S.D. Guile et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2260–2265
2265
9. Rich, D. H.; Homes, O. W. In Practice of Medicinal
Chemistry; Wermuth, C. G., Ed.; Elsevier: London, 2003;
pp 373–386, and references therein.
10. ACDlogD is available from ACD Labs, Toronto, Canada,
achieved due to the very high potency of the lead com-
pound. Unfortunately, many of the amides described
here, including 30, exist as a mixture of conformational
isomers resulting from restricted rotation about both the
amide carbon–nitrogen and the carbonyl–aryl bonds.
Further studies with these compounds, including atrop-
isomeric properties and implications, will be reported in
due course.
11. A radioligand-binding assay was developed using scintil-
lation proximity assay (SPA) technology (Bosworth, N.;
Towers, P. Nature 1989 341, 167) Wheatgerm agglutinin
SPA beads (Amersham) (0.2 mg/mL) coated with Jurkat
cell membranes were incubated with [125I]-38 (0.1 nM) in
the absence or presence of increasing concentrations of
test compound. Unlabelled 3 (1 lM) was used to define
non-specific binding. The test compounds were diluted in
DMSO and then assay buffer (50 mM HEPES, 0.1 mM
EDTA and 150 mM NaCl, pH 7.4) containing 0.5%
bovine serum albumin (BSA) such that the final concen-
tration of DMSO in the assay was 0.5%. The final
concentration of BSA in the total assay volume of 200 lL
was 0.05%. The assay reagents were incubated for 18 h at
room temperature and radioactivity bound to the mem-
brane-coated beads was determined using a Topcount
scintillation counter (Perkin Elmer).
References and notes
1. Shaw, J. P.; Utz, P. J.; Durand, D. B.; Toole, J. J.; Emmel,
E. A.; Crabtree, G. R. Science 1988, 241, 202.
2. Liu, J.; Farmer, J. D. J.; Lane, W. S.; Friedman, J.;
Weissman, I.; Schreiber, S. L. Cell 1991, 66, 807.
3. Michne, W. F.; Schroeder, J. D.; Guiles, J. W.; Trea-
surywala, A. M.; Weigelt, C. A.; Stansberry, M. F.;
McAvoy, E.; Shah, C. R.; Baine, Y.; Sawutz, D. G.;
Miller, P. B.; Stankunas, B. M.; Reid, J.; Bump, E.;
Schlegel, D. J. Med. Chem. 1995, 38, 2557.
4. Schreiber, S. L. Science 2000, 287, 1964.
The radioligand 125I-38 was prepared from the heterocycle
39 (Bantick, J.; Cooper, M.; Perry, M.; Thorne, P.
WO9929695) as shown below.
5. Murray, C. M.; Raymond Hutchinson, R.; Bantick, J.
R.; Belfield, G. P.; Benjamin, A. D.; Brazma, D.;
Bundick, R. V.; Cook, D. I.; Craggs, R. I.; Edwards, S.;
Evans, L. R.; Harrison, R.; Holness, E.; Jackson, A. P.;
Jackson, C. G.; Kingston, L. P.; Perry, M. W. D.; Ross,
A. R. J.; Rugman, P. A.; Sidhu, S. S.; Sullivan, M.;
Taylor-Fishwick, D. A.; Walker, P. C.; Whitehead, Y.
M.; Wilkinson, D. J.; Wright, A.; Donald, D. K. Nat.
Chem. Biol. 2005, 1, 371.
O
O
S
OH
125I
N
N
N
N
a,b,c,d
N
NH
6. Teague, S. J.; Davis, A. M.; Leeson, P. D.; Oprea, T.
Angew. Chem., Int. Ed. 1999, 38, 3743.
iBu
125I-38
iBu
39
7. Oprea, T. I.; Davis, A. M.; Teague, S. J.; Leeson, P. D.
J. Chem. Inf. Comput. Sci. 2001, 41, 1308.
8. Kano, S.; Yuasa, Y.; Yokomatsu, T.; Shibuya, S. Hetero-
cycles 1983, 20, 2035.
(a) i—2-chloromethyliodobenzene, Cs2CO3, DMF; ii—
LDA, TsS(CH2)3OTBDMS, THF; (b) (CH3)6Sn2,
Pd(PPh3)4, toluene; (c) chloramine-T, Na125I, methanol;
(d) TBAF, THF.