1124
Z. Zhu et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1121±1124
masked lactone linkers for phosphate prodrugs. The
even lower bio-reconversion rate of compound 16 over
compound 21 implied that the poor enzymatic cleavage
of the phosphate groups, rather than the rate of the
subsequent lactonization of the linkers, was more likely
to be responsible for the low reconversion. This limited
enzymatic access to the phosphate groups of compound
16 and 21 could be due to a hindered environment
imposed by the indole ring or possibly due to tight
binding of the compounds to plasma protein.13d Com-
pound 9, with p-hydroxymethylbenzoyloxymethoxy-
carbonyl as the linker, was reconverted back to
PD154075 in 59.5% in vivo. This high reconversion of 9
to PD154075 could attribute to its longer and more
¯exible linker which provides easier access for alkaline
phosphatase.
2. (a) Rudd, J. A.; Jordan, C. C.; Naylor, R. J. Br. J. Phar-
macology 1996, 119, 931. (b) Gardner, C. J.; Twissell, D. J.;
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chapter 9.
In conclusion, in the preparation of aqueous soluble
prodrugs of PD154075, a novel phosphate prodrug
approach for an indole group has been developed. By
using p-hydroxymethylbenzoyloxymethoxycarbonyl as
the linker, compound 9 was found to be a good prodrug
candidate for PD154075 with signi®cantly increased
aqueous solubility, sucient stability in aqueous solu-
tion and extensive bio-reconversion in vivo. With the
increasing challenges in drug delivery of complex ther-
apeutic agents, this approach provides an important
new prodrug strategy for drug candidates containing an
indole moiety.
11. Safadi, M.; Oliyai, R.; Stella, V. J. Pharm. Res. 1993, 10, 1350.
12. Bundgaard, H.; Falch, E.; Jensen, E. J. Med. Chem. 1989,
32, 2503.
Acknowledgements
The authors would like to thank Dr. Klaus Steiner for
the generous supply of PD154075 and Drs. Fred M.
Hershenson, Thomas F. Mich, Michael D. Taylor for
helpful discussions.
13. (a) Wang, B.; Gangwar, S.; Pauletti, G. M.; Siahaan, T. J.;
Borchardt, R. T. J. Org. Chem. 1997, 62, 1363. (b) Nicolaou,
M. G.; Yuan, C.-S.; Borchardt, R. T. J. Org. Chem. 1996, 61,
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ina, V.; Knipe, J. O.; Rose, W. C.; Casazza, A. M.; Vyas, D.
M. Bioorg. Med. Chem. Lett. 1995, 5, 247. (d) Ueda, Y.; Mik-
kilineni, A. B.; Knipe, J. O.; Rose, W. C.; Casazza, A. M.;
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