Improved synthesis and structural reassignment of MC1568: A class IIa selective HDAC inhibitor

Article abstract of DOI:10.1021/jm401945k

An improved synthesis and structural reassignment of the class IIa selective histone deacetylase (HDAC) inhibitor MC1568 are described.

Full text of DOI:10.1021/jm401945k

Brief Article
pubs.acs.org/jmc
Improved Synthesis and Structural Reassignment of MC1568: A Class
IIa Selective HDAC Inhibitor
Cassandra L. Fleming,† Trent D. Ashton,† Vidhi Gaur,‡ Sean L. McGee,‡ and Frederick M. Pfeffer*,†
†Research Centre for Chemistry and Biotechnology, School of Life and Environmental Sciences, Deakin University, Waurn Ponds,
Victoria, 3216, Australia
‡Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, Victoria, 3216, Australia
S
* Supporting Information
ABSTRACT: An improved synthesis and structural reassign-
ment of the class IIa selective histone deacetylase (HDAC)
inhibitor MC1568 are described.
In this Brief Article we present the reassigned structure of
MC1568 and a robust procedure for its synthesis.12
INTRODUCTION
■
The dysregulation of histone deacetylase (HDAC) enzymes is
associated with a variety of disease states including cancer,
cellular metabolism disorders, and inflammation.1−3 It is
therefore no surprise that the design and synthesis of HDAC
inhibitors is of interest for the treatment of these
conditions.1,4,5 In humans, the HDAC family comprises 18
enzymes categorized into four distinct classes (classes I, IIa/IIb,
III, and IV). Each class is defined according to structural
similarities, gene expression patterns, cellular localization, tissue
distribution, and number of active sites.1,4−8
RESULTS AND DISCUSSION
■
Compound MC1568 was first reported among a series of
similarly disubstituted pyrroles and has since been used as a
biological tool.12,14 The compound has also been the starting
point for a number of structure−activity relationship and
molecular modeling studies.13,14
During efforts to repeat the synthesis of MC1568 several
peculiarities with the reported structure of formylated pyrrole 5
were noted (Scheme 1). Despite using a modified synthesis,15
a
It has been reported that HDAC5 represses important
glucose transporters in the skeletal muscle.9 Hence, selectively
inhibiting the HDAC5 isoform may be beneficial for the
regulation of skeletal muscle metabolism and offer a new
pathway to treat conditions such as diabetes.4,9
α
Scheme 1. Synthesis of Aldehyde 6
To the best of our knowledge, rocilinostat is the only class II
isoform selective HDAC inhibitor to successfully reach clinical
trials.10 The lack of potent class II HDAC inhibitors currently
in clinical trials is most likely due to the fact that only a handful
of class IIb (HDAC6) selective inhibitors have been reported
and even fewer for the selective inhibition of class IIa
enzymes.11 In 2005 the group of Mai reported MC1568 (1),
one of the only known selective inhibitors of class IIa HDACs
to be documented in the literature (Figure 1).12,13
α
Reagents and conditions: (a) (EtO)2P(O)CH2CO2Et, tBuOK, THF,
21 °C, 24 h (74%); (b) (COCl)2, DMF, microwave, 100 °C, 14 min
(83%).
product spectroscopically identical to that reported by Mai was
obtained.12 However, a coupling constant of 4.5 Hz for the
pyrrole protons (δH 6.65 and 6.90) was recorded in the H
1
3
4
NMR spectra, indicative of JH3,H4 coupling. Typical JH3,H5
coupling constant for pyrrole is approximately 1.5 Hz.16
1
Moreover, it was observed that the H NMR resonance
corresponding to the N-methyl group appeared to encounter
significant anisotropic deshielding from the newly installed
Figure 1. Published structure of class II selective HDAC inhibitor,
MC1568 (1), and its actual structure (2).
Received: December 18, 2013
Published: January 22, 2014
© 2014 American Chemical Society
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Journal of Medicinal Chemistry
Brief Article
carbonyl (δH 3.68 in the pyrrole 4 to δH 4.03 in the formylated
pyrrole 6; ΔδH = 0.35). A comparable trend was observed for a
similar N-methylpyrrole system reported by Rapoport et al., in
which both 4- and 5-substituted pyrroles were isolated (Figure
2).17
carried out to obtain MC1568 (2). In most cases modifications
were made to the reported procedure (see Experimental
Section).
Optimum results for the condensation of aldehyde 6 with 3′-
fluoroacetophenone to give chalcone 10 employed Ba(OH)2 in
MeOH and microwave irradiation at 40 °C for 30 min. The
chalcone was consistently isolated in high yield (96−98%, five
repeats, Scheme 2).
α
Scheme 2. Synthesis of MC1568 (2)
Figure 2. Synthesis of 2,4- and 2,5-substituted pyrroles as reported by
Rapoport (δH refers to N-Me).17
Rapoport identified that when Friedel−Crafts conditions
(dichloromethyl methyl ether (HCl2COMe), AlCl3) were
employed, the aldehyde was introduced exclusively to the 4-
position of the pyrrole ring (8), and little change (from δH 3.85
to δH 4.00, ΔδH = 0.15) in the chemical shifts corresponding to
the N-methyl protons was observed.17 This trend has also been
observed in other reports in which 2,4-substituted pyrroles
were synthesized using similar Friedel−Crafts conditions.18,19
In contrast, Vilsmeier−Haack formylation of ester (7) gave a
1:2 mixture of 4- and 5-formylated pyrroles. The N-methyl
protons of the 5-formylated pyrrole (9) are assigned to the
singlet at δH 4.30 (from δH 3.85, ΔδH = 0.45), due to the
additional anisotropic deshielding of the aldehyde.17
α
Reagents and conditions: (a) 3′-fluoroacetophenone, Ba(OH)2,
MeOH, microwave, 40 °C, 30 min (96−98%); (b) (i) NH2OTHP,
EDCI·HCl, HOBt, Et3N, CH2Cl2, 21 °C, 16 h (70%); (ii) p-TsOH·
H2O, MeOH, 21 °C, 30 min (70%).
For the installation of the hydroxamic acid moiety, coupling
and deprotection of a protected hydroxylamine, O-(methyoxy-
2-propyl)hydroxylamine was originally reported.12 In our hands
commercially available O-(tetrahydro-2H-pyran-2-yl)-
hydroxylamine (NH2OTHP) was coupled to acid 10 using
EDCI. Deprotection of the THP group was achieved by
treatment with p-TsOH in MeOH at 21 °C to afford
analytically pure (LCMS) MC1568 (2) in good yield (70%,
Scheme 2).
The HSQC spectrum of aldehyde 6 synthesized in this study
showed that the two pyrrole 1H NMR resonances (δH 6.65 and
6.90) correlated to 13C NMR resonances δC 111.0 and 124.2,
respectively (Figure 3). The aldehyde proton (δH 9.58)
As only a general procedure for the final two synthetic steps
were originally reported, NMR spectra of MC1568 (2) were
not provided.12 Therefore, analysis of 1H and 13C NMR
spectra, in conjunction with 1D NOE and 2D NMR
experiments (HSQC and HMBC), was used to confirm the
successful synthesis of MC1568 (2). Detailed synthesis and
characterization are provided in the Experimental Section and
Supporting Information.
In conclusion the structure of the class II selective inhibitor
MC1568 has been reassigned from a 2,4- to a 2,5-disubstituted
pyrrole and an improved synthesis developed with an overall
yield of 30% achieved over five steps. Preliminary biological
evaluation confirmed class II selectivity (see Supporting
Information) and further supports the reassigned structure as
the active isomer.
Figure 3. Key HSQC, HMBC, and NOE correlations of formylated
pyrrole 6 in CDCl3.
correlated to the 13C NMR resonance δC 180.2. In the
HMBC the N-methyl protons showed correlations to the
quaternary carbons (δC 134.2 and 137.9) of the pyrrole. A
HMBC correlation between the H-4 proton (δH 6.90) and the
aldehyde carbon (δC 180.2) was also observed. If the reported
2,4-substitution pattern was present (aldehyde 5), a HMBC
correlation between both pyrrole protons (H-3 and H-5) and
the aldehyde carbon would be expected. These results
unequivocally confirm that formylation occurred at the 5-
position of the pyrrole, not the 4-position as originally
reported.12
EXPERIMENTAL SECTION
■
General. General reagents and solvents for the synthesis of
compounds were analytical grade (AR) and used as supplied.
Anhydrous THF was obtained using a Pure Solv (Innovative
Technologies) solvent drying system. Oxalyl chloride was distilled
under N2 before use. Melting points are uncorrected and were
determined using a Bibby Stuart Scientific SMP3 melting point
apparatus. NMR spectra were collected on a JEOL Eclipse JNM-Ex
270 MHz, 400 MHz FT-NMR, or Bruker Avance 500SB spectrometer
as specified. Samples were dissolved (0.5 mL) in either deuterated
chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-d6).
High resolution mass spectra (HRMS) were recorded on an Aligent
Technologies LC/MSD TOF mass spectrometer. Column chromatog-
The proposed structural reassignment of intermediate 6 was
further supported by 1D selective NOE difference experiments
(Figure 3). The remaining steps of the synthesis were then
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Journal of Medicinal Chemistry
Brief Article
raphy was performed using Merck 230−400 silica gel. Petroleum
spirits refer to the fraction boiling between 40 and 60 °C. Microwave
mediated reactions were conducted using a CEM Discover S-class
microwave reactor, operating at a frequency of 50/60 Hz and
continuous irradiation power from 0 to 200 W. All reactions were
conducted in a 10 mL microwave vial sealed with a Teflon snap cap.
Purity of the described compound was determined by LCMS.
Chromatographic analysis was performed on an Agilent HPLC/MS
system using a Poroshell 120 EC-C18 column (3.0 mm × 50 mm, 2.7
μm). HPLC conditions were as follows; injection volume = 1 μL;
solvent A = H2O containing 0.1% formic acid; solvent B = MeCN
containing 0.1% formic acid; compound was eluted with a gradient of
5−100% solvent B over 3.8 min; flow = 0.5 mL/min. All biologically
active compounds were >98% pure as analyzed by HPLC
= 22.7 Hz), 117.3, 118.1, 119.7 (d, 2JC−F = 21.6 Hz), 124.4 (d, 4JC−F
=
2.4 Hz), 130.9 (d, 3JC−F = 8.1 Hz), 131.0, 131.8, 133.8, 134.4, 140.3 (d,
1
4
3JC−F = 6.4 Hz), 162.4 (d, JC−F = 243.5 Hz), 167.8, 186.9 (d, JC−F
=
2.5 Hz). HRMS (ESI, m/z): calculated for C17H14FNO3 [M + H]+
300.1031; found 300.1032.
3-(5-(3-(3-Fluorophenyl)-3-oxo-1-propen-1-yl)-1-methyl-1H-
pyrrol-2-yl)-N-hydroxy-2-propenamide (2). To a stirring solution
of 3-(5-(3-(3-fluorophenyl)-3-oxo-1-propen-1-yl)-1-methyl-1H-pyrrol-
2-yl)-2-propenoic acid 10 (220 mg, 0.74 mmol) in CH2Cl2 (5 mL)
was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (103 mg, 0.88
mmol), EDCI·HCl (456 mg, 2.94 mmol), anhydrous HOBt (199 mg,
1.47 mmol), and Et3N (526 mg, 5.20 mmol). After the mixture was
stirred at 21 °C for 16 h, it was transferred into a separatory funnel and
was washed with brine (2 × 10 mL), dried over MgSO4, and
concentrated to dryness. Purification by flash column chromatography
(2% MeOH in 1:1 EtOAc/petroleum spirits) afforded the THP-
protected hydroxamic acid (202 mg, 70%, Rf = 0.18) as a red oil that
solidified upon standing. To a solution of this THP-protected
hydroxamic acid (142 mg, 0.356 mmol) in MeOH (10 mL) was
added p-TsOH·H2O (20 mg, 0.107 mmol). After the mixture was
stirred at 21 °C for 1 h, an orange precipitate formed that was isolated
by gravity filtration and further purified by recrystallization (DMSO/
H2O) to afford the title compound (80 mg, 70%) as an orange solid;
mp 216−218 °C (lit. 212−215 °C).12 1H NMR (270 MHz, DMSO-
d6): δ 3.76 (s, 3H, NCH3), 6.37 (d, J = 15.5 Hz, 1H, CH
CHONHOH), 6.72 (d, J = 4.0 Hz, 1H, pyrrole H-3), 7.25 (d, J = 4.0
Hz, 1H, pyrrole H-4), 7.53 (m, 3H, CHCHONHOH, ArH-2,5),
7.75 (m, 2H, COCHCH, COCHCH), 7.90 (d, J = 10.2 Hz, 1H,
ArH-4), 7.97 (d, J = 7.6 Hz, 1H, ArH-6), 9.03 (br s, 1H, NHOH),
10.72 (br s, 1H, NHOH). 13C NMR (100 MHz, DMSO-d6): δ 31.2,
Ethyl 3-(1-Methyl-1H-pyrrol-2-yl)-2-propenoate (4). To a
stirring solution of triethyl phosphonacetate (565 mg, 2.04 mmol)
in THF (15 mL) at 0 °C was added potassium tert-butoxide (265 mg,
2.38 mmol). After 30 min, a suspension of N-methyl-2-pyrrolecarbox-
aldehyde 3 (186 mg, 1.70 mmol) in THF (5 mL) was added, and the
mixture was stirred at 21 °C for 24 h. The mixture was diluted with
H2O (50 mL) and the aqueous phase extracted with EtOAc (3 × 25
mL). The combined organic layer was washed with saturated NaHCO3
(10 mL), brine (10 mL), dried over MgSO4, and concentrated.
Purification by flash column chromatography (30% Et2O in petroleum
spirits) afforded the title compound (225 mg, 74%, Rf = 0.3) as a pale
1
yellow oil. H NMR (270 MHz, CDCl3): δ 1.30 (t, J = 7.3 Hz, 3H,
CH2CH3), 3.68 (s, 3H, NCH3), 4.22 (q, J = 7.0 Hz, 2H, CH2CH3),
6.13 (m, 2H, pyrrole H-4, CHCHO), 6.64 (dd, J = 4.1, 1.6 Hz, 1H,
pyrrole H-3), 6.72 (t, J = 2.2 Hz, 1H, pyrrole H-5), 7.58 (d, J = 15.7
Hz, 1H, CHCHO). 13C NMR (67.5 MHz, CDCl3): δ 14.3, 33.7,
60.8, 109.7, 112.0, 112.7, 126.5, 129.4, 132.0, 167.9. HRMS (ESI, m/
z): calculated for C10H13NO2 [M + H]+ 180.1019; found 180.1026.
Ethyl 3-(5-Formyl-1-methyl-1H-pyrrol-2-yl)-2-propenoate
(6). In a 10 mL microwave vial, a solution of oxalyl chloride (213
mg, 1.67 mmol) in DMF (1 mL) was stirred at 0 °C for 45 min. A
solution of ethyl 3-(1-methyl-1H-pyrrol-2-yl)-2-propenate 4 (100 mg,
0.56 mmol) in DMF (0.5 mL) was added, and the resulting mixture
was heated using microwave irradiation at 100 °C for 14 min. After the
mixture was cooled to 21 °C, H2O (9 mL) was added, affording a
precipitate, which was isolated by vacuum filtration. The title
compound was obtained (95 mg, 83%) as a fine tan solid; mp 124−
125 °C (lit. 102−104 °C).20 1H NMR (270 MHz, CDCl3): δ 1.33 (t, J
= 7.2 Hz, 3H, CH2CH3), 4.03 (s, 3H, NCH3), 4.26 (q, J = 7.2 Hz, 2H,
CH2CH3), 6.40 (d, J = 15.6 Hz, 1H, CHCHO), 6.65 (d, J = 4.5 Hz,
1H, pyrrole H-3), 6.90 (d, J = 4.5 Hz, 1H, pyrrole H-4), 7.61 (d, J =
111.6, 114.8, 115.3 (d, 2JC−F = 21.8 Hz), 117.9, 118.7, 120.2 (d, 2JC−F
=
3
21.1 Hz), 124.9, 126.4, 131.5 (d, JC−F = 7.7 Hz), 132.5, 133.5, 135.7,
3
1
140.9 (d, JC−F = 6.3 Hz), 162.9 (d, JC−F = 243.9 Hz), 163.6, 187.4.
HRMS (ESI, m/z): calculated for C17H15FN2O3 [M + H]+ 315.1139;
found 315.1138. HPLC: tR = 3.50 min.
ASSOCIATED CONTENT
■
S
* Supporting Information
Results and experimental protocols for cytotoxicity and
inhibitory property testing and full H NMR, 13C NMR, and
1
2D NMR spectra of compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Phone: +61 3 5227 1439. E-mail: fred.pfeffer@deakin.edu.au.
■
1
15.8 Hz, 1H, CHCHO), 9.58 (s, 1H, CHO). H NMR (270 MHz,
DMSO-d6): δ 1.25 (t, J = 7.1 Hz, 3H, CH2CH3), 3.93 (s, 3H, NCH3),
4.20 (q, J = 7.1 Hz, 2H, CH2CH3), 6.63 (d, J = 15.7 Hz, 1H, CH
CHO), 6.97 (d, J = 4.4 Hz, 1H, pyrrole H-3), 7.06 (d, J = 4.4 Hz, 1H,
pyrrole H-4), 7.61 (d, J = 15.7 Hz, 1H, CHCHO), 9.58 (s, 1H,
CHO). 13C NMR (67.5 MHz, CDCl3): δ 14.4, 32.6, 60.9, 111.0, 120.8,
124.2, 130.5, 134.2, 137.9, 166.6, 180.2. HRMS (ESI, m/z): calculated
for C11H13NO3 [M + H]+ 208.0968; found 208.0961.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
C.L.F. thanks the Research Centre for Chemistry and
Biotechnology for a top up scholarship. This work has been
supported by grants from Diabetes Australia Research Trust
and National Health and Medical Research Council (NHMRC)
of Australia to S.L.M. S.L.M. is supported by a NHMRC Career
Development Fellowship. This work has also been supported
by grants from the Australian Research Council (Grant
LP100100087) to F.M.P. and T.D.A.
3-(5-(3-(3-Fluorophenyl)-3-oxo-1-propen-1-yl)-1-methyl-1H-
pyrrol-2-yl)-2-propenoic Acid (10). In a 35 mL microwave vial, a
solution containing 3′-fluoroacetophenone (134 mg, 0.97 mmol) and
barium hydroxide octahydrate (1.220 g, 3.86 mmol) in MeOH (5 mL)
was stirred at 21 °C for 15 min. A solution of ethyl 3-(5-formyl-1-
methyl-1H-pyrrol-2-yl)-2-propenate 6 (200 mg, 0.97 mmol) was
added, and the mixture was heated using microwave irradiation at 40
°C for 30 min. The mixture was diluted with H2O (20 mL) and
adjusted to pH 7 using 1 M HCl. The orange precipitate was isolated
by vacuum filtration, washing thoroughly with H2O to afford the
desired compound (283 mg, 98%) as an orange solid; mp 209−211 °C
(lit. 210−212 °C).12 1H NMR (270 MHz, DMSO-d6): δ 3.75 (s, 3H,
NCH3), 6.36 (d, J = 13.5 Hz, 1H, CHCHOOH), 6.86 (d, J = 5.4
Hz, 1H, pyrrole H-3), 7.24 (d, J = 5.4 Hz, 1H, pyrrole H-4), 7.53 (m,
3H, CHCHOOH, ArH-2,5), 7.74 (m, 2H, COCHCH, COCH
CH), 7.89 (d, J = 8.1 Hz, 1H, ArH-4), 7.97 (d, J = 8.1 Hz, 1H, ArH-6).
13C NMR (125 MHz, DMSO-d6): δ 30.5, 112.6, 114.1, 114.7 (d, 2JC−F
ABBREVIATIONS USED
HDAC, histone deacetylase
■
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