PolyAspirin truly offer a huge capacity of drugs and an easily
manipulated system for drug delivery.3 However, the release
of drug units in a linear polymeric drug can still be “sudden”
because the hydrolytic degradation may occur at any spot
of the polymer backbone or even at multiple spots simulta-
neously.
In this communication, we demonstrate a novel approach
to incorporate multiple drug units (i.e., L-DOPA) into a
cascade structure to form a dendrimer prodrug (Figure 1)
in refluxing acetone to give the BnO-DOPA-NHBoc-
COOMe 3,6 which was hydrolyzed by 1 N aqueous NaOH
in MeOH/THF at room temperature followed by acidification
to afford BnO-DOPA-NHBoc-COOH 4.7
Scheme 2 shows the synthesis of the building block 6 and
the Boc-protected core 8. Compound 4 was treated with 4.5
equiv of ethylene glycol in the presence of dicyclohexyl-
carbodiimide (DCC) and 4-(dimethylamino)-pyridinium p-
toluenesulfonate (DPTS) to give 5,8 which was then stirred
with succinic anhydride in pyridine to provide the building
block 6 for the continuous synthesis of high-generation
dendrimer prodrugs.9 The BnO-G0-NHBoc 7 was produced
by simultaneously coupling two units of 4 with ethylene
glycol in the presence of DCC and DPTS and then was
hydrogenolyzed with a palladium catalyst (5% Pd/C) to yield
the HO-G0-NHBoc 8,10 which was used as the core to
develop high-generation dendrimer prodrugs.
Scheme 2. Synthesis of Building Block 6 and Core 8
(Boc-G0)
Figure 1. Structure of the second-generation L-DOPA dendrimer
prodrug (HO-G2-NH2).
The synthesis of a high generation of drug dendrimers was
achieved with a routine coupling and deprotecting procedure
(Scheme 3). The core 8 was coupled with four units of the
building block 6 to afford BnO-G1-NHBoc 9, which was
then deprotected back to the catechol function by hydro-
genolysis with H2/Pd-C (Parr apparatus) to give HO-G1-
NHBoc 10. The deprotection of amine groups of 10 via
acidification gave the desired first-generation L-DOPA
based on L-DOPA.4 This is believed to be the first time that
a dendrimer is made of and used as an intrinsic drug or
prodrug instead of as a carrier for encapsulation or conjuga-
tion. Such a well-defined dendritic architecture will be
expected to provide a sequential and better controlled release
profile by losing the periphery drug entities first, then the
interior ones, and lastly the core units.
(2) (a) Pasut, G.; Scaramuzza, S.; Schiavon, O.; Mendich, R.; Veronese,
F. M. J. Bioact. Compat. Polym. 2005, 20, 213-230. (b) Bryan, J. Pharma.
J. 2004, 273, 793-794. (c) Delort, E.; Darbre, T.; Reymond, J.-L. J. Am.
Chem. Soc. 2004, 126, 15642-15643. (d) Liu, M.; Kono, K.; Fre´chet, J.
M. J. J. Polym. Sci. Part A: Polym. Chem. 1999, 37, 3492-3503.
(3) (a) Whitaker-Brothers, K.; Uhrich, K. E. J. Biomed. Mater. Res.:
Part A 2006, 764, 470-479. (b) Miao, J.; Xu, G.; Zhu, L.; Tian, L.; Uhrich,
K. E.; Aliva-Orta, C. A.; Hsiao, B. S.; Utz, M. Macromolecules 2005, 38,
7074-7082. (c) Prudencio, A.; Schmeltzer, R. C.; Uhrich, K. E. Macro-
molecules 2005, 38, 6895-6901. (d) Harten, R. D.; Svach, D. J.; Schmeltzer,
R.; Uhrich, K. E. J. Biomed. Mater. Res.: Part A. 2005, 72A(4), 354-362.
(e) Schmeltzer, R.; Schmalenberg, K.; Uhrich, K. E. Biomacromolecules
2005, 6(1) 359-367.
Synthesis of the L-DOPA dendrimer prodrugs started from
commercially available L-DOPA 1 (Scheme 1), which was
Scheme 1. Synthesis of Boc- and Bn-Protected
L-DOPA-COOH4
(4) Chai, M.; Tang, S. Method of Preparing Dendritic Drugs. U.S.
Provisional Patent Application, January 24, 2006.
(5) (a) Hunter, L.; Hutton, C. A. Aust. J. Chem. 2003, 56, 1095-1098.
(b) Gaucher, A.; Barbeau, O.; Hamchaoui, W.; Vandrommer, L.; Wright,
K.; Wakselman, M.; Mazaleyrat, J. P. Tetrahedron Lett. 2002, 8241-8244.
(6) Clary, M. T.; Adejare, A.; Shams, G.; Feller, D. R.; Miller, D. D. J.
Med. Chem. 1987, 30, 86-90.
(7) Hu, B. H.; Messersmith, P. B. Tetrahedron Lett. 2000, 40, 5795-
5798.
(8) Moore, J. S.; Stupp, S. I. Macromolecules 1990, 23, 65-70.
(9) Luman, N. R.; Smeds, K. A.; Grinstaff, M. W. Chem.-Eur. J. 2003,
9, 5618-5626.
(10) Hanessian, S.; Liak, T. S.; Vanasse, B. Synthesis 1981, 5, 396-
397.
converted to the corresponding methyl ester and then
immediately N-protected by treatment with di-tert-butyl-
dicarbonate to synthesize HO-DOPA-NHBoc-COOMe 2.5
Then, the catechol function of 2 was treated with potassium
carbonate, sodium iodide, and an excess of benzyl bromide
4422
Org. Lett., Vol. 8, No. 20, 2006