2504
G. E. Atkinson et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2501–2505
The introduction of Dhp residue (peptides 14 and 21)
led to a potency enhancement in the context of the Ser2
peptide. This appeared to indicate that a reduction in
the degree of rotational freedom of the phenyl ring is
tolerated. The other significant observation was that the
introduction of C-terminal 2S-phenylalaninol produced
a small improvement in potency. Here, it is likely that
the a-hydroxyl group makes a unique H-bond contact
with the guanidino function of Arg250 in cyclin A (see
Fig. 1).
These encouraging results not only highlight a generic
methodology for probing structure–activity relation-
ships using b-hydroxyamino acid building blocks, but
also provide a framework for the design of peptidomi-
metics and small molecules that target the cyclin
recruitment-site.
Scheme 5. Reagents and conditions: (i) FmocPhe[ CH2OH], DIEA,
ClCH2CH2Cl-THF (3:1), 24 h; (ii) piperidine-DMF (1:4); (iii) Fmoc-
amino acid-TBTU-HOBt-DIEA (1:1:1:2; 4–8 equiv); (iv) Boc2O (4–8
equiv), DMF; (v) TFA-H2O-iPr3SiH (90:8:2), 2 h.
Acknowledgements
The most striking and unexpected observation is that
the (2R,3S)-Pse8-, i.e., d-threo-Pse-containing peptides 6
and 18 retained good potency, although they are some-
what less potent compared to the (2S,3R)-Pse8 peptides
5 and 17, respectively. We are currently exploring the
implications of these results.
We are grateful to the BBSRC, UK and Cyclacel Ltd.
for the funding of a CASE studentship (to GEA).
References and Notes
Furthermore, the above hypothesized complimentary
interactions between the peptide ligand and C-RS is
highly fastidious, since the presence of a bulky b-acet-
oxy group within Pse8-residue in peptides 12, 13, 19 and
20 resulted in decreased binding competency and kinase
inhibitory activity. Interestingly, the potency order
appears to be reversed for the (2S,3R)- and (2R,3S)-
forms in both pairs of peptide derivatives, although the
differences may not be significant. Nevertheless these
results suggest that the b-acetoxy group precludes the
complementary interactions more in the context of the
l-derivatives.
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Figure 1. Molecular model of cyclin A-peptide 1 complex.5,7 To aid
viewing of the model, only a portion of the cyclin groove is shown.
The pro-S b-H is highlighted in yellow, the cyclin groove Arg250 resi-
due’s side-chain in blue.