2 research outputs found
Synthesis and Evaluation of Analogues of <i>N</i>âPhthaloylâlâtryptophan (RG108) as Inhibitors of DNA Methyltransferase 1
DNA
methyltransferases (DNMT) are promising drug targets in cancer provided
that new, more specific, and chemically stable inhibitors are discovered.
Among the non-nucleoside DNMT inhibitors, <i>N</i>-phthaloyl-l-tryptophan <b>1</b> (RG108) was first identified as
inhibitor of DNMT1. Here, <b>1</b> analogues were synthesized
to understand its interaction with DNMT. The indole, carboxylate,
and phthalimide moieties were modified. Homologated and conformationally
constrained analogues were prepared. The latter were synthesized from
prolinoÂhomotryptophan derivatives through a methodology based
aminoâzincâeneâenolate cyclization. All compounds
were tested for their ability to inhibit DNMT1 in vitro. Among them,
constrained compounds <b>16</b>â<b>18</b> and NPys
derivatives <b>10</b>â<b>11</b> were found to be
at least 10-fold more potent
than the reference compound. The cytotoxicity on the tumor DU145 cell
line of the most potent inhibitors was correlated to their inhibitory
potency. Finally, docking studies were conducted in order to understand
their binding mode. This study provides insights for the design of
the next-generation of DNMT inhibitors
Identification of Novel Inhibitors of DNA Methylation by Screening of a Chemical Library
In order to discover new inhibitors of the DNA methyltransferase
3A/3L complex, we used a medium-throughput nonradioactive screen on
a random collection of 1120 small organic compounds. After a primary
hit detection against DNA methylation activity of the murine Dnmt3A/3L
catalytic complex, we further evaluated the EC<sub>50</sub> of the
12 most potent hits as well as their cytotoxicity on DU145 prostate
cancer cultured cells. Interestingly, most of the inhibitors showed
low micromolar activities and little cytotoxicity. Dichlone, a small
halogenated naphthoquinone, classically used as pesticide and fungicide,
showed the lowest EC<sub>50</sub> at 460 nM. We briefly assessed the
selectivity of a subset of our new inhibitors against hDNMT1 and bacterial
Dnmts, including M. SssI and EcoDam, and the protein lysine methyltransferase
PKMT G9a and the mode of inhibition. Globally, the tested molecules
showed a clear preference for the DNA methyltransferases, but poor
selectivity among them. Two molecules including Dichlone efficiently
reactivated YFP gene expression in a stable HEK293 cell line by promoter
demethylation. Their efficacy was comparable to the DNMT inhibitor
of reference 5-azacytidine