corresponding rise in PCAF activation; and (3) both small variations in the length of
the aliphatic chain and the introduction of heteroatoms into it abolish any HAT
modulatory activity [85, 86].
The rhizome of Curcuma longa, also indicated as turmeric, is a commonly used
remedy in both Indian and Chinese traditional medicines. One of its principal
components is represented by the natural product curcumin (10) that, among various
other in vitro activities, has shown the capability to inhibit p300 with a potency in the
micromolar range (IC 50 ¼ 25 μM) [87]. The cinnamoyl moieties of 10 are required
for p300 inhibition because by functioning as Michael acceptors, they react covalently with a crucial cysteine residue within the active site of the enzyme [88]. Given
the thiol reactivity and, more generally, its pleiotropic nature, 10 cannot be considered a selective HATi as it also targets diverse other proteins playing a crucial role in
many epigenetic and non-epigenetic cellular networks [89]. Moreover, like other
phytochemicals, 10 is also able to disrupt cell membranes, so it cannot be excluded
that some of its biological effects are the result of this feature [90]. Presently,
curcumin is under evaluation in many clinical trials for various disease conditions,
but the results of the first completed placebo-controlled, double-blinded trials
(e.g. colon and pancreatic cancer, Alzheimer’s disease and radiation dermatitis)
have revealed that the translation from in vitro to in vivo conditions leads to a
massive drop in the activity of 10, with high chemical instability, extremely low oral
bioavailability and unspecific reactivity as the main causes of inefficacy [91]. Various
synthetic derivatives of 10 have been shown to inhibit p300 in vitro with a better
potency than the prototype, but all of them, sharing with the lead the main mechanism of action (thiol reactivity), are able to interact with multiple off-targets, and
their non-specific nature makes hard and almost useless to draw correlations between
observations in vitro and in vivo [92].
The polyisoprenylated benzophenone obtained from Garcinia indica called
garcinol (11a) is a low micromolar inhibitor of p300 and PCAF (IC 50 ¼ 7 and
5 μM, respectively) [93]. Isogarcinol (11b), the product of its intramolecular cyclization, is also a low micromolar inhibitor of p300 and PCAF, while the semisynthetic derivative LTK-14 (11c), obtained through the mono-methylation of
11b, is a selective inhibitor of p300 (IC 50 ¼ 5–7 μM) [94]. Data of isothermal
titration calorimetry suggest that the binding mode of 11c is different from those of
11a and 11b. In fact, while the two natural HATi have likely two principal binding
sites, with the hydroxyl groups of the catechol motif accommodated by the acetylCoA binding pocket, and the isoprenoid chains interacting close to the substratebinding site region, LTK-14 is a non-competitive inhibitor for both histone and
acetyl-CoA substrates that likely binds only to the second binding site of 11a and
11b, since the methylation of one of the two catechol hydroxyl groups impedes the
interactions with the acetyl-CoA binding pocket [94]. In addition, probably due to
differences in specificity, 11c is much less toxic than its parent compounds in
cellular tests (HeLa cell line) [95]. The molecular simplification of garcinol led to
the benzylidenebarbituric acid EML425 (11d), which is a potent and selective p300/
CBP inhibitor (IC 50 ¼ 2.9 and 1.1 μM for p300 and CBP, respectively) [96]. Despite
the presence of an α,β-unsaturated carbonyl system would suggest a thiol reactivity
Histone Acetyltransferase Enzymes: From Biological Implications to Most. . .
109
the aliphatic chain and the introduction of heteroatoms into it abolish any HAT
modulatory activity [85, 86].
The rhizome of Curcuma longa, also indicated as turmeric, is a commonly used
remedy in both Indian and Chinese traditional medicines. One of its principal
components is represented by the natural product curcumin (10) that, among various
other in vitro activities, has shown the capability to inhibit p300 with a potency in the
micromolar range (IC 50 ¼ 25 μM) [87]. The cinnamoyl moieties of 10 are required
for p300 inhibition because by functioning as Michael acceptors, they react covalently with a crucial cysteine residue within the active site of the enzyme [88]. Given
the thiol reactivity and, more generally, its pleiotropic nature, 10 cannot be considered a selective HATi as it also targets diverse other proteins playing a crucial role in
many epigenetic and non-epigenetic cellular networks [89]. Moreover, like other
phytochemicals, 10 is also able to disrupt cell membranes, so it cannot be excluded
that some of its biological effects are the result of this feature [90]. Presently,
curcumin is under evaluation in many clinical trials for various disease conditions,
but the results of the first completed placebo-controlled, double-blinded trials
(e.g. colon and pancreatic cancer, Alzheimer’s disease and radiation dermatitis)
have revealed that the translation from in vitro to in vivo conditions leads to a
massive drop in the activity of 10, with high chemical instability, extremely low oral
bioavailability and unspecific reactivity as the main causes of inefficacy [91]. Various
synthetic derivatives of 10 have been shown to inhibit p300 in vitro with a better
potency than the prototype, but all of them, sharing with the lead the main mechanism of action (thiol reactivity), are able to interact with multiple off-targets, and
their non-specific nature makes hard and almost useless to draw correlations between
observations in vitro and in vivo [92].
The polyisoprenylated benzophenone obtained from Garcinia indica called
garcinol (11a) is a low micromolar inhibitor of p300 and PCAF (IC 50 ¼ 7 and
5 μM, respectively) [93]. Isogarcinol (11b), the product of its intramolecular cyclization, is also a low micromolar inhibitor of p300 and PCAF, while the semisynthetic derivative LTK-14 (11c), obtained through the mono-methylation of
11b, is a selective inhibitor of p300 (IC 50 ¼ 5–7 μM) [94]. Data of isothermal
titration calorimetry suggest that the binding mode of 11c is different from those of
11a and 11b. In fact, while the two natural HATi have likely two principal binding
sites, with the hydroxyl groups of the catechol motif accommodated by the acetylCoA binding pocket, and the isoprenoid chains interacting close to the substratebinding site region, LTK-14 is a non-competitive inhibitor for both histone and
acetyl-CoA substrates that likely binds only to the second binding site of 11a and
11b, since the methylation of one of the two catechol hydroxyl groups impedes the
interactions with the acetyl-CoA binding pocket [94]. In addition, probably due to
differences in specificity, 11c is much less toxic than its parent compounds in
cellular tests (HeLa cell line) [95]. The molecular simplification of garcinol led to
the benzylidenebarbituric acid EML425 (11d), which is a potent and selective p300/
CBP inhibitor (IC 50 ¼ 2.9 and 1.1 μM for p300 and CBP, respectively) [96]. Despite
the presence of an α,β-unsaturated carbonyl system would suggest a thiol reactivity
Histone Acetyltransferase Enzymes: From Biological Implications to Most. . .
109