seem mostly to be the consequence of its promiscuous inhibition of multiple
enzymes [80]. For the low cell permeability due to its high lipophilicity, 5a has
been the object of an extensive med-chem optimization effort aimed at generating
derivatives with increased solubility in water as well as better inhibitory potency and
isoform selectivity. Recently, Wapenaar et al. reported a series of 5a derivatives
differing in regiochemistry, alkyl chain length and chemical composition that were
tested against both p300 and MOF [79]. Among them, two derivatives, 5b and 5c,
showed an inhibitory potency against MOF (IC 50 ¼ 37 and 57 μM, respectively)
better than 5a (IC 50 ¼ 64 μM). Since both compounds, despite differing in the
regiochemistry, possess a linear decyl aliphatic chain instead of the pentadecyl tail of
5a, it has been proposed that the hydrophobic contacts due to the aliphatic chain
could play a key role in the interactions of this chemotype with MOF [79].
A yeast phenotypic screening where the reduction of S. cerevisiae viability was
correlated to Gcn5 inhibition led to the identification of the quinoline 6 (MC1626) as
a sub-millimolar HATi also effective at inhibiting acetylation and gene transcription
mediated by Gcn5 [81]. Starting from 6 a first hit optimization effort led to 7a
(MC1823), a related derivative that is also an analogue of 5a with the three substituents around the central quinoline core retaining the same relative positions as in
5a, and with the linear pentadecyl chain of the prototype substituted with a pentyl tail
[82]. More potent than 6 and 5a at inhibiting the total HAT activity of nuclear
extracts [82], 7a was the lead for a new series of anacardic acid analogues based on
the 3-carboxy-4-hydroxyquinoline moiety [83]. Among them, the 2-methyl derivatives 7b and its ethyl ester 7c resulted to be micromolar inhibitors of both p300 and
CBP, more potent than 5a [83]. Starting from 6 it has also been developed a series of
HATi bearing longer alkyl/aryl groups at the quinoline C2 position or additional side
chains at the C6 position. Among them, a few derivatives with n-propyl (8a) or
benzyl (8b) groups at C2 position or extended side chains (8c-e) at C6 position
showed twofold to threefold increased potency against p300 compared to 6, with 8e
being the most potent against p300 (IC 50 ¼ 57.5 μM) and very effective at decreasing H3/H4 acetylation in human leukaemia cells (U937) [84].
The so-called long chain alkylidene malonates (LoCAMs) are a large class of
HAT modulators derived from anacardic acid that includes SPV106 (9a) and related
compounds. Endowed with an inhibitory potency against p300/CBP comparable to
that of anacardic acid, 9a is also a PCAF activator [85]. Among the LoCAMs, the
most potent HATi are represented by the series of the bicarboxylic derivatives, with
both the ethyl esters of the prototype hydrolysed, that are strong p300 inhibitors
(IC 50 ¼ 1.3 and 1.1 μM for 9b and 9c, respectively) and partially inhibit PCAF, and
the acetoacetic derivatives that are good inhibitors of p300 (IC 50 ¼ 2.4 and 4.7 μM
for 9d and 9e, respectively), but are also strong activators of PCAF [86]. Interestingly, the corresponding acetylacetone derivatives that have both ethyl esters of 9a
replaced by acetyl groups show no effect on p300 while are pure activators of PCAF.
In summary, by a structure-activity relationship point of view, it is possible to state
that (1) the hydrolysis of the ester groups of the prototype leads to a significant p300
inhibition but decreases the affinity for PCAF; (2) in contrast, the substitution of the
carboxylic moiety for an acetyl group results in a drop of p300 inhibition and a
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D. Trisciuoglio and D. Rotili
enzymes [80]. For the low cell permeability due to its high lipophilicity, 5a has
been the object of an extensive med-chem optimization effort aimed at generating
derivatives with increased solubility in water as well as better inhibitory potency and
isoform selectivity. Recently, Wapenaar et al. reported a series of 5a derivatives
differing in regiochemistry, alkyl chain length and chemical composition that were
tested against both p300 and MOF [79]. Among them, two derivatives, 5b and 5c,
showed an inhibitory potency against MOF (IC 50 ¼ 37 and 57 μM, respectively)
better than 5a (IC 50 ¼ 64 μM). Since both compounds, despite differing in the
regiochemistry, possess a linear decyl aliphatic chain instead of the pentadecyl tail of
5a, it has been proposed that the hydrophobic contacts due to the aliphatic chain
could play a key role in the interactions of this chemotype with MOF [79].
A yeast phenotypic screening where the reduction of S. cerevisiae viability was
correlated to Gcn5 inhibition led to the identification of the quinoline 6 (MC1626) as
a sub-millimolar HATi also effective at inhibiting acetylation and gene transcription
mediated by Gcn5 [81]. Starting from 6 a first hit optimization effort led to 7a
(MC1823), a related derivative that is also an analogue of 5a with the three substituents around the central quinoline core retaining the same relative positions as in
5a, and with the linear pentadecyl chain of the prototype substituted with a pentyl tail
[82]. More potent than 6 and 5a at inhibiting the total HAT activity of nuclear
extracts [82], 7a was the lead for a new series of anacardic acid analogues based on
the 3-carboxy-4-hydroxyquinoline moiety [83]. Among them, the 2-methyl derivatives 7b and its ethyl ester 7c resulted to be micromolar inhibitors of both p300 and
CBP, more potent than 5a [83]. Starting from 6 it has also been developed a series of
HATi bearing longer alkyl/aryl groups at the quinoline C2 position or additional side
chains at the C6 position. Among them, a few derivatives with n-propyl (8a) or
benzyl (8b) groups at C2 position or extended side chains (8c-e) at C6 position
showed twofold to threefold increased potency against p300 compared to 6, with 8e
being the most potent against p300 (IC 50 ¼ 57.5 μM) and very effective at decreasing H3/H4 acetylation in human leukaemia cells (U937) [84].
The so-called long chain alkylidene malonates (LoCAMs) are a large class of
HAT modulators derived from anacardic acid that includes SPV106 (9a) and related
compounds. Endowed with an inhibitory potency against p300/CBP comparable to
that of anacardic acid, 9a is also a PCAF activator [85]. Among the LoCAMs, the
most potent HATi are represented by the series of the bicarboxylic derivatives, with
both the ethyl esters of the prototype hydrolysed, that are strong p300 inhibitors
(IC 50 ¼ 1.3 and 1.1 μM for 9b and 9c, respectively) and partially inhibit PCAF, and
the acetoacetic derivatives that are good inhibitors of p300 (IC 50 ¼ 2.4 and 4.7 μM
for 9d and 9e, respectively), but are also strong activators of PCAF [86]. Interestingly, the corresponding acetylacetone derivatives that have both ethyl esters of 9a
replaced by acetyl groups show no effect on p300 while are pure activators of PCAF.
In summary, by a structure-activity relationship point of view, it is possible to state
that (1) the hydrolysis of the ester groups of the prototype leads to a significant p300
inhibition but decreases the affinity for PCAF; (2) in contrast, the substitution of the
carboxylic moiety for an acetyl group results in a drop of p300 inhibition and a
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D. Trisciuoglio and D. Rotili