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P. Thomson et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4320–4322
(
water then brine), dried (MgSO ) and evaporated.
4
2
2
1
1
5
0
5
0
5
Flash chromatography, eluting with 50% ethyl acetate/
hexane then 100% ethyl acetate and finally 25% metha-
nol/ethyl acetate, afforded an oily, yellow solid. The res-
idue was triturated with acetonitrile and the suspension
filtered. The filtrate was concentrated in vacuo then trit-
urated with ether, and afforded an orange powder. This
was recrystallized from water/methanol and furnished a
white powder (150 mg, 11%); TLC R = 0.19, ethyl ace-
f
1
tate; mp 189–191 ꢁC; H NMR (500 MHz, DMSO) d
8
6
HPLC-RT 4.08 min (TFA 20–50%); MS (m/z, %) 330
(
.12 (2H, d, J = 7.0, ArH), 7.96 (1H, d, J = 7.0, ArH),
.13 (1H, s, N@CH), 2.51 (6H, s, 2 · CH ) ppm;
Prodrug 1
3
+
M , 4%), 167 (100%), 163 (13%), 133 (26%); analysis
C H N O S Æ1/2CH OHÆ1/2H O calcd C, 49.01; H,
1
4
14
6
2
1
3
2
4
.79; N, 23.66; found C, 48.88; H, 5.12; N 23.58.
0
5
2
2
1
1
Acknowledgment
The authors thank Angiogene Pharmaceuticals Ltd and
Cancer Research UK for generous financial assistance.
0
5
0
5
0
References and notes
1
2
. Hockel, M.; Vaupel, P. J. Natl. Cancer Inst. 2001, 93, 266.
. Yu, L. J.; Matias, J.; Scudiero, D. A.; Hite, K. M.; Monks,
A.; Sausville, E. A.; Waxman, D. J. Drug Metab. Dispos.
Prodrug 2
2
001, 29, 304.
3
4
. Hay, M. P.; Atwell, G. J.; Wilson, W. R.; Pullen, S. M.;
Denny, W. A. J. Med. Chem. 2003, 46, 2456.
. Hay, M. P.; Wilson, W. R.; Denny, W. A. Bioorg. Med.
Chem. 2005, 13, 4043.
5. Jaffar, M.; Abou-Zeid, N.; Bai, L.; Mrema, I.; Robinson,
I.; Tanner, R.; Stratford, I. J. Curr. Drug. Del. 2004, 1,
0
50
100
150
3
45.
Time / min
6. Mulchahy, R. T.; Gipp, J. J.; Schmidt, J. P.; Joswig, C.;
Borch, R. F. J. Med. Chem. 1994, 37, 1610.
7. Naylor, M. A.; Thomson, P. Mini-Rev. Med. Chem. 2001,
1, 17.
Figure 1. Loss of prodrug under air (s) and N
-TG under air (h) and N (j).
2
(d), and production of
6
2
8
. Parveen, I.; Naughton, D. P.; Whish, W. J. D.; Threadgill,
M. D. Bioorg. Med. Chem. Lett. 1999, 9, 2031.
. Nagasawa, H.; Uto, Y.; Kirk, K. L.; Hori, H. Biol. Pharm.
Bull. 2006, 29, 2335.
9
group incorporated into the prodrug, it is possible to
release the active agent using this drug delivery strategy.
We are currently evaluating this series of prodrugs in
further experiments.
1
0. Wardman, P. Curr. Med. Chem. 2001, 8, 739.
11. Thomson, P.; Naylor, M. A.; Everett, S. A.; Stratford, M.
R. L.; Lewis, G.; Hill, S.; Patel, K. B.; Wardman, P.;
Davis, P. D. Mol. Cancer Therap. 2006, 5, 2886.
1
1
2. Elgemeie, G. H. Curr. Pharm. Des. 2003, 9, 2627.
3. Coulthard, S.; Hogarth, L. Invest. New Drugs 2005, 23,
Synthetic example. 2-Amino-6-[2-(4-nitrophenyl)prop-2-
ylsulfanyl]-9H-purine (2). Sodium hydride (160 mg,
5
23.
4
4
.0 mmol) was added to 6-thioguanine (668 mg,
.0 mmol) in DMF (15 mL). After 1 h, 2-bromo-2-(4-
1
1
1
4. Kirkpatrick, D. L.; Johnson, K. E.; Sartorelli, A. C.
J. Med. Chem. 1986, 29, 2048.
5. Paine, S. W.; Ridd, J. H. J. Chem. Soc., Perkin Trans. 2
nitrophenyl)propane (1.08 g, 4.4 mmol) in DMF
5 mL) was added and the reaction was stirred for
4 h. The reaction mixture was partitioned (ethyl acetate
(
2
1
996, 2571.
6. Fitzsimmons, S. A.; Workman, P.; Grever, M.; Paull, K.;
Camalier, R.; Lewis, A. D. J. Natl. Cancer Inst. 1996, 88,
259.
and brine), the aqueous phase was extracted (ethyl ace-
tate); the organic phases were combined then washed