Anticancer Activity and\nCellular Repression of c-MYC\nby the G-Quadruplex-Stabilizing 11-Piperazinylquindoline Is Not Dependent\non Direct Targeting of the G-Quadruplex in the c-MYC Promoter

Abstract

This G-rich region of the c-MYC promoter has been shown\nto form\na G-quadruplex structure that acts as a silencer element for c-MYC\ntranscriptional control. In the present work, we have synthesized\na series of 11-substituted quindoline analogues as c-MYC G-quadruplex–stabilizing\ncompounds, and the cell-free and in vitro activity of these compounds\nwere evaluated. Two lead compounds (<b>4</b> and <b>12</b>) demonstrated good cell-free profiles, and compound <b>4</b> (2-(4-(10<i>H-</i>indolo­[3,2-<i>b</i>]­quinolin-11-yl)­piperazin-1-yl)-<i>N</i>,<i>N</i>-dimethylethanamine) significantly down-regulated\nc-MYC expression. However, despite the good cell-free activity and\nthe effect of these compounds on c-MYC gene expression, we have demonstrated,\nusing a cellular assay in a Burkitt’s lymphoma cell line (CA46-specific),\nthat these effects were not mediated through targeting of the c-MYC\nG-quadruplex. Thus, caution should be used in assigning the effects\nof G-quadruplex-interactive compounds that lower c-MYC to direct targeting\nof these promoter elements unless this assay, or similar ones, demonstrates\ndirect targeting of the G-quadruplex in cells.