2084
Z. Yan et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2083–2085
Table 1. Yields of 9, 11 and 2 (%)
The synthesis of the title compounds 2 is described in
Scheme 2. Starting material 8a was commercially avail-
able, while the synthesis of 8b has been previously
reported.7 The 4,4,7-trimethyl-4H-naphthalen-1-one 8c
was prepared from gem-dimethyl carboxylic acid 128 via
treatment with TFAA in TFA (Scheme 3). Resulting
ketone 13 was deprotonated with LHMDS and sele-
nated with PhSeBr, followed by oxidative elimination to
afford 8c. The synthesis of 8d required the intermediate
15, prepared from 149 by reaction with SO2Cl2, then
quinoline (Scheme 4). The thioenol 15 was then treated
with H2O2 to give 8d in 76% yield.
8
9
11
2
a: X=O, Y=CO
b: X=S, Y=CO
c: X=CMe2, Y=CO
d: X=O, Y=SO2
61
53
66
50
42
54
59
60
100
90
86
68
Table 2. Screening results for inhibition of tyrosine phosphatases
Finally, the desired benzyl bromides 9 were obtained in
moderate yield by benzylic bromination of 8 with NBS
in the presence of AIBN. With the starting materials 9
in hand, we adopted O’Donnell’s protocol10 to synthe-
size 2 (Scheme 2). The glycine Schiff base 10, derived
from benzophone imine and glycine methyl ester, was
benzylated with 9 to give 11 in 42–60% yield. For the
final step, imino methyl ester 11 was treated with 1 N
HCl to provide the title compounds 2 in good to excel-
lent yields (Table 1).
Compd
R
PTP1B % TC-PTP % LAR % CD45 %
inhibition inhibition inhibition inhibition
(100 mM, (100 mM, (100 mM, (100 mM,
10 mM)
10 mM)
10 mM)
10 mM)
16a
16b
16c
16d
2,5-F2-Bn
4-PhO-Ph
PhCH(Me)CH2 95, 55
cHexCH2 70, 40
95, 0
100, 75
100, 85
100, 85
90, 20
20, 10
50, 25
70, 50
50, 10
10, 0
50, 5
70, 20
55, 15
70, 20
The phosphotyrosine mimetics were successfully incor-
porated into a library containing triazolopyridazine
b-strand templates11 via solid-phase synthesis. Pre-
liminary screening for inhibition of four phosphatases
(CD45, LAR, TCPP, and PTP1B) was accomplished by
flourometric assays, using 6,8-difluoro-4-methy-
lumbelliferyl phosphate (DiFMUP, Molecular Probes)
as substrate.12 Some derivatives exhibited moderate
potency (up to 85% inhibition at 10 mM sample con-
centration) and selectivity against the tyrosine phos-
phatases assayed (see Table 2), with the type 2d
phosphotyrosine mimetic providing the best activity.13
Acknowledgements
The authors are grateful to Dr. H. Nakanishi for helpful
discussions.
References and Notes
1. (a) Johnson, L. N.; Lewis, R. J. Chem. Rev. 2001, 101,
2209. (b) Kennelly, P. J. Chem. Rev. 2001, 101, 2291. (c)
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Tonks, N. K.; Neel, B. G. Curr. Opin. Cell. Biol. 2001, 13, 182.
(e) Hunter, T. Cell 2000, 100, 113. (f) Tonks, N. K.; Neel, B. G.
Curr. Opin. Cell. Biol. 1997, 9, 193. (g) Denu, J. M.; Stuckey,
J. A.; Saper, M. A.; Dixon, J. E. Cell 1996, 87, 361. (h) Tonks,
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Scheme 2. (a) NBS/AIBN, CCl4; (b) 10% NaOH(aq), CH2Cl2,
nBu4N+HSO-4; (c) 1 N HCl.
Scheme 3. (a) TFAA, TFA, 0 ꢀC to rt, 63%; (b) (i) LHMDS, PhSeBr,
À78 ꢀC, THF, 86%; (ii) 30% H2O2, AcOH, THF, 80%.
2. (a) Blaskovich, M. A.; Kim, H.-O. Exp. Opin. Ther. Pat.
2002, 12, 871. (b) Zhang, Z.-Y. Curr. Opin. Chem. Biol. 2001,
5, 416. (c) Zhang, Z.-Y. CRC Crit. Rev. Biochem. Mol. Biol.
1998, 33, 1.
3. (a) Kim, H.-O.; Kahn, M. Combinat. Chem. High
Throughput Screening 2000, 3, 167. (b) Kim, H.-O.; Kahn, M.
Rec. Adv. Org. Chem. 2000, 1, 43.
4. A preliminary account of this research was presented at the
221st ACS Meeting, San Diego, CA, April 2001; Abstr.
MEDI-32.
Scheme 4. (a) SO2Cl2, CH2Cl2, reflux, then quinoline, 150 ꢀC, 50%;
(b) 30% H2O2, AcOH, reflux, 76%.