Catechol: A minimal scaffold for non-peptide peptidomimetics of the i + 1 and i + 2 positions of the β-turn of somatostatin

Article abstract of DOI:10.1021/ol061488x

The design, synthesis, and evaluation of a series of catechol-based non-peptide peptidomimetics of the peptide hormone somatostatin have been achieved. These ligands comprise the simplest known non-peptide mimetics of the i + 1 and i + 2 positions of the

Full text of DOI:10.1021/ol061488x

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4397-4400
Catechol: A Minimal Scaffold for
Non-Peptide Peptidomimetics of the
i
+
1 and i
+ 2 Positions of the â-Turn
of Somatostatin
Brendan P. Mowery,† Vidya Prasad,† Craig S. Kenesky,† Angie R. Angeles,†
Laurie L. Taylor,‡ Jin-Jye Feng,§ Wen-Long Chen,§ Atsui Lin,§ Fong-Chi Cheng,§
Amos B. Smith, III,*,† and Ralph Hirschmann*,†
Department of Chemistry, UniVersity of PennsylVania, Philadelphia, PennsylVania
19104, MDS Pharma SerVices, 22011 30th DriVe SE, Bothell, Washington 98021, and
MDS Pharma SerVicessTaiwan Ltd., 158 Li-Teh Road, Peitou, Taipei,
Taiwan 112, ROC
rfh@sas.upenn.edu
Received June 17, 2006
ABSTRACT
The design, synthesis, and evaluation of a series of catechol-based non-peptide peptidomimetics of the peptide hormone somatostatin have
been achieved. These ligands comprise the simplest known non-peptide mimetics of the i 1 and i 2 positions of the somatostatin -turn.
-turn induces a selective 9-fold affinity enhancement at the sst2
+
+
â
Incorporation of an additional side chain to include the i position of the
receptor.
â
Elucidation of the bioactive conformation of somatostatin-
14 (1, SRIF-14, Figure 1) by Veber and his collaborators at
Merck,1 in conjunction with the earlier results of an alanine
scan by Rivier and co-workers,2 resulted in the design and
synthesis by Veber of both the cyclic hexapeptide L-363,-
301 (2) and the more potent super agonist MK-678 (3).3 The
earlier insightful observation by Walter that there was no
definite evidence for the direct interaction of the amide
backbone of peptide hormones and neurotransmitters with
their receptors,4 a proposition that was strongly supported
by the report by Freidinger et al. of a potent retro-enantio
congener of these peptides,5 allowed Hirschmann, Nicolaou,
Smith, and co-workers to exploit the â-D-glucoside scaffold6
for the attachment of mimics of the three side chains of the
â-turn of 17 that are critical for both binding and receptor
† University of Pennsylvania.
‡ MDS Pharma Services, Bothell, WA.
§ MDS Pharma ServicessTaiwan Ltd., Taipei, Taiwan, ROC.
(1) Veber, D. F.; Holly, F. W.; Paleveda, W. J.; Nutt, R. F.; Bergstrand,
S. J.; Torchiana, M.; Glitzer, M. S.; Saperstein, R.; Hirschmann, R. Proc.
Natl. Acad. Sci. U.S.A. 1978, 75, 2636.
(4) Walter, R. Fed. Proc. 1977, 36, 1872.
(2) Vale, W.; Rivier, J.; Ling, N.; Brown, M. Metab., Clin. Exp. 1978,
27, 1391.
(3) Veber, D. F.; Freidinger, R. M.; Perlow, D. S.; Paleveda, W. J., Jr.;
Holly, F. W.; Strachan, R. G.; Nutt, R. F.; Arison, B. H.; Homnick, C.;
Randall, W. C.; Glitzer, M. S.; Saperstein, R.; Hirschmann, R. Nature 1981,
292, 55.
(5) (a) Freidinger, R. M.; Veber, D. F. Conformationally Directed Drug
Design, Peptides and Nucleic Acids as Templates of Targets; Vida, J.,
Gordon, M., Eds.; American Chemical Society: Washington, DC, 1984; p
169. (b) Arison, B. H.; Saperstein, R. In Peptides: Structure and Function,
Proceedings of the 8th American Peptide Symposium; Hruby, V. J., Rich,
D., Eds.; Pierce Chemical Co.: Rockford, IL, 1983; p 349.
10.1021/ol061488x CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/02/2006

Figure 2. MacroModel overlay of 5 (gray) with the NMR solution
structure of L-363,301 (green) in H2O using the Merck Molecular
Force Field 94.
even more impressive by the lack of stereogenic centers as
in the previous examples.8,9
Figure 1. Structures of somatostatin (1), cyclic hexapeptide
agonists 2 and 3, and the â-D-glucoside peptidomimetic (+)-4.
To assess the viability of the prospective scaffold as a
mimetic of the peptide â-turn of SRIF, we initially performed
molecular mechanics simulations employing the Merck
Molecular Force Field (MMFF94) in aqueous solution and
then compared the minimized structures of 5 to the NMR
solution structure13 of the cyclic hexapeptide L-363,301 (2).
As illustrated in Figure 2, the tryptophan and lysine residues
of 2 overlay well with the indol-3-ylethyl and 5-aminopentyl
side chains, respectively, of 5. A two-carbon linker was
chosen to ensure chemical stability of the indole side chain
(i.e., to prevent a gramine-type fragmentation).14
We therefore constructed 5 in four straightforward steps
from catechol (see Supporting Information). Biological
evaluation revealed that 5 binds the sst4 receptor with an
affinity (Ki) of 2.02 ( 0.38 µM, a value similar to that of
our original â-D-glucose-based mimetic (+)-4 (Ki ) 1.65 (
0.56 µM, sst4).15
To improve the affinity further, three approaches were
explored. First, on the basis of evidence that a fluorinated
tryptophan surrogate enhances the affinity of SRIF tetra-
decapeptide analogues,16 we proposed incorporation of a
fluorine atom at the 5-position of the indole ring to furnish
6. Second, the observation by Crider et al. of the increased
hydrophobicity imparted by chloride substituents17 suggested
the design of the 4,5-dichlorocatechol congener 7. Third, we
activation, along with the incorporation of a mimic of the
second Phe of 2, which was known to enhance binding.
With these achievements in hand, we recently sought to
identify the simplest scaffold that can replace the â-D-glucose
ring, while maintaining the side chain topology of a â-turn.
We reasoned that a benzene ring might serve this function.
As with the â-D-glucose scaffold, we used ether linkages to
attach the two most important side chains, an ethylindole to
mimic Trp8 and an aminopentyl moiety to simulate the Lys9
side chain, to arrive at the catechol-derived ligand 5 (Figure
2). Herein, we report that 5 and the subsequently designed
catechol-based SRIF ligands 6-8 bind to human somatostatin
receptor subtypes 2 and 4 (sst2 and sst4). Pleasingly, 5 is
among the simplest â-turn mimetics known, comparable in
size to the 3-thio-1,2,4-triazole8 and imidazopyrazine9 deriva-
tives reported recently by Contour-Galce´ra et al. and smaller
than the tetrahydro-â-carbolines of Poitout and co-workers,10
Hiroshi’s 4,1-benzoxazepin-2-ones,11 and Ellman’s 1,4,7-
thiadiazonane-3,6-dione scaffolds.12 This discovery is made
(6) (a) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Salvino, J.; Leahy,
E. M.; Sprengeler, P. A.; Furst, G.; Smith, A. B., III; Strader, C. D.; Cascieri,
M. A.; Candelore, M. R.; Donaldson, C.; Vale, W.; Maechler, L. J. Am.
Chem. Soc. 1992, 114, 9217. (b) Hirschmann, R.; Nicolaou, K. C.;
Pietranico, S.; Leahy, E. M.; Salvino, J.; Arison, B.; Cichy, M. A.; Spoors,
P. G.; Shakespeare, W. C.; Sprengeler, P. A.; Hamley, P.; Smith, A. B.,
III; Reisine, T.; Raynor, K.; Maechler, L.; Donaldson, C.; Vale, W.;
Freidinger, R. M.; Cascieri, M. R.; Strader, C. D. J. Am. Chem. Soc. 1993,
115, 12550.
(12) (a) Souers, A. J.; Virgilio, A. A.; Rosenquist, Å.; Fenuik, W.; Ellman,
J. A. J. Am. Chem. Soc. 1999, 121, 1817-1825. (b) Souers, A. J.;
Rosenquist, Å.; Jarvie, E. M.; Ladlow, M.; Fenuik, W.; Ellman, J. A.
Bioorg., Med. Chem. Lett. 2000, 10, 2731-2733.
(13) Veber, D. F. In PeptidessChemistry and Biology: Proceedings of
the 12th American Peptide Symposium; Smith, J. A., Rivier, J. E., Eds.;
ESCOM: Leiden, 1992; p 3.
(7) Brown, M.; Rivier, J.; Vale, W.; Guillemin, R. Biochem. Biophys.
Res. Commun. 1975, 65, 752.
(8) Contour-Galce´ra, M.-O.; Sidhu, A.; Plas, P.; Roubert, P. Bioorg. Med.
Chem. Lett. 2005, 13, 3555.
(9) Contour-Galce´ra, M.-O.; Poitout, L.; Moinet, C.; Morgan, B.; Gordon,
T.; Roubert, P.; Thurieau, C. Bioorg. Med. Chem. Lett. 2001, 11, 741.
(10) Poitout, L.; Roubert, P.; Contour-Galce´ra, M.-O.; Moinet, C.;
Lannoy, J.; Pommier, J.; Plas, P.; Bigg, D.; Thurieau, C. J. Med. Chem.
2001, 44, 2990.
(14) Snyder, H. R.; Eliel, E. L. J. Am. Chem. Soc. 1948, 70, 1703.
(15) Prasad, V.; Birzin, E. T.; McVaugh, C. T.; van Rijn, R. D.; Rohrer,
S. P.; Chicchi, G.; Underwood, D. J.; Thornton, E. R.; Smith, A. B., III;
Hirschmann, R. J. Med. Chem. 2003, 46, 1858.
(16) Meyers, C. A.; Coy, D. H.; Huang, W. Y.; Schally, A. V.; Redding,
T. W. Biochemistry 1978, 17, 2326.
(17) Crider, A. M.; Liu, S.; Li, T.; Mahajan, A.; Ankersen, M.; Stidsen,
C. E. Lett. Drug Des. Discuss. 2004, 1, 84.
(11) Hiroshi, M.; Suzuki, N.; Miki, T. WO Patent Appl. 98-JP1797, 1998.
4398
Org. Lett., Vol. 8, No. 20, 2006

expected that a C-linked benzyl group ortho to the Trp-
mimicking side chain (8) would simulate the affinity-
enhancing effect of the Phe7 side chain of somatostatin (1).
Indeed, overlaying the minimized structure of 8 with the
NMR structure of L-363,301 reveals good congruency of
the side chains (Figure 3). We thus surmised that the addition
Scheme 2. Synthesis of 8
to the requisite iodide 12 in 71% overall yield over five
steps.18 Alkylation of phenol 13 or the 4,5-dichloro coun-
terpart 14 followed by Staudinger19 reduction of the azide
and alkaline hydrolytic removal of the tert-butyl carbamate
furnished 6 and 7.
Figure 3. Proposed enhancements to the catechol scaffold.
Benzylated catechol 8 (gray) was overlaid in MacroModel with
L-363,301 (green) as before.
To acquire prospective ligand 8, known bromophenol 1720
was alkylated with 2-[1-N-(benzenesulfonyl)indol-3-yl]ethyl
iodide to furnish 18 in 83% yield. Treatment of the aryl
cuprate derived via lithium-halogen exchange and trans-
metalation of 18 with benzyl bromide led to 19, albeit in
modest yield.21 Removal of the methyl group employing
iodotrimethylsilane in dichloromethane at reflux, followed
by alkylation of the phenol with 5-azidopentyl iodide, then
furnished 20 in 40% yield for the two steps. Completion of
the synthesis of 8 was achieved via Staudinger19 reduction
and alkaline hydrolysis.
of a benzyl group to the prospective ligand would not
interfere with binding.
The syntheses of the prospective 5-fluoroindole ligands 6
and 7 and the benzyl congener 8 are outlined in Schemes 1
Scheme 1. Synthesis of 6 and 7
Binding data for ligands 5-8 at the sst2 and sst4 receptors
are provided in Table 1. The fluorinated congener 6 binds
the sst2 and sst4 receptors with an affinity similar to that of
the parent catechol ligand 5. A noticeable affinity increase
was observed for 4,5-dichlorocatechol 7 at both receptor
subtypes due presumably to the increased hydrophobicity of
the scaffold in the hydrophobic receptor environment. Of
particular note, the benzylated catechol 8, while showing no
discernible improvement in activity at sst4, displayed a 9-fold
affinity enhancement selectively at the sst2 receptor.
(18) (a) Formation of 5-fluoro-3-(2-hydroxyethyl)indole from 5-fluor-
oindol-3-ylacetic acid: Mewshaw, R. E.; Zhou, D.; Zhou, P.; Shi, X.;
Hornby, G.; Spangler, T.; Scerni, R.; Smith, D.; Schechter, L. E.; Andree,
T. H. J. Med. Chem. 2004, 47, 3823. (b) Silylation of 5-fluorotryptophol:
RajanBabu, T. V.; Chenard, B. L.; Petti, M. A. J. Org. Chem. 1986, 51,
1704.
(19) (a) Staudinger, H.; Meyer, J. HelV. Chim. Acta 1919, 2, 635. (b)
Scriven, E. F. V.; Turnbull, K. Chem. ReV. 1988, 88, 297. (c) Gololobov,
Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353.
(20) (a) Bungard, C. J.; Morris, J. C. Synthesis 2001, 741. (b) Ishizaki,
M.; Ozaki, K.; Kanematsu, A.; Isoda, T.; Hoshino, O. J. Org. Chem. 1993,
58, 3877.
(21) (a) Stahl, P.; Kissau, L.; Mazitschek, R.; Giannis, A.; Waldmann,
H. Angew. Chem., Int. Ed. 2002, 44, 1174. (b) Kissau, L.; Stahl, P.;
Mazitschek, R.; Giannis, A.; Waldmann, H. J. Med. Chem. 2003, 46, 2917.
and 2, respectively. For ligands 6 and 7, commercially
available (5-fluoroindol-3-yl)acetic acid (9) was converted
Org. Lett., Vol. 8, No. 20, 2006
4399

In summary, we have designed, constructed, and evaluated
a series of catechol-based ligands, which comprise the
simplest known non-peptide mimetics of the i + 1 and i +
2 positions of the somatostatin â-turn. That the catechol
scaffold is sufficiently versatile to permit incorporation of
an additional side chain to include the i position of the â-turn
(8), a modification that induces a selective 9-fold affinity
enhancement at the sst2 receptor, is particularly significant.
Efforts toward the synthesis of related congeners are currently
underway and will be reported in due course.
Table 1. Biological Activities of the Catechol-Based Ligands
Compared with Those of SRIF and â-D-Glucoside (+)-4
ligand
Ki, sst2
Ki, sst4
SRIF
(+)-4
5
6
7
8
6.83 ( 1.54 pM
4.52 µM15
4.69 ( 0.37 µM
3.12 ( 0.33 µM
0.749 ( 0.065 µM
0.505 ( 0.031 µM
0.462 ( 0.132 nM
1.65 ( 0.56 µM15
2.02 ( 0.38 µM
2.08 ( 0.28 µM
0.512 ( 0.120 µM
1.73 ( 0.11 µM
Acknowledgment. Financial support was provided by the
NIH through Grant GM-41821 and by Merck Research
Laboratories through an unrestricted grant. B.P.M. would also
like to thank the U.S. Department of Education for a
GAANN fellowship and Onur Atasoylu for his assistance
in the preparation of this manuscript.
Thus, incorporation of a Phe7-mimicking moiety reinforces
our contention that the minimal catechol scaffold can mimic
a peptide â-turn. With a molecular weight of 338 for the
parent ligand (5) and of 429 for 8, these ligands fall well
below the often proposed 500 Da upper limit for the optimal
molecular weight for drug candidates,22 in contrast to the
glucoside ligands, which possess molecular weights of 600
Da or more.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. AdV.
Drug DeliVery ReV. 1997, 23, 3.
OL061488X
4400
Org. Lett., Vol. 8, No. 20, 2006