Identification of 4-hydroxyquinolines inhibitors of p300/CBP histone acetyltransferases

Article abstract of DOI:10.1016/j.bmcl.2008.12.097

We identified a series of 4-hydroxyquinolines bearing a C1 to C15 alkyl chain at the C2 position and a carbethoxy/carboxy group at the C3 position of the quinoline nucleus (MC compounds), endowed with selective inhibitory activity against the p300/CBP HAT enzymes. Enzyme inhibition was investigated using in vitro HAT assays and by western blot analysis of cellular lysates to examine the acetylation levels of histone H3 and α-tubulin. When tested in U937 cells, some compounds displayed pro-apoptotic or cytodifferentiating properties.

Full text of DOI:10.1016/j.bmcl.2008.12.097

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1132–1135
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Identification of 4-hydroxyquinolines inhibitors of p300/CBP
histone acetyltransferases
Antonello Mai a, , Dante Rotili , Domenico Tarantino , Angela Nebbioso , Sabrina Castellano ,
a
a
b
c
*
c
d
b,
*
Gianluca Sbardella , Marc Tini , Lucia Altucci
a
Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P.le A. Moro 5, 00185 Roma, Italy
Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Vico L. De Crecchio 7, 80138 Napoli, Italy
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, via Ponte Don Melillo, 84084 Fisciano (SA), Italy
b
c
d
Department of Physiology and Pharmacology Siebens-Drake Medical Research Institute, Rm. 237 Schulich School of Medicine and Dentistry University of Western Ontario
London, Ontario N6G 2V4, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
We identified a series of 4-hydroxyquinolines bearing a C1 to C15 alkyl chain at the C2 position and a
carbethoxy/carboxy group at the C3 position of the quinoline nucleus (MC compounds), endowed with
selective inhibitory activity against the p300/CBP HAT enzymes. Enzyme inhibition was investigated
using in vitro HAT assays and by western blot analysis of cellular lysates to examine the acetylation levels
Received 14 November 2008
Revised 20 December 2008
Accepted 24 December 2008
Available online 30 December 2008
of histone H3 and
a-tubulin. When tested in U937 cells, some compounds displayed pro-apoptotic or
cytodifferentiating properties.
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Epigenetics
Chromatin remodeling
Histone acetyltransferase
4
-Hydroxyquinoline
Apoptosis
Cytodifferentiation
Histone acetylation
p300/CBP
In the nucleus of eukaryotic cells, DNA is highly compacted and
organized into chromatin by both histone and non-histone pro-
teins. The fundamental repeating unit of chromatin is the nucleo-
some, which consists of 147 base pairs of DNA wrapped 1.6
times around an octamer of core histone proteins H2A, H2B, H3,
and H4.1
catalyze respectively the addition to and removal of acetyl units
of histones.
5
,6
The HAT enzymes may be classified into two categories depend-
ing upon their cellular localization: type A or nuclear and type B or
cytosolic enzymes. The nuclear HATs can be grouped into several
families based on sequence similarity, including the GNAT
(GCN5-related N-acetyltransferase) family, the MYST (named after
its founding members, in particular MOZ, YBF2/SAS3, SAS2, and
TIP60) family, the p300/CBP family, some nuclear receptor coacti-
vators (like SRC-1, ACTR, TIF2), and other general transcription fac-
,2
Histones undergo extensive post translational modification at
specific amino acids within the histone tails. These modifications
include acetylation, phosphorylation, methylation, ubiquitynation,
sumoylation, and ADP-ribosylation.3
,4
7
,8
The functional implications of reversible acetylation–deacetyla-
tion have been most widely studied. Histone acetylation occurring
at the e-amino group of lysine residues in the N-terminal tails of
core histones mediates conformational changes in nucleosomes.
Two superfamilies of enzymes are involved in this process: histone
acetyltransferase (HAT) and histone deacetylase (HDAC), which
tors (such as TAFII-p250, the TFIIIC family, and others).
In addition to histones, over 40 trascription factors and 30 other
nuclear, cytoplasmic, and viral proteins have been shown to be
acetylated in vivo.
Similarly to HDACs, HATs are typically found in cells in large
multiprotein complexes, but unlike HDACs they exhibit robust cat-
alytic activity as purified proteins. Each HAT complex may regulate
a distinct set of genes and thereby specific cellular functions. For
example, the members of GNAT family (including transcriptional
coactivators, GCN5 and p300/CREB-binding protein-associated fac-
tor (PCAF)) regulate cellular growth and development. The MYST
HATs are involved in a wide range of regulatory functions including
*
Corresponding authors. Tel.: +39 06 4991 3392; fax: +39 06 491 491 (A.M.); tel.:
+39 081 566 7569; fax: +39 081 450 169 (L.A.).
E-mail addresses: antonello.mai@uniroma1.it (A. Mai), lucia.altucci@unina2.it (L.
Altucci).
0
960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.12.097

A. Mai et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1132–1135
1133
transcriptional activation, and are important for cell growth and
cell cycle regulation. The ubiquitously expressed members of the
p300/CBP family are considered as global transcriptional coactiva-
tors, and have a critical role in cell cycle regulation, cellular differ-
entiation and apoptosis.9
of epigenetic targets;34–38 we have recently employed a pheno-
typic screening assay in yeast to identify two quinolines, namely
MC1626 and MC1752 (Fig. 2), which are active at submillimolar/
3
9–41
millimolar range.
In order to improve their HAT inhibiting activity, we introduced
some chemical features typical of AA and MB-3 into the quinoline
nucleus, obtaining the 3-carboxy-4-hydroxy-2-pentylquinoline
MC1823 (4, Fig. 2) with 10/20-fold increased human HAT inhibi-
tory activity with respect to the prototypes MC1626 and
Dysfunction of HAT enzymes is often associated with several
diseases, including cancer. Nevertheless, the role of HATs in cancer
is not straightforward as these enzymes can act either as tumor
suppressors or activators depending on the type and development
stage of tumors. A global loss of H4K16 acetylation has been linked
4
0
MC1752.
1
0
to tumorigenesis, and gene targeting in mice revealed that MOZ
is essential for the generation and maintenance of hematopoietic
stem cells and for the appropriate development of myeloid, ery-
throid, and B lineage cell progenitors.11 p300 and CBP are consid-
ered to be tumor suppressors: indeed, their expression decreases
in hepatocarcinogenesis.12 p300/CBP mutations have been found
in several human leukemias, and missense or truncating mutations
in p300 have been reported in colorectal, gastric, breast, and epi-
Since 4 in human HAT inhibitory assay (U937 cell nuclear ex-
tracts) proved to be more potent than AA (% of inhibition at
50
lM: 30 (4) and 15 (AA)) and a few less active than MB-3 (44%
40
of inhibition at 50
l
M), used as reference drugs, we re-examined
two 4-related quinolines (1 and 7, cited as compounds 15 and 8 in
40
ref. respectively) previously found inactive in the phenotypic
screening in Saccharomyces cerevisiae. In addition, we prepared
additional 4-hydroxyquinolines with 3-carboxy/3-carbethoxy
functions at the C3 position, and differently sized alkyl chains
(C1 to C15 carbon units) at the C2 position (Fig. 2), for testing them
against several human HAT enzymes.
1
3–15
thelial carcinomas.
On the other hand, MOZ can generate fu-
sion genes with other HAT proteins, such as MOZ-TIF2, MOZ-CBP,
and MOZ-p300, in acute myeloid leukemia (AML) by chromosomal
1
1,16–18
translocation.
The 3-carbethoxy-4-hydroxyquinolines 1, 3, 5, and 7 were ob-
tained by reaction of the appropriate ethyl b-oxoester with isatoic
anhydride in presence of sodium hydroxide as catalyst, according
to the method described in Ref. 40. Alkaline hydrolysis of the above
esters with 4 N KOH afforded the 4-hydroxy-3-quinolincarboxylic
Mistargeted and deregulated HAT activities of GCN5/PCAF and
p300 have also been reported to play an important role in genetic
diseases and in human colorectal, breast, and pancreatic can-
1
3,14,19
cers.
Reduced cellular levels of p300 or activity has been pro-
4
0
posed to diminish stress-induced cardiac hypertrophy and
acids 2, 4, 6, and 8 (Scheme 1).
20
development of heart failure. Thus, small chemical inhibitors of
HAT enzymes (HAT inhibitors, HATi) represent novel candidates
for drug development.
The new compounds have been tested on human HAT enzymes
belonging to the p300/CBP (p300 and CBP) and GNAT (GCN5 and
PCAF) families, in comparison with AA and MB-3 as reference
drugs (Table 1) using in vitro HAT assays. Moreover, compounds
1–8 have been validated in living cells by examining the effects
In comparison to the great number of known inhibitors of
2
1,22
HDACs,
a limited number of HATi has been described to date
(Fig. 1), with various degrees of selectivity and cell permeability.
on histone H3 and a-tubulin acetylation both in human leukemia
They can be grouped into three different classes: (i) the synthetic
peptide-CoA-based bisubstrate inhibitors (Lys-CoA, specific for
p300, and H3-CoA-20, specific for PCAF),23 and their cell permeable
U937 and HEK-TE cells (Fig. 3). Finally, the effects of 1–8 on cell cy-
cle, apoptosis induction, and granulocytic differentiation in U937
cell line have been determined (Fig. S1 in Supplementary material,
Figs. 4 and 5).
24
versions LysCoA-SS-R10 and H3-CoA-20-TAT, (ii) the natural
products anacardic acid (AA),25 garcinol, and curcumin
26
27,28
that
When tested at 50 lM against immunoprecipitated p300 HAT
were described as potent p300/PCAF (AA and garcinol) or p300-
selective (curcumin) inhibitors, (iii) some small molecules, such
as the GCN5 inhibitor butyrolactone MB-3,29 a group of isothiazol-
ones that act as p300/PCAF inhibitors with interesting anticancer
from U937 cell nuclear extracts, all the compounds 1–8 showed
high inhibitory activity, regardless of the presence of carbethoxy
or carboxy group at C3, and of C1, C5, C10, or C15 carbon unit chain
at C2. The most potent compounds were the 2-methylquinolines 1
and 2, which displayed approximately 3-fold higher inhibition
3
0
31,32
properties, as well as some AA
and garcinol analogues (LTK
3
3
compounds).
We have undertaken a series of studies involving the design,
synthesis, and biological validation of small molecule modulators
O
R
OH
N
O
OC
2
H
5
OH
N
O
H
MC1626 (R = CH3)
MC1752 (R = H)
MC1823 (4)
H
3
COCHN
N
CoAS
SCoA
NH
H
O
O
2 5 3
H )
; R1 = CH
H
2
N
CH
3
CO-ARTKQTARKSTGGKAPRKQL
H3-CoA-20
1
2
3
5
6
7
8
(R = OC
(R = OH; R = CH
OH
N
O
1
3
)
Lys-CoA
1
(R = OC
2 5 5 11
H ; R = C H )
R
1
(R = OC H ; R = C10H21
2
5
)
OH
R1
(R = OH; R
(R = OC
(R = OH; R = C15
1
= C10H21)
COOH
1
2
5 31
H ; R = C15 H )
1
31
H )
HO
HO
O
O
O
anacardic acid (AA)
Figure 2. Novel quinoline-based HAT inhibitors.
O
O
OH
H
3
CO
HO
OCH
OH
3
O
O
OH
O
OH
O
curcumin
garcinol
O
2 5
C H
+
OC
2
H
5
a
O
OH
O
b
R
N
H
O
O
R
1
R1
R1
HO
N
N
N
S
X = H, Cl
3 3 2 5
R = NO , Cl, CF , OCH , COOC H
O
X
2
1, 3, 5, 7
O
2, 4, 6, 8
MB-3
isothiazolones
Scheme 1. Reagents and conditions; (a) NaOH, dioxane, reflux; (b) 4 N KOH, EtOH,
Figure 1. Known HAT inhibitors.
reflux.

1
134
A. Mai et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1132–1135
Table 1
Effects of MC compounds (50
l
M) on four different human HAT enzymesa
Compound
R
1
R % HAT remaining activity
p300-IP
CBP-GST
GCN5
PCAF-GST
Control (DMSO)
100
100
100
100
1
2
3
4
5
6
7
8
OC
OH
OC
OH
OC
OH
OC
2
OH
2
H
5
H
5
H
5
H
5
CH
CH
3
16.4
11.4
47.7
82.0
39.1
53.9
39.8
46.9
53.1
58.6
13.4
20.5
91.2
19.0
93.4
13.2
116.5
14.4
44.0
45.9
97.4
97.4
101.8
98.0
93.4
95.4
96.8
103.3
112.6
54.5
81.7
104.2
100.0
102.8
90.1
91.5
82.4
62.7
52.1
76.8
3
2
C
C
C
C
C
C
5
H
H
11
11
5
2
10
10
15
15
H
21
21
31
31
H
H
H
AA
MB-3
a
Values are means ± SD determined from at least three experiments.
Figure 4. Apoptosis induction of 5 and 7 at 20 and 100 lM in U937 cells (Annexin
V/PI method).
Figure 5. Granulocytic differentiation induced by compounds 1–8 (20 lM) in U937
cells (CD11c method).
Western blot analyses were performed on U937 cell lines to
study the effects of 1–8 on the acetylation levels of histone H3 as
well as of the non-histone substrate a-tubulin (Fig. 3A). Since the
U937 cells show only weak basal acetylation levels for both the
substrates, we pre-treated the cells with the well-known HDAC
Figure 3. (A) Effects of compounds 1–8 (100
acetylation in SAHA-pretreated U937 cells. (B) Effects of compounds 1–8 (100
on histone H3 acetylation level in HEK-TE cells.
l
M) on histone H3 and
a
-tubulin
M)
inhibitor SAHA (suberoylanilide hydroxamic acid, 2 h, 5
l
M, ‘+’ in
to increase the acetylation amounts of histone H3
-tubulin. After wash out, we determined the effects of 1-8,
used at 100 M, on acetylation levels after 4 h of treatment. AA,
curcumin, and MB-3 (all at 100 M) were used as reference drugs.
l
42,43
Fig. 3A)
and
a
l
compared to AA and MB-3. The other quinolines showed a p300
inhibitory activity comparable to those of the reference drugs, with
the exception of 4 which was less active. When we carried out as-
l
As depicted in Figure 3A, the tested quinolines induced hypoacet-
ylation on both the histone and non-histone substrates. In the acet-
yl-H3 assay, the majority of the tested compounds showed high
hypoacetylating activity comparable to that of curcumin and MB-
says with the recombinant GST-CBP fusion protein, at 50 lM high
inhibitory activity was registered with the carboxylic acid deriva-
tives (2, 4, 6, and 8), whereas the corresponding ethyl esters were
inactive. An important exception was the 3-carbethoxy-4-hydro-
xy-2-methylquinoline 1, which was as active as (if not more than)
the related carboxylic acid 2. When tested against GCN5 and PCAF
HAT enzymes, at 50 lM all compounds 1–8 displayed low (1, 5–7
against PCAF-GST) or no activity, the only active quinoline being
compound 8, which showed 37.3% of PCAF-GST inhibitory activity
at 50 lM.
3
. In contrast, 7 had no detectable effects, while 2 and AA caused
moderate reduction in H3 acetylation (Fig. 3A).
In acetyl- -tubulin assay, all the tested compounds effectively
a
decreased the acetylation levels of the substrate, with the excep-
tion of 1 and 5, which produced only marginal decreases in tubulin
acetylation, and curcumin was practically inactive using our exper-
imental conditions (Fig. 3A).

A. Mai et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1132–1135
1135
Further western blot analyses were performed to investigate
the effects compounds 1–8 at 100 M in human immortalized kid-
References and notes
l
1.
2.
3.
Kornberg, R. D.; Lorch, Y. Cell 1999, 98, 285.
Lee, K. K.; Workman, J. L. Nat. Rev. Mol. Cell Biol. 2007, 8, 284.
Biel, M.; Wascholowski, V.; Giannis, A. Angew. Chem. Int., Ed. Engl. 2005, 44,
3186.
ney epithelial cells (HEK-TE), which are transformed but not
tumorigenic. These cells show higher basal acetylation of histone
H3 compared to U937 cells. Data reported in Fig. 3B confirmed
the high hypoacetylating effects of most of our quinoline deriva-
tives in this cell system following a 3-h of treatment.
4
5
.
.
Bradbury, E. M. Bioessays 1992, 14, 9.
Mai, A.; Massa, S.; Rotili, D.; Cerbara, I.; Valente, S.; Pezzi, R.; Simeoni, S.; Ragno,
R. Med. Res. Rev. 2005, 25, 261.
Finally, the quinoline compounds 1–8 and the reference com-
pounds, AA and MB-3, were tested on U937 cells to evaluate their
effects on cell cycle, apoptosis induction, and granulocytic differen-
6. Kouzarides, T. Cell 2007, 128, 693.
7. Roth, S. Y.; Denu, J. M.; Allis, C. D. Annu. Rev. Biochem. 2001, 70, 81.
8
9
.
.
Marmorstein, R.; Roth, S. Y. Curr. Opin. Genet. Dev. 2001, 11, 155.
Carrozza, M. J.; Utley, R. T.; Workman, J. L.; Cote, J. Trends Genet. 2003, 19,
tiation. When tested at 20
cle arrest at the G1/S phase, with the total loss of cells in G2 phase
Fig. S1 in Supplementary material). The other compounds dis-
lM for 24 h, only 5 and 7 caused cell cy-
321.
10. Fraga, M. F.; Ballestar, E.; Villar-Garea, A.; Boix-Chornet, M.; Espada, J.; Schotta,
G.; Bonaldi, T.; Haydon, C.; Ropero, S.; Petrie, K.; Iyer, N. G.; Perez-Rosado, A.;
Calvo, E.; Lopez, J. A.; Cano, A.; Calasanz, M. J.; Colomer, D.; Piris, M. A.; Ahn, N.;
Imhof, A.; Caldas, C.; Jenuwein, T.; Esteller, M. Nat. Genet. 2005, 37, 391.
11. Katsumoto, T.; Yoshida, N.; Kitabayashi, I. Cancer Sci. 2008, 99, 1523.
(
played no effects on cell cycle progression (data not shown). In
the Annexin V/propidium iodide (PI) double staining apoptotic as-
say, again the only significant results were obtained with 5 and 7 at
1
2. Ohta, K.; Ohigashi, M.; Naganawa, A.; Ikeda, H.; Sakai, M.; Nishikawa, J.;
Imagawa, M.; Osada, S.; Nishihara, T. Biochem. J. 2007, 402, 559.
3. Gayther, S. A.; Batley, S. J.; Linger, L.; Bannister, A.; Thorpe, K.; Chin, S. F.; Daigo,
Y.; Russell, P.; Wilson, A.; Sowter, H. M.; Delhanty, J. D.; Ponder, B. A.;
Kouzarides, T.; Caldas, C. Nat. Genet. 2000, 24, 300.
concentrations of 20 and 100
and 7 were 1.4- to 18.3-fold more potent than AA and MB-3 in
inducing apoptosis, whereas at 100 M they were more efficient
lM for 24 h. In particular, at 20 lM 5
1
l
14. Muraoka, M.; Konishi, M.; Kikuchi-Yanoshita, R.; Tanaka, K.; Shitara, N.; Chong,
than MB-3 and 1.9- to 5.7-fold less active than AA.
J. M.; Iwama, T.; Miyaki, M. Oncogene 1996, 12, 1565.
15. Santos-Rosa, H.; Caldas, C. Eur. J. Cancer 2005, 41, 2381.
Granulocytic differentiation was evaluated through the CD11c
1
1
6. Egger, G.; Liang, G.; Aparicio, A.; Jones, P. A. Nature 2004, 429, 457.
7. Rozman, M.; Camos, M.; Colomer, D.; Villamor, N.; Esteve, J.; Costa, D.; Carrio,
A.; Aymerich, M.; Aguilar, J. L.; Domingo, A.; Sole, F.; Gomis, F.; Florensa, L.;
Montserrat, E.; Campo, E. Genes Chromosomes Cancer 2004, 40, 140.
method, by treatment of the U937 cells with 1–8 (20
lM) for
2
4 h. Subsequently, the number of the CD11c positive/PI negative
cells was determined. In this assay, some compounds (3, 6) showed
a cytodifferentiating activity similar to those of the reference
drugs, whereas 8 was more efficient.
18. Carapeti, M.; Aguiar, R. C.; Goldman, J. M.; Cross, N. C. Blood 1998, 91, 3127.
1
2
9. Ionov, Y.; Matsui, S.; Cowell, J. K. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 1273.
0. Wei, J. Q.; Shehadeh, L. A.; Mitrani, J. M.; Pessanha, M.; Slepak, T. I.; Webster, K.
A.; Bishopric, N. H. Circulation 2008, 118, 934.
In conclusion, we identified a series of 4-hydroxyquinolines
(
compounds 1–8) with differently sized (from C1 to C15 methylene
21. Minucci, S.; Pelicci, P. G. Nat. Rev. Cancer 2006, 6, 38.
2
2
2. Bolden, J. E.; Peart, M. J.; Johnstone, R. W. Nat. Rev. Drug Discov. 2006, 5, 769.
3. Lau, O. D.; Kundu, T. K.; Soccio, R. E.; Ait-Si-Ali, S.; Khalil, E. M.; Vassilev, A.;
Wolffe, A. P.; Nakatani, Y.; Roeder, R. G.; Cole, P. A. Mol. Cell 2000, 5, 589.
units) alkyl chains at C2 and a carbethoxy/carboxy group at C3,
that function as HAT inhibitors. Moreover, we tested the MC com-
pounds in human leukemia U937 cell line to study their effects on
apoptosis induction and granulocytic differentiation. When tested
against four different HAT enzymes (p300, CBP, GCN5, and PCAF),
compounds 1–8 displayed selective inhibition towards the mem-
bers of the p300/CBP family of HATs. In particular, the 3-carbeth-
oxy- and 3-carboxy-4-hydroxy-2-methylquinolines 1 and 2 were
the most potent inhibitors of p300 and CBP, and 4- to 5-fold
24. Zheng, Y.; Balasubramanyam, K.; Cebrat, M.; Buck, D.; Guidez, F.; Zelent, A.;
Alani, R. M.; Cole, P. A. J. Am. Chem. Soc. 2005, 127, 17182.
25. Balasubramanyam, K.; Swaminathan, V.; Ranganathan, A.; Kundu, T. K. J. Biol.
Chem. 2003, 278, 19134.
26. Balasubramanyam, K.; Altaf, M.; Varier, R. A.; Swaminathan, V.; Ravindran, A.;
Sadhale, P. P.; Kundu, T. K. J. Biol. Chem. 2004, 279, 33716.
27. Balasubramanyam, K.; Varier, R. A.; Altaf, M.; Swaminathan, V.; Siddappa, N. B.;
Ranga, U.; Kundu, T. K. J. Biol. Chem. 2004, 279, 51163.
28. Marcu, M. G.; Jung, Y. J.; Lee, S.; Chung, E. J.; Lee, M. J.; Trepel, J.; Neckers, L.
Med. Chem. 2006, 2, 169.
(
p300 assay) or 2- to 3-fold (CBP assay) more effective than AA
29. Biel, M.; Kretsovali, A.; Karatzali, E.; Papamatheakis, J.; Giannis, A. Angew.
and MB-3 reference drugs. In the p300 assay the other compounds
showed almost the same potency as the reference drugs, with the
exception of 4 which was less effective. In contrast, in the CBP as-
say only the other 3-carboxy derivatives 4, 6, and 8 displayed high
enzyme inhibition, whereas the corresponding ethyl esters were
totally inactive. Despite the fact that the 2-methylquinoline com-
pounds were the most potent in inhibiting the p300/CBP HATs, in
human leukemia U937 cells the 2-decyl- and 2-pentadecylquino-
line ethyl esters 5 and 7 showed the highest apoptosis induction,
and the corresponding carboxylic acids 6 and 8 produced the high-
est fraction of CD11c positive/PI negative cells, perhaps due to bet-
ter cell permeability resulting from the presence of a highly
lipophylic alkyl chain at the C2 position of the quinoline nucleus.
Studies are in progress to gain insights on structure-activity rela-
tionship of these novel p300/CBP-selective HAT inhibitors.
Chem. Int., Ed. Engl. 2004, 43, 3974.
30. Stimson, L.; Rowlands, M. G.; Newbatt, Y. M.; Smith, N. F.; Raynaud, F. I.;
Rogers, P.; Bavetsias, V.; Gorsuch, S.; Jarman, M.; Bannister, A.; Kouzarides, T.;
McDonald, E.; Workman, P.; Aherne, G. W. Mol. Cancer Ther. 2005, 4, 1521.
1. Eliseeva, E. D.; Valkov, V.; Jung, M.; Jung, M. O. Mol. Cancer Ther. 2007, 6, 2391.
2. Sbardella, G.; Castellano, S.; Vicidomini, C.; Rotili, D.; Nebbioso, A.; Miceli, M.;
Altucci, L.; Mai, A. Bioorg. Med. Chem. Lett. 2008, 18, 2788.
3. Mantelingu, K.; Reddy, B. A.; Swaminathan, V.; Kishore, A. H.; Siddappa, N. B.;
Kumar, G. V.; Nagashankar, G.; Natesh, N.; Roy, S.; Sadhale, P. P.; Ranga, U.;
Narayana, C.; Kundu, T. K. Chem. Biol. 2007, 14, 645.
34. Mai, A.; Massa, S.; Lavu, S.; Pezzi, R.; Simeoni, S.; Ragno, R.; Mariotti, F. R.;
Chiani, F.; Camilloni, G.; Sinclair, D. A. J. Med. Chem. 2005, 48, 7789.
5. Mai, A.; Massa, S.; Pezzi, R.; Simeoni, S.; Rotili, D.; Nebbioso, A.; Scognamiglio,
A.; Altucci, L.; Loidl, P.; Brosch, G. J. Med. Chem. 2005, 48, 3344.
36. Mai, A.; Rotili, D.; Massa, S.; Brosch, G.; Simonetti, G.; Passariello, C.; Palamara,
3
3
3
3
A. T. Bioorg. Med. Chem. Lett. 2007, 17, 1221.
3
7. Mai, A.; Valente, S.; Cheng, D.; Perrone, A.; Ragno, R.; Simeoni, S.; Sbardella, G.;
Brosch, G.; Nebbioso, A.; Conte, M.; Altucci, L.; Bedford, M. T. ChemMedChem
2007, 2, 987.
8. Mai, A.; Cheng, D.; Bedford, M. T.; Valente, S.; Nebbioso, A.; Perrone, A.; Brosch,
G.; Sbardella, G.; De Bellis, F.; Miceli, M.; Altucci, L. J. Med. Chem. 2008, 51, 2279.
9. Ornaghi, P.; Rotili, D.; Sbardella, G.; Mai, A.; Filetici, P. Biochem. Pharmacol.
3
Acknowledgments
3
2005, 70, 911.
This work was partially supported by grants from PRIN 2006
A.M.), FIRB RBIP067F9E and RETI FIRB RBPR05NWWC_006
A.M.), European Union (CancerDip project number 200620; Apo-
40. Mai, A.; Rotili, D.; Tarantino, D.; Ornaghi, P.; Tosi, F.; Vicidomini, C.; Sbardella,
G.; Nebbioso, A.; Miceli, M.; Altucci, L.; Filetici, P. J. Med. Chem. 2006, 49, 6897.
(
(
41. Smith, A. T.; Livingston, M. R.; Mai, A.; Filetici, P.; Queener, S. F.; Sullivan, W. J.,
Jr. Antimicrob. Agents Chemother. 2007, 51, 1109.
sys project number 200767) (L.A.), PRIN 2006 (L.A.), AIRC (L.A.)
and Regione Campania, L.5 annualità 2005 (L.A.).
42. Grant, S.; Easley, C.; Kirkpatrick, P. Nat. Rev. Drug Discov. 2007, 6, 21.
3. Marks, P. A.; Breslow, R. Nat. Biotechnol. 2007, 25, 84.
4