Vorinostat-like molecules as structural, stereochemical, and pharmacological tools

Article abstract of DOI:10.1021/ml100028g

The inhibitory activity of an ?-alkoxy analogue of the HDAC inhibitor, Vorinostat (SAHA), against the 11 isoforms of HDAC is described and evaluated with regard to structural biology information retrieved through computational methods. Preliminary absorpt

Full text of DOI:10.1021/ml100028g

pubs.acs.org/acsmedchemlett
Vorinostat-Like Molecules as Structural, Stereochemical,
and Pharmacological Tools
Stephen Hanessian,*,† Luciana Auzzas,†,‡ Andreas Larsson,†,§ Jianbin Zhang,†
,
Giuseppe Giannini,* Grazia Gallo, Andrea Ciacci, and Walter Cabri
†
ꢀ
ꢀ
ꢀ
Department of Chemistry, Universite de Montreal, P.O. Box 6128, Station Centre-ville, Montreal, QC, H3C 3J7, Canada,
‡Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Traversa La Crucca 3, I-07040 Sassari, Italy,
§Department of Chemistry, Umeå University, 901 87, Umeå, Sweden, and Sigma-Tau Research & Development,
Via Pontina Km 30.400, I-00040 Pomezia, Roma, Italy
ABSTRACT The inhibitory activity of an ω-alkoxy analogue of the HDAC inhibitor,
Vorinostat (SAHA), against the 11 isoforms of HDAC is described and evaluated with
regard to structural biology information retrieved through computational meth-
ods. Preliminary absorption and metabolism studies were performed, which
positioned this compound as a potential candidate for further preclinical studies
and delineated measures for improving its pharmacokinetic profile.
KEYWORDS HDAC promiscuous inhibitors, SAHA analogues, HDAC1-11 profile,
class IIa-specific profile, absorption and metabolism
n spite of the significant progress made in HDAC research,1-4
the quest for isoform-selective inhibitors continues to
present a major challenge.5-7 To date, detailed biostruc-
describe the details for the improved and shortened synthesis
of 2, together with the biostructural insights through mole-
cular modeling and a preliminary study of its in vitro activity
against an extended panel of HDACs.
I
tural information is available only regarding a few among the
known 11 metallo-enzymes.1,8-11 Consequently, the design of
isoform- and class-selective inhibitors is somewhat arbitrary
and derivative.1,7,12-14 In addition, complete data regarding
the factual HDAC profile for most of the early discovered
agents are not available, since the development of effective
isozyme-based assays is relatively recent.5-7,15-18 As a
consequence of the complex, pleiotropic nature of cancer,
promiscuous HDAC inhibitors such as Vorinostat (1) (SAHA,
suberoylanilide hydroxamic acid)19 (Figure 1) seem superior
and as safe in the clinic as compared to the few class-specific
agents available.5-7,15
Ligand-based approaches are a first-choice solution to
delineate the structural requirements for HDAC selectivity,
especially with the emergence of ω-aryl alkanoyl hydroxa-
mates such as Vorinostat as clinical candidates.1,7,12-14 In
this regard, simple and readily accessible surrogates are
worthy of study, provided that they bear pharmacophoric
determinants as close as possible to a maximum common
substructural consensus required to target the whole HDAC
panel. The judicious inclusion of specific appendages cap-
able of interacting with specific residues in the cap region of
HDACs can provide valuable structural, functional, and
stereochemical insight into the design of new inhibitors.
In a previous study, we determined the optimal alkyl chain
length for activity against a single isoform, HDAC2.20 De-
signed for understanding the role of the chirality in simple
ω-alkoxyanalogues ofVorinostat, compound(R/S)-2emerged
as a promising lead for its preliminary cytotoxic activity
against leukemia, colon, and lung tumor cell lines. Here, we
Although relatively simple in conception, the previous
nine-step synthesis of racemic 220 was shortened and
adapted to produce gram-scale material for pharmacological
studies (Supporting Information) (Scheme 1). The required
8-carbon chain of (R/S)-2 was assembled by a cross meta-
thesis reaction21 between an excess of methyl acrylate and
the olefin 3, readily available from (R/S)-glycidol,22 in the
presence of Grubbs' second generation catalyst in CH2Cl2 at
40 °C. Catalytic reduction to the methyl ester 4, followed by
Sc(OTf)3-assisted O-alkylation with PMB trichloroacetimi-
date,23 led to 5. This was deprotected with TBAF, and the
product was submitted to a Swern oxidation to obtain
aldehyde 6 in 94% yield for two steps. Jones oxidation of 6
led to the carboxylic acid intermediate, which was immedi-
ately coupled as a crude with aniline in the presence of
Goodman's reagent (DEBPT),24 leading to anilide 7 in 75%
yield. Finally, conversion to hydroxamic acid (R/S)-2 was
easily achieved by treating methyl ester 7 with hydroxyla-
mine and NaOH in MeOH. Enantiopure 2 could be obtained
starting from (R)- or (S)-3 or by Mitsunobu inversion of
configuration of the individual alcohols.20 Using this proto-
col, the synthesis of (R/S)-2 was achieved in seven steps from
3 in 37% overall yield.
In preliminary testing against HeLa immunopurified
HDAC2 assay,20 (R/S)-2 exhibited comparable if not improved
Received Date: December 30, 2009
Accepted Date: March 3, 2010
Published on Web Date: March 11, 2010
r
2010 American Chemical Society
70
DOI: 10.1021/ml100028g ACS Med. Chem. Lett. 2010, 1, 70–74
|

pubs.acs.org/acsmedchemlett
nanomolar potency over Vorinostat. Surprisingly, no signifi-
cant difference in inhibitory activity was found between (R/S)-
2 and its individual enantiomers against this HDAC isoform.25
A subsequent antiproliferative evaluation against three differ-
ent human cancer cell lines (NB4, H460, and HCT-116)
substantiated the potential of 2 as a promising candidate for
further profiling.
The potency of racemic and enantiopure 2 to inhibit 11
isolated human HDAC isozymes in the presence of a fluoro-
genic peptide bound to the RHKK(Ac) fragment of p53
(residues 379-382) as the substrate is shown in Table 1.18
Vorinostat,19 trichostatin A (TSA),26 and NVP-LAQ82427 were
used as reference compounds.
found between the racemic 2 and its individual enantiomers,
which proved to be equipotent against all of the zinc-
dependent HDACs. To gain more insight into this equiva-
lence, a docking analysis of the individual enantiomers of 2
was performed based on the crystal structures of HDAC88
and HDAC7,9 which were chosen as representatives of class I
and II HDACs, respectively (Figure 2).28 In binding these
isoforms, a T-shape arrangement was observed for both
enantiomers of ligand 2, which projected its aromatic motifs
out from the active site channel toward lipophilic pockets
located in opposite directions on the enzyme surface. The
Phe208 and Phe152 residues in the rim of HDAC8 were
found to engage in π-π interactions with either the anilide
or the p-methoxybenzyl moieties of each enantiomer.
The relative distances between each Phe residue and the
aromatic moieties of both enantiomers, together with the
corresponding number of interactions, are shown in Table 2.29
The sum of π-π interactions produced by the (S)- and (R)-
enantiomers of 2 with both Phe residues was found to be
almost the same in HDCA8. Overall, 13 interactions were
detected in the case of (S)-2, and 11 were detected in the case
of (R)-2, which may account for the slight difference shown
by the enantiomers in binding this isoform [IC50(R)/(S) = 3.3].
The binding was further stabilized by interactions between
the amide bonds of the (R)- and (S)-isomers with a conserved
water molecule as well as with a conserved Asp residue8
(Asp101 in HDAC8). In addition, a H-bond between the
methoxy group of the (S)-isomer and the Lys33 in HDAC8
contributed to stabilization of the complex. This Lys residue
is peculiar to HDAC88 and may also play a part in the small
difference in activity between the enantiomers.
From this investigation, we confirmed the role of 2 as a
promiscuous inhibitor, displaying an activity comparable to
Vorinostat against all HDACs. No significant difference was
Figure 1. Structure of Vorinostat (SAHA) and the ω-alkoxy analogue 2.
Scheme 1. Synthesis of ω-Alkoxy Analogue 2a
Upon binding to HDAC7, analogous interactions were
observed in the rim of this isozyme, involving Phe738
(Phe208 in HDAC8), Phe679 (Phe152 in HDAC8), and the
aromatic groups of both enantiomers of 2. In this case, three
and four π-π interactions stabilizing the complex of (S)- and
(R)-2, respectively, via their anilide and PMB rings, were
recorded as compared to HDAC8 (Table 2). A conserved
water molecule stabilized the isomers through interactions
with the amide and the ether bonds of (S)-2 and (R)-2,
respectively. An interaction was found between the
Asp626 and the amide bond of (R)-2, which might explain
its marginally higher activity over the (S)-enantiomer
[IC50(S)/(R) = 3.4]. In addition, further π-π interactions were
observed between the Phe737 and the PMB ring of (R)-2 and
a Reagents and conditions: (a) (i) CH2dCHCO2Me, Grubbs' second
generation catalyst (3 mol %), CH2Cl2, 40 °C, 1 h (97%); (ii) H2, Pd-C,
MeOH, 18 h (97%). (b) CCl3C(dNH)OPMB, Sc(OTf)3 (10 mol %), MePh,
0 °C to room temperature, 12 h (58%). (c) (i) TBAF, THF, 0 °C to room
temperature, 4 h (95%); (ii) (COCl)2, DMSO, CH2Cl2, -78 °C, then Et3N,
-78 °C to room temperature (99%). (d) (i) Jones reagent, 0 °C, 5 min
(99%); (ii) DEBPT, DIPEA, THF, then PhNH2, 0 °C to room temperature,
48 h (75%). (e) HONH2(aq), 1.0 N NaOH, MeOH, 0 °C to room
temperature (95%).
Table 1. In Vitro Inhibitory Activity of Racemic and Enantiopure 2 against HDAC1-11 Isoforms (IC50, nM)a
HDAC1
HDAC2
HDAC3
HDAC4
HDAC5
HDAC6
HDAC7
HDAC8
HDAC9
HDAC10
HDAC11
Vorinostat
TSA
258.00
7.12
921.00
22.95
350.00
10.32
493.00
12.07
378.00
16.48
28.60
0.42
344.00
22.46
243.00
89.53
316.00
38.12
456.00
20.10
362.00
15.15
NVP-LAQ824
(R/S)-2
(S)-2
3.23
15.70
10.50
5.82
5.58
5.93
6.11
3.84
8.24
8.41
5.58
53.40
95.30
48.50
254.00
234.00
122.00
131.00
131.00
172.50
648.00
555.00
364.00
134.00
205.00
151.00
20.10
21.00
18.10
432.00
733.00
219.00
331.00
236.00
781.00
247.00
382.00
262.00
179.00
323.00
161.00
197.00
278.00
189.00
(R)-2
a Values are the means of a minimum of three experiments and are given in the nanomolar range. Compound 2 was tested in 10-dose IC50 mode in
triplicate with 3-fold serial dilution starting from 50 μM solutions. In the case of TSA and Vorinostat, a 10 μM solution was used. Screening was performed
by Reaction Biology Corp. (Malvern, PA).
r
2010 American Chemical Society
71
DOI: 10.1021/ml100028g ACS Med. Chem. Lett. 2010, 1, 70–74
|

pubs.acs.org/acsmedchemlett
Figure 2. Left: best docking solutions of (S)-2 (yellow) and (R)-2 (green) on HDAC8 crystal structure.28 Right: best docking solutions of (S)-2
(yellow) and (R)-2 (green) on HDAC7 crystal structure.28 H-bonds between the ligands and the enzyme are shown as dashed lines. Calculated
€
with Glide v. 5.0 Schrodinger, L.L.C. (New York, www.schrodinger.com). For additional details, see the Supporting Information.
Table 2. π-π Interaction Distances (Å) and Number of Interactions29 between the Aromatic Rings of (S)- and (R)-2 and the Phe Residues in
the Rim of HDAC8 (Phe208 and Phe152) and HDAC7 (Phe738 and Phe679)a
HDAC8
HDAC7
no. of interactions
no. of interactions
no. of interactions
no. of interactions
Phe208
(Phe208)
Phe152
(Phe152)
Phe738
(Phe738)
Phe679
(Phe679)
(S)-23.5-4.9 (Anil)
(R)-23.7-4.4 (PMB)
6
7
4.9-5.6 (PMB)
4.1-5.0 (Anil)
7
4
4.3 (Anil)
5.0 (PMB)
1
1
5.2-5.5 (PMB)
4.9-5.3 (Anil)
3
3
a Anil, anilide ring; PMB, p-methoxybenzyl ring.
Table 3. In Vitro Inhibitory Activity of (R/S)-2 against Class IIa
HDAC Isoforms (IC50, μM)a
the anilide motif of (S)-2, equally reinforcing the binding of
both enantiomers.
Despite the different Phe binding interaction sites observed
for the two isomers of 2 against these HDACs, the levels of their
inhibitory activity were not appreciably changed. Overall, their
binding mode suggested that the lipophilic interactions had a
major role in stabilizing their individual complexes.30 In part, our
hypothesis is also confirmed by a detailed structural comparison
between HDAC1 and HDAC8.31 Considering the high level of
conservation of Phe residues among the HDAC isoforms,8-11
these interactions might explain the lack of discrimination
between the individual enantiomers.
It has been recently argued that the enzymatic activity
associated with class IIa HDACs ectopically expressed in
mammalian cells might be the result of a residual contami-
nation by class I HDACs present in class IIa immunocom-
plexes.16 In view of this possibility, we deemed it necessary
to extend our assay to include this method of HDAC profiling
with (R/S)-2. The in vitro test was performed in the presence
of the class IIa-specific fluorogenic substrate acetyl-Lys-
(trifluoroacetyl)-AMC, using Vorinostat and TSA as the refer-
ence compounds (Table 3; see also the Supporting
Information). Given the low sensitivity of this substrate, a
remarkable decrease in the activity for all of the tested
compounds was observed, which was in the micromolar
range. For this reason, the two enantiomers of 2 were not
tested. Although compound (R/S)-2 was found to be as active
as Vorinostat against HDAC7 and HDAC9, and slightly less
active against HDAC5, it was totally inactive toward HDAC4.
HDAC4
HDAC5
HDAC7
HDAC9
Vorinostatb
TSA
6.64
5.51
2.56
24.8
49.5
4.23
82.8
56.3
5.59
58.6
7.92
(R/S)-2
>1000
a Values are the means of a minimum of three experiments and are
given in the micromolar range. Substrate concentration, 10 μM. b Data
from Reaction Biology Corp. (http://www.reactionbiology.com/HDACS/
HDACsClass2ASub%20Controlcurves.pdf).
Thus, a dramatic difference was observed between the
activities of (R/S)-2 and Vorinostat in the class IIa-specific
assay against HDAC4, as compared to the results shown in
Table 1 in the class I-II-IV profiling assay. As suggested by the
Gallinari group,16 this might be due to the presence of a
residual deacetylase activity from contaminant class I
HDACs in traditional profiling assays. The generality of this
observation must be validated by a careful scrutiny of the
appropriate substrates and the purity of recombinant iso-
enzymes enabling accurate HDAC profiling.3,5-7,15-17
Preliminary assays were performed on (R/S)-2 to assess its
absorption and metabolism. Human colorectal carcinoma-
derived cells (Caco-2 cell line) were used as an established in
vitro model for the prediction of (R/S)-2 absorption across
the human intestine.32 A transport study was performed to
obtain apparent permeability coefficients (Papp) in the apical
to basolateral direction, and the result was compared to
r
2010 American Chemical Society
72
DOI: 10.1021/ml100028g ACS Med. Chem. Lett. 2010, 1, 70–74
|

pubs.acs.org/acsmedchemlett
Vorinostat and to the reference compounds cimetidine,
vinblastine, and caffeine (Supporting Information). Accord-
ing to this model, a high intestinal permeability can be
predicted for Papp coefficients higher than 50. In this assay,
a good level of oral absorption was predicted for (R/S)-2,
REFERENCES
(1)
(2)
(3)
(4)
Zhang, L.; Fang, H.; Xu, W. Strategies in Developing Promis-
ing Histone Deacetylase Inhibitors. Med. Res. Rev. 2009, DOI:
10.1002/med.20169.
Paris, M.; Porcelloni, M.; Binaschi, M.; Fattori, D. Histone
Deacetylase Inhibitors: From Bench to Clinic. J. Med. Chem.
2008, 51, 1505–1529.
Bolden, J. E.; Peart, M. J.; Johnstone, R. W. Anticancer
Activities of Histone Deacetylase Inhibitors. Nat. Rev. Drug
Discovery 2006, 5, 769–784.
Minucci, S.; Pelicci, P. G. Histone Deacetylase Inhibitors and
the Promise of Epigenetic (and More) Treatments for Cancer.
Nat. Rev. Cancer 2006, 6, 38–51.
which showed a Papp value higher than Vorinostat (Papp
=
219.2 vs Papp = 77.6 nm/s) and comparable to caffeine
(Papp = 312.4 nm/s).
The metabolism study was performed upon incubation of
(R/S)-2 with human cryopreserved hepatocytes (HC2 and
H655) and by subsequent quantification of the remaining
parent compound from the incubated supernatant by
UPLC.33 The metabolicstability wasdefined asthe percentage
of parent compound lost over time in the active test system.
Vorinostat was used as a reference compound, together with
7-ethoxycoumarin and 7-hydroxycoumarin as the positive
controls of hepatocyte competence for phase I and II meta-
bolism, respectively (0.42% left after 90 min at 1 μM con-
centration and 2.08% left under the same conditions).33
Although a lower stability was observed for (R/S)-2 as com-
pared to Vorinostat (23% left after 90 min at 1 μM concentra-
tion vs 61% left under the same conditions for Vorinostat),
measures for improving its pharmacokinetic profile can be
taken based on the chemical modification at specific sites.34
In conclusion, we have studied the structural and stereo-
chemical effects of an optimized ω-alkoxy analogue of
Vorinostat as a probe to assess its in vitro activity profile
against 11 isoforms of HDAC. Although a higher permeability
was noted for compound 2 in the Caco-2 assay as compared
to Vorinostat, a faster rate of metabolism was observed. It is
possible that O-demethylation or benzylic carbon oxidation
is taking place, which could be avoided with appropriate
functional group modifications. Results pertaining to these
and other variations will be disclosed in due course.
(5)
(6)
Witt, O.; Deubzer, H. E.; Milde, T.; Oehme, I. HDAC Family: What
Are the Cancer Relevant Targets?. Cancer Lett. 2009, 277, 8–21.
Khan, N.; Jeffers, M.; Kumar, S.; Hackett, C.; Boldog, F.;
Khramtsov, N.; Qian, X.; Mills, E.; Berghs, S. C.; Carey, N.;
Finn, P. W.; Collins, L. S.; Tumber, A.; Rithchie, J. W.; Jensen,
P. B.; Lichenstein, H. S.; Sehested, M. Determination of the
Class and Isoform Selectivity of Small-Molecule Histone
Deacetylase Inhibitors. Biochem. J. 2008, 409, 581–589.
Bieliauskas, A. V.; Pflum, M. K. H. Isoform-Selective Histone
Deacetylase Inhibitors. Chem. Soc. Rev. 2008, 37, 1402–1413.
Vannini, A.; Volpari, C.; Gallinari, P.; Jones, P.; Mattu, M.; Carfí,
(7)
(8)
€
A.; De Francesco, R.; Steinkuhler, C.; Di Marco, S. Substrate
Binding to Histone Deacetylase as Shown by the Crystal
Structure of the HDAC8-Substrate Complex. EMBO Rep.
2007, 8, 879-884 and references therein.
Schuetz, A.; Min, J.; Allali-Hassani, A.; Schapira, M.; Shuen,
M.; Loppnau, P.; Mazitschek, R.; Kwiatkowski, N. P.; Lewis,
T. A.; Maglathin, R. L.; McLean, T. H.; Bochkarev, A.; Plotnikov,
A. N.; Vedadi, M.; Arrowsmith, C. H. J. Human HDAC7
Harbors a Class IIa Histone Deacetylase-Specific Zinc Binding
Motif and Cryptic Deacetylase Activity. J. Biol. Chem. 2008,
283, 11355–11363.
(9)
(10) Bottomley, M. J.; Lo Surdo, P.; Di Giovine, P.; Cirillo, A.;
Scarpelli, R.; Ferrigno, F.; Jones, P.; Neddermann, P.; De
€
Francesco, R.; Steinkuhler, C.; Gallinari, P.; Carf, A. Structural
SUPPORTING INFORMATION AVAILABLE Synthetic pro-
cedures, 1H and 13C NMR spectra of hydroxamic acid 2, experi-
mental procedures for biological assays, molecular modeling
procedures, and selection of recent references for complete and
partial HDAC profiling. This material is available free of charge via
the Internet at http://pubs.acs.org.
and Functional Analysis of the Human HDAC4 Catalytic
Domain Reveals a Regulatory Structural Zinc-binding Do-
main. J. Biol. Chem. 2008, 283, 26694-26704 and references
therein.
(11) http://www.actrec.gov.in/histone/infobase.htm.
(12) Hu, F.; Chou, C. J.; Gottesfeld, J. M. Design and Synthesis of
Novel Hybrid Benzamide-Peptide Histone Deacetylase Inhi-
bitors. Bioorg. Med. Chem. Lett. 2009, 19, 3928–3931.
(13) Olsen, C. A.; Ghadiri, M. R. Discovery of Potent and Selective
Histone Deacetylase Inhibitors via Focused Combinatorial
Libraries of Cyclic R3β-Tetrapeptides. J. Med. Chem. 2009, 52,
7836-7846 and references therein.
(14) Bowers, A. A.; Greshock, T. J.; West, N.; Estiu, G.; Schreiber,
S. L.; Wiest, O.; Williams, R. M.; Bradner, J. E. Synthesis
and Conformation-Activity Relationships of the Peptide Iso-
steres of FK228 and Largazole. J. Am. Chem. Soc. 2009, 131,
2900–2905.
AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should be
addressed. Tel: þ1-514-343-6738. Fax: þ1-514-343-5728. E-mail:
stephen.hanessian@umontreal.ca. Tel: þ39-06-9139-3640. Fax:
þ39-06-9139-3638. E-mail: giuseppe.giannini@sigma-tau.it.
Funding Sources: We thank NSERC of Canada for financial
assistance. A postdoctoral grant from Wenner-Gren Foundation,
Sweden, is kindly acknowledged by A.L.
(15) Blackwell, L.; Norris, J.; Suto, C. M.; Janzen, W. P. The Use of
Diversity Profiling to Characterize Chemical Modulators of
the Histone Deacetylases. Life Sci. 2008, 82, 1050–1058.
(16) Lahm, A.; Paolini, M.; Pallaoro, M.; Nardi, M. C.; Jones, P.;
Nedderman, P.; Sambucini, S.; Bottomley, M. J.; Lo Surdo, P.;
ACKNOWLEDGMENT We thank Dr. Alexandra Furtos, Dalbir
ꢀ
Sekong, and Dr. Sylvie Bilodeau of Centre Regional de Spectro-
ꢀ
ꢀ
€
scopie and of Service de RMN de l'Universite de Montreal for their
kind assistance. L.A. thanks the Italian National Research Council
(CNR), Institute of Biomolecular Chemistry, Italy, for a sabbatical
leave.
Carfí, A.; Koch, U.; De Francesco, R.; Steinkuhler, C.; Gallinari,
P. Unraveling the Hidden Catalytic Activity of Vertebrate Class
IIa Histone Deacetylases. Proc. Natl. Acad. Sci. U.S.A. 2007,
104, 17335–17340.
r
2010 American Chemical Society
73
DOI: 10.1021/ml100028g ACS Med. Chem. Lett. 2010, 1, 70–74
|

pubs.acs.org/acsmedchemlett
(17) Bradner, J. E.; West, N.; Grachan, M. L.; Greenberg, E. F.;
Haggarty, S. J.; Warnow, T.; Mazitschek, R. Chemical Phylo-
genetics of Histone Deacetylases. Nat. Chem. Biol. 2010, 6,
238-243 and references therein.
Trends and Selectivities. J. Chem. Inf. Model. 2009, 49, 2774–
2785.
ꢀ
(32) Gres, M.-C.; Julian, B.; Bourrie, M.; Meunier, V.; Roques, C.;
Berger, M.; Boulenc, X.; Berger, Y.; Fabre, G. Correlation
Between Oral Drug Absorption in Humans, and Apparent
Drug Permeability in TC-7 Cells, a Human Epithelial Intestinal
Cell Line: Comparison with the Parental Caco-2 Cell Line.
Pharm. Res. 1998, 15, 726–733.
(18) For a recent example of HDAC profiling in the development of
€
a potent inhibitor, see the following: Arts, J.; King, P.; Marien,
€
A.; Floren, W.; Belien, A.; Janssen, L.; Pilatte, I.; Roux, B.;
Decrane, L.; Gilissen, R.; Hickson, I.; Vreys, V.; Cox, E.; Bol, K.;
Talloen, W.; Goris, I.; Andries, L.; Du Jardin, M.; Janicot, M.;
Page, M.; van Emelen, K.; Angibaud, P. JNJ-26481585, a Novel
`Second Generation' Oral Histone Deacetylase Inhibitor,
Shows Broad-Spectrum Preclinical Antitumoral Activity. Clin.
Cancer Res. 2009, 15, 6841–6851. For further selected
examples, see the Supporting Information.
(33) Li, P. E.; Lu, C.; Brent, J. A.; Pham, C.; Fackett, A.; Ruegg, C. E.;
Silber, P. M. Cryopreserved Human Hepatocytes: Character-
ization of Drug-Metabolizing Enzyme Activities and Applica-
tions in Higher Throughput Screening Assays for Hepatotoxi-
city, Metabolic Sability, and Drug-Dug Interaction Potential.
Chem.-Biol. Interact. 1999, 121, 17–35.
(34) For a comparison of pharmacokinetics of Vorinostat with
certain mercaptoacetamides, see the following: Konsoula, R.;
Jung, M. Int. J. Pharm. 2008, 361, 19-25.
(19) Marks, P. A.; Breslow, R. Dimethyl Sulfoxide to Vorinostat:
Development of This Histone Deacetylase Inhibitor as an
Anticancer Drug. Nat. Biotechnol. 2007, 25, 84–90.
(20) Hanessian, S.; Auzzas, L.; Giannini, G.; Marzi, M.; Cabri, W.;
Barbarino, M.; Vesci, L.; Pisano, C. ω-Alkoxy Analogues of
SAHA (Vorinostat) as Inhibitors of HDAC: A Study of Chain-
Length and Stereochemical Dependence. Bioorg. Med. Chem.
Lett. 2007, 17, 6261–6265.
(21) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. A
General Model for Selectivity in Olefin Cross Metathesis.
J. Am. Chem. Soc. 2003, 125, 11360–11370.
(22) Dixon, D. J.; Ley, S. V.; Tate, E. W. A Total Synthesis of (þ)-
Goniodiol Using an Anomeric Oxygen-to-Carbon Rearrange-
ment. J. Chem. Soc., Perkin Trans. 1 1998, 3125–3126.
(23) Rai, A. N.; Basu, A. An Efficient Method for para-Methoxy-
benzyl Ether Formation with Lanthanum Triflate. Tetrahedron
Lett. 2003, 44, 2267–2269.
(24) Li, H.; Jiang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.; Goodman, M.
3-(Diethoxyphosphoryloxy)-1,2,3- benzotriazin-4(3H)-one
(DEPBT): A New Coupling Reagent with Remarkable Resis-
tance to Racemization. Org. Lett. 1999, 1, 91–93.
(25) (S) isomers of simple ω-substitute amide derivatives of SAHA
have been reported as potent HDAC inhibitors, although any
relationship about chirality was not described; see the follow-
ing: Richon, V.; Marks, P. A.; Rifkind, R. A.; Breslow, R.;
Belvedere, S.; Gershell, L.; Miller, T. A. Novel Class of Cyto-
differentiating Agents and Histone Deacetylase Inhibitors,
and Methods of Use Thereof. WO0118171-A2, 2001.
(26) Mori, K.; Koseki, K. Synthesis of Trichostatin A, a Potent
Differentiation Inducer of Friend Leukemic Cells, and Its
Antipode. Tetrahedron 1988, 44, 6013–6020.
(27) Remiszewski, S. W. The Discovery of NVP-LAQ824: From
Concept to Clinic. Curr. Med. Chem. 2003, 10, 2393–2402.
(28) High-resolution HDAC8/MS-344 and HDAC7/TSA complexes
were used (PDB codes: 1T67 and 3C10, respectively). These
are better resolved than the cocrystals of SAHAwith the same
HDACs (1T69 and 3COZ, respectively). In addition, a water
molecule is present only in 1T67, which is thought to be
responsible for the stabilization of MS-344 through its amide
bond. See ref 8.
(29) Calculated with LPC software. This is freely accessible at
http://bip.weizmann.ac.il/oca-bin/lpccsu. Sobolev, V.;Sorokine,
A.; Prilusky, J.; Abola, E. E.; Edelman, M. Automated Analysis of
Interatomic Contacts in Proteins. Bioinformatics 1999, 15,
327-332.
(30) Davis, A. M.; Teague, S. J. Hydrogen Bonding, Hydrophobic
Interactions, and Failure of the Rigid Receptor Hypothesis.
Angew. Chem., Int. Ed. 1999, 38, 736–749.
(31) Ortore, G.; Di Colo, F.; Martinelli, A. Docking of Hydroxamic
Acids into HDAC1 and HDAC8: A Rationalization of Activity
r
2010 American Chemical Society
74
DOI: 10.1021/ml100028g ACS Med. Chem. Lett. 2010, 1, 70–74
|