Design, Synthesis and Biological Evaluation of 4‐Amino‐N‐(4‐aminophenyl)benzamide Analogues of Quinoline‐Based SGI‐1027 as Inhibitors of DNA Methylation

Abstract

Quinoline derivative SGI-1027 (N-(4-(2-amino-6-methylpyrimidin-4-ylamino)phenyl)-4-(quinolin-4-ylamino)benzamide) was first described in 2009 as a potent inhibitor of DNA methyltransferase (DNMT) 1, 3A and 3B. Based on molecular modeling studies, performed using the crystal structure of Haemophilus haemolyticus cytosine-5 DNA methyltransferase (MHhaI C5 DNMT), which suggested that the quinoline and the aminopyridimine moieties of SGI-1027 are important for interaction with the substrates and protein, we designed and synthesized 25 derivatives. Among them, four compounds—namely the derivatives 12, 16, 31 and 32—exhibited activities comparable to that of the parent compound. Further evaluation revealed that these compounds were more potent against human DNMT3A than against human DNMT1 and induced the re-expression of a reporter gene, controlled by a methylated cytomegalovirus (CMV) promoter, in leukemia KG-1 cells. These compounds possessed cytotoxicity against leukemia KG-1 cells in the micromolar range, comparable with the cytotoxicity of the reference compound, SGI-1027. Structure–activity relationships were elucidated from the results. First, the presence of a methylene or carbonyl group to conjugate the quinoline moiety decreased the activity. Second, the size and nature of the aromatic or heterocycle subsitutents effects inhibition activity: tricyclic moieties, such as acridine, were found to decrease activity, while bicyclic substituents, such as quinoline, were well tolerated. The best combination was found to be a bicyclic substituent on one side of the compound, and a one-ring moiety on the other side. Finally, the orientation of the central amide bond was found to have little effect on the biological activity. This study provides new insights in to the structure–activity relationships of SGI-1027 and its derivative.

Resveratrol-salicylate derivatives as selective DNMT3 inhibitors and anticancer agents

“…Interestingly, the negative effect of adding acetyl groups on DNMT3 inhibition is milder than that of adding methoxy groups, given that compounds 11 and 12 still showed some degree of inhibition on both DNMT3A and DNMT3B enzymes (IC 50 ’s in the 100–215 μM range; Table 1). The observation that methoxy groups reduce DNMT inhibition seems to be in agreement with a recent report by Rilova et al, in which they reported that dimethoxytriazine groups decreased the DNMT3A inhibitory activity of quinolone-based DNMT inhibitors (58). …”

“…Nevertheless, recent developments with small molecule inhibitors have showed that in vitro DNMT3A inhibition is possible without the presence of carboxylate groups (58). Thus, results of this work showed that compounds bearing either a free carboxylic acid (9), or a carboxylate methyl ester (10), exerted a better inhibitory profile than resveratrol against both DNMT3 enzymes (see Table 1).…”

Computational fishing of new DNA methyltransferase inhibitors from natural products

“…However, two of them, azacitidine and decitabine, have been approved by FDA (Food and Drug Administration) for the treatment of myelodysplastic syndromes [25,26]. Moreover, non-nucleoside DNMTis, such as RG-108 [27], which was identified via virtual screening methods; and SGI-1027, a quinoline derivative, have been proposed as DNMTis [28,29]. However, the weak inhibitory activity of these compounds [30] indicates a need for the search of more effective inhibitors in the future.…”

DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge

“…Consequently, derivatives ( 16 ) and ( 17 ) also showed a DNA-competitive inhibition of DNMT. Compound ( 16 ) is the most potent DNMT1 inhibitor among them [4,42,43]. …”