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J. Amin et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3346–3348
OH
OH
O
OH
O
O
O
O
O
HO
HO
HO
O
O
O
OH
HO
OH
OH
HO
HO
O
O
OH
OH
O
OH
O
HO
O
NH2
NH
NH
HO
HO
HO
HO
O
NHOH
HO
O
O
O
O
O
O
OH
OH
O
OH
O
O
O
O
i)
ii)
HO
O
OH
HO
O
OH
HO
O
HO
HO
HO
OH
OH
OH
OH
O
O
O
HO
HO
OH
OH
HO
OH
HO
HO
HO
O
O
O
O
O
OH
OH
O
OH
OH
HO
OH
O
HO
O
O
OH
O
HO
O
O
HO
HO
HO
O
O
O
OH
OH
OH
3b
3
3a
Scheme 1. Synthesis of 3. Reagents and conditions: (i) ClCO(CH2)6CO2CH3, rt, 24 h, pyridine; (ii) NH2OH, KOH, 24 h, MeOH, under N2.
Table 1
IC50 values for HDACis versus SAHA 1a
Compound
HDAC1
HDAC2
IC50 M) (SD)
HDAC3
IC50 M) (SD)
HDAC6
IC50 M) (SD)
HDAC8
IC50 M) (SD)
IC50
(lM) (SD)
IC50 M) (SD)
(l
(
l
(
l
(
l
(l
1
3
0.052 (0.003)
0.63 (0.05)
0.09 (0.01)
1.2 (0.1)
0.067 (0.006)
1.6 (0.2)
0.019 (0.002)
0.12 (0.01)
1.35 (0.009)
6 (0.3)
a
IC50 values for compounds (lM) with standard deviation (SD) in parentheses. Assays were performed in duplicate.
4. Marks, P. A. Expert Opin. Investig. Drugs 2010, 19, 1049.
effects on the leukaemia cancer cell line (K562) were, however, ob-
served for 3, pointing to a lack of cellular penetration for this
analogue.
In conclusion, we have synthesized a HDACi bearing a bulky b-
CD ‘‘cap’’ with moderate inhibition of HDACs, notably HDAC6, with
an IC50 of 120 nM. We are currently aiming to perform X-ray stud-
ies on compound 3. Moreover, we also intend to investigate smal-
5. Somoza, J. R.; Skene, R. J.; Katz, B. A.; Mol, C.; Ho, J. D.; Jennings, A. J.; Luong, C.;
Arvai, A.; Buggy, J. J.; Chi, E.; Tang, J.; Sang, B. C.; Verner, E.; Wynands, R.; Leahy,
E. M.; Dougan, D. R.; Snell, G.; Navre, M.; Knuth, M. W.; Swanson, R. V.; McRee,
D. E.; Tari, L. W. Structure 2004, 12, 1325.
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Billadeau, D. D. J. Med. Chem. 2008, 51, 4370; (b) Li, G.; Jiang, H.; Chang, M.; Xie,
H.; Hu, L. J. Neurosci. 2011, 304, 1; (c) Marek, L.; Hamacher, A.; Hansen, F. K.;
Kuna, K.; Gohlke, H.; Kassack, M. U.; Kurz, T. J. Med. Chem. 2013, 56, 427; (d)
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7. (a) Spencer, J.; Amin, J.; Wang, M.; Packham, G.; Syed Alwi, S. S.; Tizzard, G. J.;
Coles, S. J.; Paranal, R. M.; Bradner, J. E.; Heightman, T. D. ACS Med. Chem. Lett.
2011, 2, 358; (b) Spencer, J.; Amin, J.; Boddiboyena, R.; Packham, G.; Cavell, B.
E.; Syed Alwi, S. S.; Paranal, R. M.; Heightman, T. D.; Wang, M.; Marsden, B.;
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ler supramolecular structures such as more liphophilic
a-
cyclodextrins incorporated into HDACis combined with lipophilic
chains given that similar three-dimensional cap groups were re-
cently shown to exhibit excellent HDACi potency.15
Acknowledgments
Oxford Nanopore Technology Ltd is thanked for funding. The
EPSRC Mass Spectrometry Service (Swansea University) is thanked
for HRMS measurements.
8. Chini, M. G.; Terracciano, S.; Riccio, R.; Bifulco, G.; Ciao, R.; Gaeta, C.; Troisi, F.;
Neri, P. Org. Lett. 2010, 23, 5382.
9. Tang, W.; Luo, T.; Greenberg, E. F.; Bradner, J. E.; Schreiber, S. L. Bioorg. Med.
Chem. Lett. 2011, 21, 2601. and references cited therein.
10. Nakao, Y.; Yoshida, S.; Matsunaga, S.; Shindoh, N.; Terada, Y.; Nagai, K.;
Yamashita, J. K.; Ganesan, A.; van Soest, R. W. M.; Fusetani, N. Angew. Chem., Int.
Ed. 2006, 45, 7553.
Supplementary data
11. For a comprehensive review on HDACi isoform selectivity, see Bieliauskas, A.
V.; Pflum, M. K. H. Chem. Soc. Rev. 2008, 37, 1402.
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Uekama, K.; Minami, K.; Hirayama, F. J. Med. Chem. 1997, 40, 2755.
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Supplementary data associated with this article can be found, in
the
online
version,
at
References and notes
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