RESUMO
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.
Assuntos
Alcaloides/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Quadruplex G/efeitos dos fármacos , Indóis/química , Indóis/farmacologia , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Quinolinas/química , Quinolinas/farmacologia , Antineoplásicos/síntese química , Regulação da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Indóis/síntese química , Concentração Inibidora 50 , Neoplasias/metabolismo , Regiões Promotoras Genéticas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/genética , Quinolinas/síntese química , Elementos Silenciadores TranscricionaisRESUMO
In the title compound, C(22)H(24)N(4)O, the aromatic moiety is essentially planar (r.m.s. deviation of a least-squares plane fitted through all non-H atoms = 0.0386â Å) and is rotated by 89.98â (4)° from the piperazine ring, which adopts the expected chair conformation. The propanol chain is not fully extended away from the piperazine ring. In the crystal, there are two unique hydrogen-bonding inter-actions. One is an O-Hâ¯N inter-action which, together with an inversion-related symmetry equivalent, forms a ring motif. The second is an N-Hâ¯N inter-action which links adjacent mol-ecules by means of a chain motif which propagates in the c-axis direction. Overall, a two-dimensional hydrogen-bonded structure is formed.
