New Tool for Light-Controlled Release of Anticancer Agents
Irradiation of 13: Prodrug 13 (14.5 mg, 8.6 mol) in D2O (0.55 mL)
in a Pyrex NMR tube was irradiated in a RPR-200 Rayonet photo-
reactor equipped with 16 of 350 nm lamps for 10 and 20 min. The
progress of the photoreaction was monitored with NMR spec-
troscopy.
from 4 in buffer solutions. In their pseudoequilibrium mix-
tures obtained with different approaches, aldophosphamide
(4) was the minor component.[10] Our results from unbuff-
ered D2O are in agreement with the early observations. PM
(1), the β-elimination product of 4, only appeared as a weak
peak (δ = 13.68 ppm) in the spectrum taken after 6 h. Nev-
ertheless, the signal of the inorganic phosphate (δ =
0.90 ppm),[11] the hydrolysis product from 1 via the phos-
phoramidic diacid intermediate, appeared after 6 h and
steadily grew at the expense of the other peaks.[12]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, spectroscopic data, 1H and 13C NMR
spectra.
Acknowledgments
The NMR study shows that the fate of photochemically
generated 4 is consistent with that of aldophosphamide ob-
This work was financially supported by the University of Alabama
tained through other approaches,[10] proving that com- at Birmingham (UAB). We thank Dr. Michael J. Jablonsky for as-
sistance with NMR spectroscopy and Dr. Sanjay Raikar for opti-
mizing the preparation of compound 10.
pound 13 is a useful precursor to 4. In addition, cytotoxic
acrolein and the postulated O-quinone methide intermedi-
ate from fragmentation of 13 will be produced at the acti-
vation site to enhance cancer cell death.[2b,13] Although
acrolein is known as an alkylating agent and to be highly
toxic to cancer cell lines, it does not contribute to the anti-
cancer activity of 2; instead, it causes hemorrhagic cysti-
tis.[14] With the new approach, locally produced acrolein
should have a much reduced side effect on other organs.
The pharmacological properties of prodrug 13 are currently
under investigation.
[1] a) B. A. Chabner, J. M. Collins (Eds.), Cancer Chemotherapy:
Principles and Practice, J. L. Lippincott, Philadelphia, PA,
1991; b) E. Watson, P. Dea, K. K. Chan, J. Pharm. Sci. 1985,
74, 1283–92; c) V. L. Boyd, J. D. Robbins, W. Egan, S. M. Lude-
man, J. Med. Chem. 1986, 29, 1206–1210.
[2] For recent reviews of CP and related prodrugs, see: a) J. Zhang,
Q. Tian, S.-F. Zhou, Curr. Drug Ther. 2006, 1, 55–84; b) M. E.
Colvin, J. N. Quong, Advances in DNA Sequence-Specific
Agents 2002, 4, 29–46; c) S. M. Ludeman, Biomed. Chem. 2000,
163–187; d) S. M. Ludeman, Curr. Pharm. Des. 1999, 5, 627–
643; e) J. E. Wright, Cancer Ther. 1997, 23–79; f) J. Liang, M.
Huang, W. Duan, X.-Q. Yu, S. Zhou, Curr. Pharm. Des. 2007,
13, 963–78; g) C. T. Dang, Expert Rev. Anticancer Ther. 2006,
6, 427–436; h) K. Misiura, Mini-Rev. Med. Chem. 2006, 6, 395–
400; i) J. Zhang, Q. Tian, S. Y. Chan, S. C. Li, S. Zhou, W.
Duan, Y.-Z. Zhu, Drug Metabolism Rev. 2005, 37, 611–703; j)
P. H. Rooney, C. Telfer, M. C. E. McFadyen, M. T. Melvin,
G. I. Murray, Curr. Cancer Drug Targets 2004, 4, 257–265; k)
E. A. Chiocca, D. J. Waxman, Methods Mol. Med. 2004, 90,
203–222.
[3] a) V. T. Vu, C. C. Fenselau, M. Colvin, J. Am. Chem. Soc. 1981,
103, 7362–7364; b) K. Hemminki, Cancer Res. 1985, 45, 4237–
4243.
[4] a) L. F. Tietze, T. Feuerstein, Curr. Pharm. Des. 2003, 9, 2155–
2175 and references cited therein; b) M. Jain, C.-H. Kwon, J.
Med. Chem. 2003, 46, 5428–5436.
Conclusions
A novel photoactivated phosphamide mustard prodrug
equipped with a new phototrigger was designed and synthe-
sized. The prodrug effectively released aldophosphamide
upon irradiation at 350 nm, but it is stable under laboratory
lighting. The PPG moiety has remarkable dark stability and
was carried through a multistep synthesis. It was readily
modified for the prodrug application and can be potentially
useful in releasing other biologically important substances
in aqueous environments.
[5] T. J. Dougherty, C. H. Gomer, B. W. Henderson, G. Jori, D.
Kessel, M. Korbelik, J. Moan, Q. Peng, J. Natl. Cancer Inst.
1998, 90, 889–905.
[6] a) P. Wang, H. Hu, Y. Wang, Org. Lett. 2007, 9, 1533–1535; b)
P. Wang, H. Hu, Y. Wang, Org. Lett. 2007, 9, 2831–2833; c) P.
Wang, Y. Wang, H. Hu, C. Spencer, X. Liang, L. Pan, J. Org.
Chem. 2008, 73, 6152–6157.
Experimental Section
N-{2-[2-(TBS)oxyethyl]-4,4-diphenyl-4H–1,3-benzodioxin-6-yl}acet-
amide (11): A stirring mixture of 10 (900 mg, 2.70 mmol) and 3-
(tert-butyldimethylsilyloxy)-1-propanal (762 mg, 4.05 mmol) in p-
xylene (4.0 mL) was heated to 140 °C in a sealed tube under an
argon atmosphere. After 1.5 h, the reaction was allowed to attain
room temperature and the solvent was removed under vacuum. The
crude products were purified by silica-gel column chromatography
(petroleum ether/ethyl acetate, 2:1; Rf = 0.3) to produce 11 (1.41 g,
89%). 1H NMR (300 MHz, CDCl3): δ = 7.48–7.42 (br. s, 1 H), 7.37
(dd, J = 8.9, 2.6 Hz, 1 H), 7.35–7.27 (m, 5 H), 7.25–7.15 (m, 5 H),
6.84 (d, J = 9.0 Hz, 1 H), 6.82 (d, J = 2.7 Hz, 1 H), 5.13 (t, J =
5.4 Hz, 1 H), 3.82–3.71 (m, 2 H), 2.06 (q, J = 5.9 Hz, 2 H), 1.94
(s, 3 H), 0.74 (s, 9 H), –0.06 (s, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 200.4, 168.3, 149.1, 145.9, 143.7, 130.4, 129.0, 128.1,
128.0, 127.8, 127.5, 125.6, 121.6, 121.3, 117.3, 93.1, 84.1, 58.0, 37.9,
[7] P. Wang, Y. Wang, H. Hu, X. Liang, Eur. J. Org. Chem. 2009,
208–211.
[8] a) It is well established that PEG improves the aqueous solubil-
ity, circulation half-life, and other pharmacokinetic properties
of a drug. It is also known that PEG conjugates (MW Ͼ 10 K
Dalton) have higher accumulation in tumors than in normal
tissues as a result of the “enhanced permeation and retention
effect” associated with macromolecules; b) R. B. Greenwald,
Y. H. Choe, J. McGuire, C. D. Conover, Adv. Drug Delivery
Rev. 2003, 55, 217–250.
[9] 31P NMR spectra were recorded at 161.97 MHz and chemical
shifts were measured relative to external H3PO4 (85%) in a
coaxial capillary tube.
[10] a) R. F. Borch, T. R. Hoye, T. A. Swanson, J. Med. Chem.
1984, 27, 490–494; b) G. Zon, S. M. Ludeman, E. M. Sweet,
W. Egan, L. R. Phillips, J. Pharm. Sci. 1982, 71, 443–446.
[11] The chemical shifts of the intermediates are not identical to
the values reported by others,[10,12] owing to the sensitivity of
25.7, 24.1, 18.0, –5.46, –5.51 ppm. IR (neat): ν = 3019, 2957, 2930,
˜
1678, 1497, 1393 cm–1. HRMS (ESI): calcd. for C26H28NO4Si [M –
C4H9]+ 446.1788; found 446.1794.
Eur. J. Org. Chem. 2009, 2055–2058
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