Benzothiophene Selective Estrogen Receptor Modulators with Modulated Oxidative Activity and Receptor Affinity

Abstract

The regulation of estrogenic and antiestrogenic effects of selective estrogen receptor modulators (SERMs) is thought to underlie their clinical use. Most SERMs are polyaromatic phenols susceptible to oxidative metabolism to quinoids, which are proposed to be genotoxic. Conversely, the redox reactivity of SERMs may contribute to antioxidant and chemopreventive mechanisms, providing a new approach to improve the therapeutic properties of SERMs. An improved synthetic strategy was developed to generate a family of benzothiophene SERMs. Using computational modeling methods and measurements of antioxidant activity and estrogen receptor (ER) ligand binding, this SERM family was shown to provide both a range of ERalpha/ERbeta selectivity from 1.2- to 67-fold and a range of redox activity. Antioxidant activity was successfully modulated by varying a substituent remote from the OH group; the source of the antioxidant capacity. An efficient synthetic procedure is reported yielding benzothiophene SERMs wherein redox activity and ER affinity are modulated.

Structural modulation of reactivity/activity in design of improved benzothiophene selective estrogen receptor modulators: induction of chemopreventive mechanisms

“…The potential detrimental effects of quinoid formation are hence prevented, but this raises the question about whether the putative beneficial effects, notably chemoprevention via induction of phase II enzymes, are also lost. A family of benzothiophene SERMs has been developed (20) to answer the following questions: Does benzothiophene SERM bioactivation lead to induction? Is this property lost if bioactivation to a quinoid is structurally blocked?…”

“…Reagents BTC {the ''benzothiophene core'' 2-(4-hydroxyphenyl)-benzo[b]thiophen-6-ol} was synthesized following literature procedures and the X-DMA SERMs using our improved methods (20,21). Other reagents were purchased from Sigma unless stated otherwise.…”

“…In accord with this assessment, the observed induction of NQO1 by X-DMA SERMs in MCF-7 cell lines stably transfected with ERa or ERh was very modest and was not ER dependent. For example, SO 2 Me-DMA, which is a ligand for ERa (IC 50 = 27 nmol/L) but not for ERh (20), gave 1.2-fold induction of NQO1 in both ERa-and ERhpositive MCF-7 cells. In ER(À) MCF-7 cells, DMA showed significant induction of NQO1, which is compatible with its ability to induce NQO1 via ER-independent activation of the ARE.…”

“…More recent work on 2,3-t-butyl-4-hydroxyanisole implicated activation of kinase cascades converging on Nrf2 in NQO1 induction (31). The X-DMA family members that are blocked from diquinone methide formation (X = H, F, Br, OMe, SO 2 Me) were observed in the 1,1-diphenyl-2-picrylhydrazyl radical scavenging assay to act as phenolic antioxidants (20). Measurement herein of the classic antioxidant activity of the X-DMA SERMs in peroxyl radical trapping showed that the superior antioxidants were those able to undergo twoelectron oxidation to quinoids (DMA, NH 2 -DMA; Table 1; Fig.…”

Tamoxifen: Catalyst for the change to targeted therapy

“…Finally, the importance of understanding the unique pharmacology of tamoxifen can be placed in perspective. In retrospect, tamoxifen could, in fact, be viewed as the lead compound that was essential to initiate the synthesis of a broad range of new SERMs for the treatment of diseases as diverse as osteoporosis (86)(87)(88)(89)(90)(91)(92) and rheumatoid arthritis (93,94) and the subsequent extrapolation of the SERM concept to all members of the nuclear receptor superfamily (76). The advances documented with targeting tamoxifen now offer the promise of designing drugs to treat diseases previously thought to be impossible.…”