Anticancer activity and cellular repression of c-MYC by the G-quadruplex-stabilizing 11-piperazinylquindoline is not dependent on direct targeting of the G-quadruplex in the c-MYC promoter.
This G-rich region of the c-MYC promoter has been shown to form a G-quadruplex structure that acts as a silencer element for c-MYC transcriptional control. In the present work, we have synthesized a series of 11-substituted quindoline analogues as c-MYC G-quadruplex-stabilizing compounds, and the cell-free and in vitro activity of these compounds were evaluated. Two lead compounds (4 and 12) demonstrated good cell-free profiles, and compound 4 (2-(4-(10H-indolo[3,2-b]quinolin-11-yl)piperazin-1-yl)-N,N-dimethylethanamine) significantly down-regulated c-MYC expression. However, despite the good cell-free activity and the effect of these compounds on c-MYC gene expression, we have demonstrated, using a cellular assay in a Burkitt's lymphoma cell line (CA46-specific), that these effects were not mediated through targeting of the c-MYC G-quadruplex. Thus, caution should be used in assigning the effects of G-quadruplex-interactive compounds that lower c-MYC to direct targeting of these promoter elements unless this assay, or similar ones, demonstrates direct targeting of the G-quadruplex in cells.
College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA.
Peda V L
PV
Boddupally
Seongmin
S
Hahn
Cristina
C
Beman
Biswanath
B
De
Tracy A
TA
Brooks
Vijay
V
Gokhale
Laurence H
LH
Hurley
D000470:Alkaloids / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054856:G-Quadruplexes / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009369:Neoplasms / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000235:genetics; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D037941:Silencer Elements, Transcriptional
D000470:Alkaloids; D000970:Antineoplastic Agents; D007211:Indoles; D016271:Proto-Oncogene Proteins c-myc; D011804:Quinolines; C016712:quindoline