Table 1 Rate constants for onset inactivation of the PTPs by
organochalcogenanes 1–12
whose mode of action likely involves at least two steps: binding to
the PTP active site followed by covalent modification of the active
site Cys residue. It is worthwhile to point out that the kinetic
parameters KI and ki for compound 3 compare very favorably to
those determined for previously described activity-based probes
for the PTPs, including a-bromobenzyl phosphonate18 and aryl
vinyl sulfonates.19
In summary, the results highlight the potential for develop-
ing hypervalent chalcogenated based small molecule probes to
modulate PTP activity in signaling and in diseases. Among the
organochalcogenanes used as inhibitor of PTPs, organotelluranes
showed to be more potent than organoselenanes for inhibi-
tion of PTP1B and the YopH. The general reactivity of the
organotelluranes toward the PTPs should facilitate the design
of novel activity-based PTP probes. Additionally, PTP isozyme-
specific organotelluranes based inhibitors could be developed by
introducing specificity determinants into the aryl group to increase
potency and selectivity.
Inactivator
Code
PTP1Ba
YopHb (kobs
,
Structure
(kobs, min-1)
min-1)
1
2
3
4
5
0.46 0.15
0.48 0.12
0.53 0.25
0.30 0.19
0.22 0.25
0.25 0.17
0.39 0.22
0.89 0.21
0.92 0.19
0.18 0.12
Acknowledgements
L.W. and Z.-Y.Z. were supported in part by the National Institutes
of Health Grants CA126937 and CA152194. L.P. and L.H.A.
thank CNPq, CAPES and FAPESP for financial support.
6
0.21 0.18
0.43 0.25
0.31 0.15
0.20 0.16
0.20 0.23
0.46 0.19
0.60 0.39
0.09 0.14
0.74 0.22
0.59 0.10
0.39 0.20
0.30 0.11
1.07 0.46
0.65 0.46
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1350 | Org. Biomol. Chem., 2011, 9, 1347–1351
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