Synthesis of 2-(p-chlorobenzyl)-3-aryl-6-methoxybenzofurans as selective ligands for antiestrogen-binding sites. Effects on cell proliferation and cholesterol synthesis

Abstract

A series of nonsteroidal compounds, 2-(p-chlorobenzyl)-3-aryl-6- methoxybenzofurans derived from the 2-(p-chlorobenzyl)-6-methoxy-3(2H)-benzofuranones has been synthesized. The key steps in the synthesis were reactions of 2-(p-chlorobenzyl)-6-methoxy-3(2H)-benzofuranones with the arylorganometallic reagents followed by dehydration of the resulting carbinols. The benzofurans are ligands for antiestrogen-binding sites (AEBS) and display no significant interaction with the estrogen receptor (ER). All bind to AEBS with equivalent or greater affinity than tamoxifen. These compounds decrease [3H]thymidine incorporation in AEBS-containing EL4 lymphoid cells and MCF7 breast cancer cells in a concentration-dependent manner between 10(-8) and 10(-6) M and are generally more inhibitory than tamoxifen. In contrast, they have no effect on [3H]thymidine incorporation by an AEBS-deficient variant of the MCF7 cell line, RTx6. The present findings of (1) selective and high affinity binding of the benzofurans to AEBS, (2) their concentration-dependent inhibition of [3H]thymidine incorporation in AEBS-containing cells, and (3) their lack of antiproliferative effect in an AEBS-deficient cell line suggest a functional role for AEBS in mediating the antigrowth effect of these compounds. Two of the more active benzofuran compounds also significantly inhibited de novo cholesterol biosynthesis in EL4 cells which lack ER. This effect could be obtained after 5 h of treatment and preceded significant loss of cell viability. This is the first demonstration that selective ligands of AEBS (other than the known nonsteroidal antiestrogens) interfere with cholesterol biosynthesis-an action that may contribute to their antigrowth effect.

Benzothiepin-derived molecular scaffolds for estrogen receptor modulators: synthesis and antagonistic effects in breast cancer cells

“…The replacement of the OH group on compound 14 (cLog P ¼ 5.99) with lipophilic fluorine as in 13c (cLog P ¼ 6.86) results in a decrease in the IC 50 value from 306 nM to 18.5 nM indicating the positive effect of the fluorine on the antiproliferative activity. These results compare very favourably with the antiproliferative activity reported for tamoxifen [31], fluorotamoxifen [32,33], benzocycloheptenes and related dibenzothiepins. [34][35][36].…”

Cholinesterase Inhibitors: Xanthostigmine Derivatives Blocking the Acetylcholinesterase-Induced β-Amyloid Aggregation

“…The residue was crystallized from toluene to give 0.3 g of 7a (50% yield), mp 152-154°C. 1 (26). A solution of 25 (0.20 g, 0.63 mmol) in water was treated with sodium acetate (0.065 g, 0.75 mmol), the mixture was refluxed for 1 h, allowed to cool to room temperature, and extracted with methylene chloride.…”

Microsomal epoxide hydrolase of rat liver is a subunit of theanti-oestrogen-binding site

“…The Rtx-6 cells were similar to MCF-7 cells in their ER content and functionality, suggesting a correlative link between the lack of AEBS and the insensitivity of these cells to tamoxifen [10] and to a specific AEBS ligand [11,12]. Other studies have reported dose-dependent cytostatic and cytotoxic effects of anti-oestrogens on ER-negative lymphoid cells that contain a high level of microsomal AEBS, thus underlining the importance of AEBS in the mediation of growth control [12][13][14]. A diphenylmethane or [4-(phenylmethyl)phenoxy]ethanamine ; mEH, microsomal epoxide hydrolase ; RT-PCR, reverse transcriptase-mediated PCR.…”