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Fig. 1. Selected DNMT inhibitors.
Fig. 2. NSC compounds reported as DNMT inhibitors.
demonstrated efficacy in the clinic, they suffer from several liabilities
such as high toxicity, low chemical and plasmatic stability,18 poor
tumors.19 Derivatives of Vidaza and Dacogen have been prepared to
improve their chemical stability, but these analogues also rely on DNA
incorporation to unfold their activity.20
starting points for hit-to-lead campaigns targeting DNMTs. Due to our
interest in the development of DNMT inhibitors, we initiated in 2011 a
program aimed at exploring the SAR of NSC 319745 (4). Although we
were unable to reproduce the DNMT inhibitory activity of this com-
pound under our assay conditions, our efforts led to the discovery of
phenol derivative (8) that inhibited DNMT3A with an IC50 of 36 μM.30
Recently, hydroxamic derivatives of NSC 319745 that showed dual
inhibition against HDAC and DNMTs were reported.31 NSC 137546 (5)
also served as a starting point for lead discovery, resulting in compound
9 which inhibited DNMT1 and 3A in a concentration-dependent
manner in the micromolar range.32 To the best of our knowledge, the
SAR of NSC 106084 (6) and 14778 (7) has never been explored. Even
though these compounds possess chemical scaffolds shared by several
act as a photoreactive moiety34 and a diphenolic methylene structure in
NSC 14778 that could lead to quinone methides, we felt that, once their
activity confirmed, these compounds could be suitably modified by
extensive SAR activities to remove or replace unwanted chemical fea-
tures that are associated with PAINS. Therefore, we would like to report
herein the synthesis of NSC 106084 and 14778 and the evaluation of
their DNMT inhibitory activity.
Several natural products have been reported to inhibit DNMTs.21
However, in addition to having low potency and poor pharmacokinetic
profiles, many of them operate via an unknown mode of action or show
pan-activity against other targets. Procainamide, procaine, and hy-
dralazine are drugs that have been approved for cardiac arrhythmias,
for local anesthesia and for treatment of hypertension, respectively.
Using a drug repurposing strategy, these compounds have been shown
to moderately inhibit DNMTs22 and lead optimization programs have
RG-108 (2)24 and SGI-1027 (3),25 two of the most well character-
ized non-nucleoside DNMT inhibitors, are commonly utilized as re-
ference compounds in biochemical and cellular DNA methylation as-
tency based on a quinazoline-quinoline scaffold which mimicks the
deoxycytidine substrate and the SAM cofactor have also been developed
DNMT inhibitors with moderate potency have been reported.28 Despite
decades of work on DNA methyltransferases, Vidaza and Dacogen re-
main the only two approved drugs that target these epigenetic enzymes.
In light of the liabilities associated with current DNMT inhibitors, there
is an urgent need for novel small molecules that can modulate the ac-
tivity of DNMTs through reversible binding and that possess adequate
biophysical and pharmacokinetic properties, low toxicity, and good
chemical stability.
The synthesis of NSC 106084 (6) commenced with the formation of
acid chloride 11 by treatment of carboxylic acid 10 with oxalyl chloride
in the presence of a catalytic amount of DMF (Scheme 1). Reacting 11
triethylamine afforded the Weinreb amide 12 in 88% yield which was
then reacted with 4-methoxy-phenylmagnesium bromide to afford the
unsymmetrical diaryl ketone 13 in 96% yield. Demethylation of both
methyl ethers using boron tribromide quantitatively afforded bis-
phenol 14 which was then reacted with tert-butyl bromo acetate in
acetone in the presence of potassium carbonate to afford 15 in 93%
yield. Lastly, removal of both tert-butyl groups by treatment with excess
trifluoroacetic acid provided pure NSC 106084 (6) who's structure was
confirmed by X-ray diffraction analysis.
NSC 319745 (4), 137546 (5), 106084 (6) and 14778 (7) are DNMT
inhibitors that were discovered using a docking-based virtual screening
campaign of the National Cancer Institute (NCI) compound collection
(Fig. 2). These virtual screening hits showed 34%, 27%, 22% and 29%
biochemical assay.29 Of these, only NSC 14778 inhibited DNMT3B
(60% at 100 μM). These compounds were suggested to be potential
Methylene disalicylic acid 7 has previously been prepared by con-
sulfuric acid.35 Fluoro,36 chloro,37 methyl and trifluoromethyl38 deri-
vatives have also been obtained using this approach. Compound 7 has
2