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C. M. Marson et al. / Bioorg. Med. Chem. Lett. 12 (2002) 255–259
acylating role for the anhydrides. As expected, the
length and nature of the lipid chain markedly influences
the prenyl-protein transferase activity. The lack of an
alkyl (including prenyl) chain, as in itaconic anhydride
5a, excludes prenyl-protein transferase activity, whereas
the longest chain tested (5d) gave excellent inhibition of
GGPTase-I. Moreover, 5d is highly selective for
GGPTase-I/FPTase (50:1), and 5b also shows good
selectivity (11:1). Interestingly, a 2:1 E/Z mixture of 5c
shows excellent selectivity (1:50) for FPTase. Accord-
ingly, the anhydrides 5b, 5c and 5d could be useful as
probes for the selective inhibition of either FPTase or
GGPTase-I.
than either the diacid 3d or dimethyl ester 4d deriva-
tives, as an inhibitor of GGPTase-I. Whether an anhy-
dride can generally function as a neutral bioisostere of
the charged and biologically labile diphosphate group
of FPP is an important issue to be investigated.
GGPTase-I inhibitors have been proposed to prevent
hyperplastic remodeling and to act on vascular lesions
by inducing apoptotic regression.22 Consequently, the
advent of these non-peptidic inhibitors of GGPTase-I,
whose activity can be tuned by altering the lipid chain
length and type, indicates potential therapeutic value
and use as biochemical probes.
The uniqueness of the anhydride function is shown by
comparison with a variety of related functional groups
including diacids, monomethyl ester carboxylic acids,20
the triacid 6 and CoQ10. Thus, FPTase IC50 values for
the diacids 3b, 3c, and 3d were all >1000 mM; that for
3e was 402 mM. GGPTase-I IC50 values for the mono-
methyl ester derived from the carboxylic acids 3c, 3d
and 3e were each >1000 mM; those for the diacids 3b
and 3c were 900, and 420 mM, respectively. FPTase/
GGPTase-I IC50 values (ratio of mM) for various non-
anhydride compounds were: 4b, 900:500; 4c,
>1000:185; 4d: >1000: >1000; CoQ, 500:1000; 6,
166:252. Despite the lengthy prenylated chain of CoQ,
and the possibility of it acting as a Michael acceptor or
participating in redox processes, CoQ was not found to
be a significant inhibitor of GGPTase-I.
Acknowledgements
Financial support from the Mandeville Trust is grate-
fully acknowledged.
References and Notes
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The synthetic GGPTase-I inhibitors 5b and 5d are more
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Table 1. In vitro inhibition of recombinant protein prenyl-
transferases19
FPTase
IC50 (mM)
GGPTase-I
IC50 (mM)
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5a
5b
>1000
449Æ38
190Æ23
9Æ0.3
>1000
40.2Æ1.5
136Æ9
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3507.
(E)-5c
3:1(E/Z)-5c
5d
5e
5f
503Æ37
20.8Æ0.2
401Æ8
>1000
>1000
854Æ80
229Æ15