generate stable analogues (such as zebularine (7) and 5-fluorocytidine (8)) and
prodrugs (reviewed in [59–61]). The most promising prodrug is the dinucleotide
version of 5azadC (6), SGC-110 (9, guadecitabine), which is in clinical trials against
several haematological and solid cancers. Very interesting results are also being
obtained in the clinic by combination studies with other epigenetic inhibitors,
conventional chemotherapies or immunotherapies [38, 62].
Nevertheless, despite being the most potent compounds to demethylate DNA
identified to date, they induce other effects due to their chemical instability, their
Non-nucleoside inhibitors
N
HN
N
H
O
H
N
N
N
NH 2
SGI-1027, 13
EC 50 (DNMT3Acat)= 0.8 μM
EC 50 (DNMT1)= 10 μM
Flavonoids
O
O
NO2
Cl
O2N
flavanone 69, 15
EC 50 (Dnmt3A/3L)= 0.4 μM
Procainamides conjugates
Miscellaneous
N
H
O
N
N
H
N
O
O
conjugate 12, 16
EC 50 (Dnmt3A/3L)= 8.2 μM
EC 50 (DNMT1)= 4.9 μM
N
HO
O
NH
O
O
maleimide 5, 10
inh(DNMT1)= 60% at 100 μM
(H2C)12
H
N
N
HO2C
O
16, 12 (2R,3S)
EC 50 (DNMT1)= 50 μM
RG108 derivatives
SGI1027 and derivatives
N
HN
NH
N
H
N
N
CH 3
NH 2
Cpd5, 14
EC 50 (DNMT3Acat)= 0.7 μM
EC 50 (DNMT1)= 5.7 μM
N
H
HO
S
Cl
NO2
SW155246, 20
IC 50 DNMT1D581 = 1.2 μM
IC 50 Dnmt3A= 38 μM
N
H
N
O
S
O
SID49645275, 21
IC 50 DNMT1 = 0.8 μM
O
O
Cl
Cl
Cpd9, 19
EC 50 (Dnmt3A/3L)= 0.46 μM
EC 50 (DNMT1)= 1.6 μM
COOH
COOH
OH
OH
HO
OH
N
H
O
O
O
laccaic acid, 25
IC 50 DNMT1= 0.65 μM
N
N
N
N
HN
N
Cpd14, 27
EC 50 (DNMT3A)= 9 μM
O
N
HO
O
NH
O
O
RG119-1, 11
EC 50 (DNMT3Acat)= 3.2 μM
EC 50 (DNMT1)= 19 μM
Bisubstrate and transition-state analogues
N
N
HN
O
68, 17
EC 50 (DNMT3Acat))= 1.1 μM
EC 50 (DNMT1)= 100 μM
N
H
N
N
O
N
N
N
N
N
CH 3
N
N
O
CH 3
HO
OH
NH 2
prototype, 18
Dual inhibitors
N
H
O
N
H
O
Cl
CF 3
OH
22
IC 50 (HDAC1/HDAC6)= 57/17 nM
inh(DNMT1)=70% at 100 μM
N
HN
O
O
N
O
N
CM-272, 23
IC 50 (G9A) = 8 nM
IC 50 (DNMT1) = 0.38 μM
O
O
N
N
N
N
O
O
Cl
26
EC50(DNMT3Acat)= 2.1 μM
N
O
HN
HO
DC_517, 24
IC 50 (DNMT1)= 1.7 μM
O
OH
OH
HO
O
H
OH
HO
N
N
N
NH 2
O
5-Azacytidine
(Vidaza ®)
5
5-Aza-2'-deoxycytidine
(Dacogen™)
6
O
H
O
HO
N
N
N
NH 2
O
P
O
ONa
NH
N
N
N
O
OH H
O
NH 2
O
Nucleoside inhibitors
SGI-110
(Guadecitabine)
9
O
H
OH
HO
N
N
O
Zebularine
7
O
H
OH
HO
N
N
NH 2
O
F
5-Fluoro-2'-deoxycytidine
8
N
N
N
O
NH 2
Fig. 3 Collection of inhibitors of DNMTs. Top panel: the nucleoside inhibitors (the substitution on
position 5 of cytosine is indicated in bold red). Bottom panel: the non-nucleoside inhibitors. The
half maximal inhibitory concentration (IC 50 ) or the half maximal efficacy concentration (EC 50 ) is
indicated for DNMT1, DNMT3A and/or the DNMT3A/3L complex
Chemical Compounds Targeting DNA Methylation and Hydroxymethylation
263
prodrugs (reviewed in [59–61]). The most promising prodrug is the dinucleotide
version of 5azadC (6), SGC-110 (9, guadecitabine), which is in clinical trials against
several haematological and solid cancers. Very interesting results are also being
obtained in the clinic by combination studies with other epigenetic inhibitors,
conventional chemotherapies or immunotherapies [38, 62].
Nevertheless, despite being the most potent compounds to demethylate DNA
identified to date, they induce other effects due to their chemical instability, their
Non-nucleoside inhibitors
N
HN
N
H
O
H
N
N
N
NH 2
SGI-1027, 13
EC 50 (DNMT3Acat)= 0.8 μM
EC 50 (DNMT1)= 10 μM
Flavonoids
O
O
NO2
Cl
O2N
flavanone 69, 15
EC 50 (Dnmt3A/3L)= 0.4 μM
Procainamides conjugates
Miscellaneous
N
H
O
N
N
H
N
O
O
conjugate 12, 16
EC 50 (Dnmt3A/3L)= 8.2 μM
EC 50 (DNMT1)= 4.9 μM
N
HO
O
NH
O
O
maleimide 5, 10
inh(DNMT1)= 60% at 100 μM
(H2C)12
H
N
N
HO2C
O
16, 12 (2R,3S)
EC 50 (DNMT1)= 50 μM
RG108 derivatives
SGI1027 and derivatives
N
HN
NH
N
H
N
N
CH 3
NH 2
Cpd5, 14
EC 50 (DNMT3Acat)= 0.7 μM
EC 50 (DNMT1)= 5.7 μM
N
H
HO
S
Cl
NO2
SW155246, 20
IC 50 DNMT1D581 = 1.2 μM
IC 50 Dnmt3A= 38 μM
N
H
N
O
S
O
SID49645275, 21
IC 50 DNMT1 = 0.8 μM
O
O
Cl
Cl
Cpd9, 19
EC 50 (Dnmt3A/3L)= 0.46 μM
EC 50 (DNMT1)= 1.6 μM
COOH
COOH
OH
OH
HO
OH
N
H
O
O
O
laccaic acid, 25
IC 50 DNMT1= 0.65 μM
N
N
N
N
HN
N
Cpd14, 27
EC 50 (DNMT3A)= 9 μM
O
N
HO
O
NH
O
O
RG119-1, 11
EC 50 (DNMT3Acat)= 3.2 μM
EC 50 (DNMT1)= 19 μM
Bisubstrate and transition-state analogues
N
N
HN
O
68, 17
EC 50 (DNMT3Acat))= 1.1 μM
EC 50 (DNMT1)= 100 μM
N
H
N
N
O
N
N
N
N
N
CH 3
N
N
O
CH 3
HO
OH
NH 2
prototype, 18
Dual inhibitors
N
H
O
N
H
O
Cl
CF 3
OH
22
IC 50 (HDAC1/HDAC6)= 57/17 nM
inh(DNMT1)=70% at 100 μM
N
HN
O
O
N
O
N
CM-272, 23
IC 50 (G9A) = 8 nM
IC 50 (DNMT1) = 0.38 μM
O
O
N
N
N
N
O
O
Cl
26
EC50(DNMT3Acat)= 2.1 μM
N
O
HN
HO
DC_517, 24
IC 50 (DNMT1)= 1.7 μM
O
OH
OH
HO
O
H
OH
HO
N
N
N
NH 2
O
5-Azacytidine
(Vidaza ®)
5
5-Aza-2'-deoxycytidine
(Dacogen™)
6
O
H
O
HO
N
N
N
NH 2
O
P
O
ONa
NH
N
N
N
O
OH H
O
NH 2
O
Nucleoside inhibitors
SGI-110
(Guadecitabine)
9
O
H
OH
HO
N
N
O
Zebularine
7
O
H
OH
HO
N
N
NH 2
O
F
5-Fluoro-2'-deoxycytidine
8
N
N
N
O
NH 2
Fig. 3 Collection of inhibitors of DNMTs. Top panel: the nucleoside inhibitors (the substitution on
position 5 of cytosine is indicated in bold red). Bottom panel: the non-nucleoside inhibitors. The
half maximal inhibitory concentration (IC 50 ) or the half maximal efficacy concentration (EC 50 ) is
indicated for DNMT1, DNMT3A and/or the DNMT3A/3L complex
Chemical Compounds Targeting DNA Methylation and Hydroxymethylation
263