Figure 1.
Quinazoline-based modulators of epigenetic targets.
(A) Known quinazolines (1–3) as G9a/GLP inhibitors. (B) Novel 6,7-desmethoxyquinazolines 4–18. (C) Synthetic scheme for the preparation of 4–18.
Table 1.
Percent of inhibition of 4–18 against hDNMT1 and hDNMT3A.
Figure 2.
Inhibition values of 4, 10, 13 and 14 against the catalytic domain of hDNMT3A, hDNMT1 and G9a.
*Values are means of at least three experiments. †Compounds were tested in a 10-dose IC50 mode with 2-fold serial dilution starting at 400 µM. For 4, 13 and 14 it was no possible to determine IC50 values (see File S1).
Figure 3.
Effect of selected compounds on the induction of the luciferase signal at the CMV-luc construct in KG-1 cells.
(A) CMV-luc construct to detect changes in methylation at the CMV promoter in KG-1 cells. (B) Modulation of induction of luciferase expression of CMV-luc after treatment with different doses of 1, 4, 10, 13 and 14. SGI-1027 was used as a reference drug. Values are means of at least two experiments. Cytotoxicity of DNMT inhibitors in KG-1 cells causes a decrease or loss of luciferase induction.
Figure 4.
Docking studies of 4 and 14 into the DNMT3A active site.
Experimental (A) and theoretical (B and C) binding mode of AdoHcy (A), 4 (B) and 14 (C) in the DNMT3A active site. Protein is depicted as light yellow ribbons and sticks while ligands are depicted as red sticks. Hydrogen-bonds are depicted as dashed blue lines.
Figure 5.
Effects of selected compounds in human lymphoma U-937 and RAJI cells.
Cells were treated with the indicated concentration of compounds 4, 10, 13 and 14 for up to 72 h. Antiproliferative effects (left) and cell death induction (right) on (A) U-937 and (B) RAJI lymphoma cell lines. Results are the mean ± SD of at least three independent experiments. *, **, *** indicate p<0.05, p<0.01, p<0.005 versus untreated cells, respectively.
Table 2.
Effect of selected quinazoline analogues 4, 10, 13 and 14 on human lymphoma U-937 and RAJI cell viability at 48 h*.