reproduces the position and angular projection of the i, i+3,
i+4, and i+7 groups.
Superimposition of the four CH3-C bonds on the indane
with i, i+3, i+4, and i+7 CH3-C groups on an all-Ala helix
shows a good matching with an rms difference of 0.92 Å
(Figure 2B).
Figure 1. (A) 4,7-Diphenyl-1,6-disubstituted indanes. (B) Energy-
minimized (MM2) tetramethyldiphenylindanes. (C) Atropisomer of
A.
Our previous helix mimetics reproduced the i, i+4, and
i+7 groups that project from one face of the helix and often
make critical hydrophobic contacts to a target protein.
However, in many helix/protein complexes, additional
interactions come from residues flanking the hydrophobic
face of the helix. For example, in the case of Bak and Bad
peptides binding to Bcl-xL, important contacts are made by
residues in the i, i+3, i+4, and i+7 positions (VGRQLAIIG
and YGRELRRM, respectively).10 The importance of i, i+3,
i+4, and i+7 helical residues is also seen in the complex
between the tumor suppressor p53 and its oncogenic regula-
tory protein Hdm-2.11 p53 binds through a helical domain
(16NETFSDLWKLLP27) with critical interactions being
made to Hdm-2 by Phe19, Trp23, and Leu26 with additional
contact from Leu22. The importance of the i+3 residue is
demonstrated by a recent nanomolar level peptide-based
inhibitor of Hdm-2 (AcPheMetAibPmp-6ClTrp-GluAc3c-
LeuNH2) which has a Pmp residue (a derivative of Tyr)
adjacent to the central Trp.12 Therefore, we report here the
design and synthesis of a new synthetic scaffold which
mimics i, i+3, i+4, and i+7 residues of the R-helices.
Our principal goal in this study was to develop general
approaches to helix mimetic scaffolds that could be targeted
to different proteins by changing the nature of the substit-
uents. This is exactly analogous to the natural use of
R-helices as common scaffolds for mediating protein-protein
interactions with selectivity being imparted by modifications
in the shape and charge characteristics of the side-chain
residues. Our approach to mimicking the i, i+3, i+4, and
i+7 groups on a helix involves combining the terphenyl
strategy (i, i+4, i+7) with a 1,6-disubstituted indane that
had previously been reported to reproduce the angular
projection of adjacent residues (i and i+1) on the helix.13
As shown in Figure 1B, MM2 calculations on tetramethyl-
substituted 4,7-diphenylindanes reveal that a conformation
with aryl-aryl torsion angles of 67° and 62° closely
Figure 2. (A) Poly-Ala R-helix with i, i+3, i+4, and i+7 groups.
(B) Stereoview of rms difference (0.92 Å) overlay of R-helix and
tetramethyldiphenylindane.
The synthesis of 4,7-diphenyl-1,6-disubstituted indanes
began with indanone 1, which was prepared from o-cresol
by treatment with chloropropionyl chloride, subsequent Fries
rearrangement and Friedel-Crafts reaction, and methylation
of the 7-hydroxyindanone.14 Reaction of ketone 1 with
i-propylmagnesium bromide in the presence of cerium
chloride and subsequent elimination gave the indene which
was catalytically hydrogenated to the key 7-methoxy-2,6-
disubstituted indane, 2 (Scheme 1). Suzuki coupling between
the boronic acid 4, which was derived from 3 after NBS
bromination of 2, and triflate 5 containing the i+4 binding
side chain gave 1,4,6-trisubstituted indane, 6. The next
coupling, which would establish the i+1 binding group, with
an extremely hindered triflate 7 was explored using original
and modified Suzuki and Stille coupling methods.
Although many useful coupling methods have been
recently developed for sterically hindered and less-reactive
aryl halides, there is no efficient Suzuki method for 2,6-
disubstituted triflates. Although a coupled product could not
be obtained by Suzuki-type reactions, the modified Stille
condition involving a Pd/Cu cocatalyst and harsh reaction
conditions gave the desired compound 9 in a very low yield
(<20%) (Scheme 2).15 The yield could be improved to 71%
by a prolonged dropwise addition of the aryltributyltin 8 as
a dilute solution in DMF. To our best knowledge, 7 is one
(13) (a) Horwell, D. C.; Howson, W.; Nolan, W. P.; Ratcliffe, G. S.;
Rees, D. C.; Willems, H. M. G. Tetrahedron 1995, 51, 203. (b) Horwell,
D. C.; Pritchard, M.; Raphy, J.; Ratcliffe, G. Immunopharmacology 1996,
33, 68. (c) Horwell, D. C.; Howson, W.; Ratcliffe, G. S.; Willems, H. M.
G. Bioorg. Med. Chem. 1996, 4, 33.
(14) Tsai, T. Y.; Nambiar, K. P.; Krikorian, D.; Botta, M.; Marini-Bettolo,
R.; Wiesner, K. Can. J. Chem. 1979, 57, 2124.
(10) Petros, A. M.; Nettesheim, D. G.; Wanf, Y.; Olejniczak, E. T.;
Meadows, R. P.; Mack, J.; Fesik, S. W. Protein Sci. 2000, 9, 2528.
(11) Chene, P.; Jahnke, W. Angew. Chem., Int. Ed. 2002, 41, 1702.
(12) Garcia-Echeverria, C.; Chene, P.; Blommers, M. J. J.; Furet, P. J.
Med. Chem. 2000, 43, 3205.
(15) Saa, J. M.; Martorell, G. J. Org. Chem. 1993, 58, 1963.
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Org. Lett., Vol. 8, No. 9, 2006