achieved through these synthetic methods for the evaluation of their antiproliferative activities towards both androgen-sensitive (LNCaP) and androgen-insensitive prostate cancer cell lines (PC-3 and DU145) using the WST-1 cell proliferation assay. These derivatives exhibited greater in vitro antiproliferative potency than silibinin. Among them, 11, 29, 31, 37, and 40 were identified as five optimal derivatives with IC50 values in the range of 1.40–3.06 µM, representing a 17- to 52-fold improvement in potency compared to silibinin. All these five optimal derivatives can arrest the PC-3 cell cycle in the G0/G1 phase and promote PC-3 cell apoptosis. Derivatives 11, 37, and 40 are more effective than 29 and 31 in activating PC-3 cell apoptosis.
Highlights
Silybin ((1), Figure 1), known as silibinin, exists in nature as an approximately equimolar mixture of two diastereomers of silybin A and silybin B with opposite configurations at C-10 andC-11 [1]
As illustrated in Scheme 1, the synthesis of 7-O-substituted-2,3-dehydrosilybins (9–14) started with selective benzylation (81%) of the C-7 phenolic hydroxyl group of silibinin, according to the procedure reported by Kren et al and us [23,28]
A 10–14 h reaction time serves as a critical factor for the optimal yield (40–55%) of this oxidation reaction. We found that this oxidation cannot be quenched with hydrochloric acid because it selectively demethylated the 5-OMe of the product. 5,7,20-O-Trimethyl-2,3-dehydrosilybin
Summary
Silybin ((1), Figure 1), known as silibinin, exists in nature as an approximately equimolar mixture of two diastereomers of silybin A and silybin B with opposite configurations at C-10 andC-11 [1]. The mixture of diastereoisomeric silybin A and silybin B was originally thought to be a pure compound and named silybin [4]. Later, it was re-termed as silibinin to emphasize that it is a mixture [5]. Silibinin (1) is the first and well-studied member of flavonolignans [4] and the key chemical and medicinal component of milk thistle The earliest record on the medicinal merit of Milk thistle for preventing and treating various hepatotoxicity is Hieronymus Bock’s book published in 1539 [7,8].
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