A convenient synthesis of the new histone deacetylase inhibitor scriptaid

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A Convenient Synthesis of the New
Histone Deacetylase Inhibitor Scriptaid
a
a
Mariana S. Gerova & Ognyan I. Petrov
a
Department of Applied Organic Chemistry, Faculty of Chemistry
and Pharmacy , University of Sofia “St. Kliment Ohridski”, 1 James
Bourchier Avenue, 1164, Sofia , Bulgaria
Published online: 30 Jan 2014.
To cite this article: Mariana S. Gerova & Ognyan I. Petrov (2014) A Convenient Synthesis of the New
Histone Deacetylase Inhibitor Scriptaid, Organic Preparations and Procedures International: The New
Journal for Organic Synthesis, 46:1, 76-79, DOI: 10.1080/00304948.2014.866471
To link to this article: http://dx.doi.org/10.1080/00304948.2014.866471
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Organic Preparations and Procedures International, 46:76–79, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2014.866471
OPPI BRIEF
A Convenient Synthesis of the New Histone
Deacetylase Inhibitor Scriptaid
Mariana S. Gerova and Ognyan I. Petrov
Department of Applied Organic Chemistry, Faculty of Chemistry and Pharmacy,
University of Sofia “St. Kliment Ohridski”, 1 James Bourchier Avenue, 1164,
Sofia, Bulgaria
Histone deacetylase (HDAC) inhibitors represent a new promising class of anticancer
agents, because of their ability to induce cell cycle arrest, differentiation and apoptosis of
1–3
cancer cells. A number of products such as naturally occurring trichostatin A, trapoxins
A and B, romidepsin as well as the synthetic derivatives suberoylanilide hydroxamic acid
(SAHA), oxamflatin, belinostat, NVP-LAQ-824, valproic acid and MS-275 have been
identified as HDAC inhibitors and have been shown to possess significant anticancer activity
4
–12
in several preclinical and clinical studies.
(
Currently, two HDAC inhibitors – SAHA
ꢀR
ꢀR
Vorinostat or Zolinza ) and romidepsin (Istodax ), have been approved by the FDA
for the treatment of cutaneous T-cell lymphoma in patients with progressive, persistent
or recurrent disease.1
0,11
The therapeutic potential of HDAC inhibitors has spurred the
synthesis of a large number of hydroxamic acids, cyclic peptides, short-chain fatty acids,
benzamides and electrophilic ketones.3
,4,10,12
Amongst them, hydroxamic acid derivatives
have received the most attention because of their favorable pharmacokinetic profile and
1
0,12
high activity against both hematological and solid tumors at well-tolerated doses.
13
Scriptaid (3) was identified by Su et al. from a library of 16,320 compounds in
a luciferase reporter assay. The compound is a hydroxamic acid and possesses the three
pharmacophores common for this class of HDAC inhibitors, a hydroxamic acid zinc-binding
group, a hydrophobic spacer, and a recognition cap group. The initial investigations of
scriptaid showed that it is an effective HDAC inhibitor with low toxicity and high activity
13
similar to those of SAHA. A recent in vitro study revealed that scriptaid provoked growth
inhibition, cell cycle arrest and apoptosis in human endometrial cancer and ovarian cancer
14
cells. An accumulation of acetylated H3 and H4 histone proteins was observed in these
cell lines, confirming the effect of scriptaid as HDAC inhibitor.
Submitted by July 12, 2013.
Address correspondence to Ognyan I. Petrov, Department of Applied Organic Chemistry, Faculty
of Chemistry and Pharmacy, University of Sofia “St. Kliment Ohridski”, 1 James Bourchier Avenue,
1164, Sofia, Bulgaria. E-mail: opetrov@chem.uni-sofia.bg
76

A Convenient Synthesis of Scriptaid
77
Scheme 1
To the best of our knowledge, there are no previous reports on the synthesis of com-
pound 3 in the scientific and patent literature. Here we report a general and efficient two-step
procedure (Scheme 1) for the preparation of scriptaid under mild reaction conditions and
56% overall yield. The reported method can be easily scaled up or used to quickly synthesize
a large number of derivatives for further evaluation.
As shown in Scheme 1, the reaction of 1,8-naphthalic anhydride (1) and ε-
aminocapronic acid was carried out by refluxing in propionic acid for 4 hours and led
to the carboxylic acid 2 in 79% yield. Conversion of carboxylic acid 2 to the target hydrox-
amic acid 3 was achieved via a mixed anhydride formed from 2 and ethyl chloroformate
in the presence of triethylamine. The mixed anhydride was reacted in situ with freshly pre-
pared hydroxylamine to yield scriptaid (3) in 71%. The reactions of this two-step procedure
for the synthesis of scriptaid were repeated three times and the yields were reproducible
within 5%.
Experimental Section
Melting points (mp) were determined on a Boetius hot-stage microscope and are uncor-
1
13
rected. Infrared spectra (IR) were recorded on a Specord 71 spectrometer. H NMR and C
NMR spectra were acquired on a Bruker AV600 spectrometer in dimethyl sulfoxide-d6.
Chemical shifts were reported in parts per million (ppm, δ) relative to the solvent peak (δ
1
13
2
.50 ppm for H; δ 39.5 ppm for C NMR). Coupling constants (J) were measured in hertz
(
(
Hz). Reactions were monitored by thin-layer chromatography (TLC) on silica gel plates
Kieselgel 60 F254).
6
-[1,3-Dioxo-1H-benzo[de]isoquinolin-2(3H)-yl]hexanoic acid (2)
A suspension of 1,8-naphthalic anhydride (1, 1.98 g, 10 mmol) and ε-aminocapronic acid
1.98 g, 15 mmol) in propionic acid (50 mL) was refluxed for 4 h, until the anhydride 1
(
was no longer detectable by TLC (toluene:chloroform:ethyl acetate/3:1:1). The obtained
solution was poured into ice-water (200 mL) with vigorous stirring. The product was pre-
cipitated, filtered and washed with water (50 mL). Recrystallization from ethanol afforded 2
◦
1 1
15
◦
(
1
2.46 g, 79%) as a white powder, mp 135–136 C (lit. mp 136 C). IR (nujol): 2900–3100,
−
690, 1660, 1590, 1430,1340, 1220, 790 cm . H NMR (DMSO-d6, 600 MHz): δ 1.31–1.36
(m, 2H, CH2), 1.51–1.56 (m, 2H, CH2), 1.59–1.64 (m, 2H, CH2), 2.21 (t, 2H, CH2CO,

78
Gerova and Petrov
J = 7.4), 4.01 (t, 2H, NCH2, J = 7.4), 7.84 (t, 2H, ArH, J = 7.6), 8.42 (d, 2H, ArH, J =
1
3
8
.2), 8.46 (d, 2H, ArH, J = 7.1), 12.00 (s, 1H, COOH). C NMR (DMSO-d6, 151 MHz):
δ 24.7, 26.5, 27.7, 33.9, 39.9, 122.5, 127.7, 127.8, 131.2, 131.7, 134.7, 163.8, 174.9.
6
-[1,3-Dioxo-1H-benzo[de]isoquinolin-2(3H)-yl]-N-hydroxyhexaneamide (Scriptaid, 3)
To a cooled solution of carboxylic acid 2 (1.40 g, 4.5 mmol) in tetrahydrofuran (10 mL),
triethylamine (0.9 mL, 6.3 mmol) was added, followed by ethyl chloroformate (0.6 mL,
6
.0 mmol). A precipitate of triethylamine hydrochloride appeared. The mixture was stirred
◦
at 0 C for 15 min and then filtered off. The filtrate was added to a suspension of hydroxy-
lamine, prepared by mixing of solutions of hydroxylamine hydrochloride (0.54 g, 7.8 mmol)
in methanol (10 mL) and potassium hydroxide (0.44 g, 6.2 mmol) in methanol (5 mL).
The resulting mixture was stirred 1 h at room temperature (TLC - chloroform:methanol /
9:1). The solvents were evaporated under reduced pressure and water (50 mL) was added
to the residue. The obtained precipitate was filtered off, washed with water and dried in air.
◦
Recrystallization from acetonitrile gave 3 (0.95 g, 71%) as white crystals, mp. 152–153 C.
−1 1
IR (nujol): 3150–3100, 3050, 1640, 1610, 1590, 1450, 1350, 790 cm . H NMR (DMSO-
d6, 600 MHz): δ 1.28–1.33 (m, 2H, CH2), 1.51–1.56 (m, 2H, CH2), 1.59–1.64 (m, 2H,
CH2), 1.95 (t, 2H, CH2CO, J = 7.4), 3.99–4.00 (m, 2H, NCH2), 7.83–7.86 (m, 2H, ArH),
1
3
8
1
1
.42–8.47 (m, 4H, ArH), 8.68 (s, 1H, OH), 10.34 (s, 1H, NH). C NMR (DMSO-d6,
51 MHz): δ 25.4, 26.6, 27.8, 32.6, 40.0, 122.5, 127.7, 127.8, 131.2, 131.7, 134.8, 163.8,
69.5.
Anal. Calcd for C18H18N2O4: C, 66.25; H, 5.56; N, 8.58. Found: C, 66.12; H, 5.77; N,
8.36.
Acknowledgment
This work was supported by grant 27/2013 from the Sofia University Scientific Research
Fund.
References
1
2
3
4
5
6
7
8
9
. P. A. Marks, T. Millery and V. M. Richon, Curr. Opin. Pharmacol., 3, 344 (2003).
. P. A. Marks and M. Dokmanovic, Expert Opin. Investig. Drugs, 14, 1497 (2005).
. W. K. Rasheed, R. W. Johnstone and H. M. Prince, Expert Opin. Investig. Drugs, 16, 659 (2007).
. W. K. Kelly, O. A. O’Connor and P. A. Marks, Expert Opin. Investig. Drugs, 11, 1695 (2002).
. T. A. Miller, Expert Opin. Ther. Patents, 14, 791 (2004).
. C. Monneret, Eur. J. Med. Chem., 40, 1 (2005).
. M. Paris, M. Porcelloni, M. Binaschi and D. Fattori, J. Med. Chem., 51, 1505 (2008).
. P. Bertrand, Eur. J. Med. Chem., 45, 2095 (2010).
. P. A. Marks, Expert Opin. Investig. Drugs, 19, 1049 (2010).
1
0. J. M. Wagner, B. Hackanson, M. L u¨ bbert and M. Jung, Clin. Epigenet., 1, 117 (2010).

A Convenient Synthesis of Scriptaid
79
1
1
1
1
1
1. F. Thaler and S. Minucci, Expert Opin. Drug Discov., 6, 393 (2011).
2. T. A. Miller, D. J. Witter and S. Belvedere, J. Med. Chem., 46, 5097 (2003).
3. G. H. Su, T. A. Sohn, B. Ryu and S. E. Kern, Cancer Res., 60, 3137 (2000).
4. N. Takai, T. Ueda, M. Nishida, K. Nasu and H. Narahara, Int. J. Mol. Med., 17, 323 (2006).
5. F. Nolde, J. Qu, C. Kohl, N. G. Pschirer, E. Reuther and K. M u¨ llen, Chem. Eur. J., 11, 3959
2005).
(