Carbohydrate-Based Small-Molecule Scaffolds for the Construction of Universal Pharmacophore Mapping Libraries

Full text of DOI:10.1021/jo980164m

2802
J . Org. Chem. 1998, 63, 2802-2803
Sch em e 1a
Ca r boh yd r a te-Ba sed Sm a ll-Molecu le
Sca ffold s for th e Con str u ction of Un iver sa l
P h a r m a cop h or e Ma p p in g Libr a r ies
Michael J . Sofia,* Rachael Hunter, Tin Yau Chan,†
Andrew Vaughan, Richard Dulina, Huiming Wang, and
David Gange
Transcell Technologies Inc., 8 Cedar Brook Drive,
Cranbury, New J ersey 08512
Received February 2, 1998
Combinatorial chemistry occupies a prominent position
in the modern drug discovery process.1 Because of its ability
to generate large numbers of structurally diverse molecules,
combinatorial chemistry has been able to reduce the drug
discovery timeline by meeting the compound needs of high
throughput screening programs. Continued success will rely
heavily on the development of new chemical platforms for
constructing useful combinatorial molecular diversity. By
rapidly defining novel three-dimensional functional group
relationships, i.e., pharmacophores, the ideal combinatorial
chemical platform will allow access to broad diversity space,
thus facilitating the identification of tight binding ligands
against a wide variety of biomolecular targets.
a
Reagents and conditions: (a) Na2CO3, BnOCOCl, H2O, 4 °C; (b)
CH3OH, HCl-dioxane, 60 °C; (c) (CH3O)2C(CH3)2, p-TsOH, DMF, rt;
(d) NaH, CH3I, THF, rt; (e) p-TsOH, Amberlite, rt; (f) TEMPO3, NaOCl,
n-Bu4NCl, KBr, NaHCO3, NaCl, H2O, 0 °C; (g) 10% Pd-C, H2 (40 psi),
EtOAc; (h) Fmoc-Cl, NaHCO3, DIPEA, dioxane-H2O, rt. DIPEA )
N,N-diisopropylethylamine; TEMPO ) 2,2,6,6-tetramethyl-1-piperidi-
nyloxy.
Monosaccharides possess a unique set of characteristics,
which makes them particularly attractive as platforms
around which to design primary screening libraries. Hex-
oses are enantiomerically pure and conformationally rigid.
They provide a defined three-dimensional spatial arrange-
ment of substituents, are highly functionalized, and there-
fore, provide high intrinsic combinatorial density. The
unique characteristics of monosaccharides were first recog-
nized by Hirschmann, Nicolaou, and Smith in their success-
ful use of â-D-glucose as a â-turn mimetic in the design of
nonpeptide somatostatin mimetics and were later exploited
by others.2 The discovery that hexose derivatives also bind
with high affinity to several pharmacologically important
receptors suggests that, as priviledged platforms, monosac-
charide systems are valuable for generating combinatorial
libraries. However, readily accessible carbohydrate-based
combinatorial platforms have yet to be described.
requirements needed for pharmacophoric chiral molecular
recognition. The desired three-point motif was achieved by
a scaffold design that incorporated a carboxylic acid moiety,
a free hydroxyl group, and a protected amino group. This
functional group triad afforded the chemoselectivity neces-
sary for rapid combinatorial solid-phase synthesis, allowing
us to maximize molecular diversity while minimizing the
number of solid-phase synthetic steps.
In this report, we describe the first effective solid-phase
chemical method for the preparation of carbohydrate-based
universal pharmacophore mapping libraries as a new strat-
egy for identifying novel receptor ligands.
To investigate the potential of carbohydrates for the
preparation of universal pharmacophore mapping libraries,
two monosaccharide scaffolds 1 and 2 were prepared as
outlined in Schemes 1 and 2. Three sites of diversification
were incorporated into each scaffold to provide the minimal
Chemical diversity was introduced at the three combina-
torial sites on each scaffold using the solid-phase chemistry
exemplified in Schemes 3-5. To minimize the number of
solid-phase chemistry steps, the first diversification step
occurred by attaching the scaffold to the solid support
through a prelinked diversity element. Consequently, each
glycocarboxylic acid was linked to the free amine of an amino
acid functionalized carboxytrityl Tentagel resin,5 furnishing
the scaffold functionalized resins 12 and 13. In Schemes 4
and 5, isopropyl isocyanate, 2,4-dimethoxybenzoic acid, and
4-nitrobenzoic acid were used to demonstrate the efficiency
of the solid-phase chemistry strategy. Carbamate formation6
at the free hydroxyl site followed by amide formation at the
deprotected amine site produced the desired resin-linked
trifunctionalized scaffolds. For scaffold 2, an additional step
was required to remove the acetate protecting group at C-2.
All products were cleaved from the solid support with 10%
* To whom correspondence should be addressed. E-mail: sofia@
transcell.com.
† Current address: Schering-Plough Research Institute, Kenilworth, NJ .
(1) Gallop, M. A.; Barrett, R. W.; Dower, W. J .; Fodor, S. P. A.; Gordon,
E. M. J . Med. Chem. 1994, 37, 1233-1251. (b) Gordon, E. M.; Barrett, R.
W.; Dower, W. J .; Fodor, S. P. A.; Gallop, M. A. J . Med. Chem. 1994, 37,
1385-1400.
(2) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Leahy, E. M.; Salvino,
J .; Arison, B.; Cichy, M. A.; Spoors, P. G.; Shakespear, 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, 12550-12568. (b) Hirschmann, R,; Wenqing,
Y.; Cascieri, M. A.; Strader, C. D.; Maechler, L.; Cichy-Knight, M. A.; Hynes,
J ., J r.; van Rijn, R. D.; Sprengeler, P. A.; Smith, A. B., III. J . Med. Chem.
1996, 39, 2441-2448. (c) von Roedern, E. R.; Lohof, E.; Hessler, G.;
Hoffmann, M.; Kessler, H. J . Am. Chem. Soc. 1996, 118, 10156-10167. (d)
Wessel, H. P.; Banner, D.; Gubernator, K.; Hilpert, K.; Muller, K.; Tschopp,
T. Angew. Chem., Int. Ed. Engl. 1997, 36, 751-752. (e) Ramamoorthy, P.
S.; Gervay, J . J . Org. Chem. 1997, 62, 7801-7805.
(3) Davis, N. J .; Flitsch, S. L. Tetrahedron Lett. 1993, 34, 1181-1185.
(4) Baer, H. H. Methods Carbohydr. Chem. 1972, 6, 245-249.
(5) NovasynTGT resin is a Tentagel-based resin that has been amino
functionalized and derivatized with a 4-carboxytrityl linker. It is available
from Novabiochem.
(6) Duggan, M. E.; Imagire, J . S. Synthesis 1989, 131-132.
S0022-3263(98)00164-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/16/1998

Communications
J . Org. Chem., Vol. 63, No. 9, 1998 2803
Sch em e 2a
Sch em e 5a
4
a
Reagents and conditions: (a) NaIO4, H2O, 0-25 °C; (b) NaOCH3,
CH3NO2, CH3OH, 0 °C to rt; (c) PhCH(OCH3)2, p-TsOH, DMF, 65 °C;
(d) Ac2O, C6H5N, 0 °C; (e) 20% Pd(OH)2-C, H2 (40 psi), AcOH-CH3OH;
(f) FmocONSu, DIPEA, THF, rt; (g) TEMPO, NaOCl, n-Bu4NCl, KBr,
NaHCO3, NaCl, H2O, 0 °C.
Sch em e 3a
a
Reagents and conditions: (a) 0.5 M i-PrNCO/DMF, cat. Cu(I)Cl,
rt; (b) 20% piperidine/DMF, rt; (c) 2,4-dimethoxybenzoic acid, HATU,
DIPEA, DMF, rt; (d) 0.1 M LiOH/THF-CH3OH, rt; (e) 10% TFA/1,2-
dichloroethane, rt.
analysis, the purity of these products was shown to be >90%.
We also demonstrated that urea formations, sulfonamide
formations, and reductive alkylations at the deprotected
amine site of each scaffold occur efficiently on the solid phase
(data not shown).
A library based on scaffolds 1 and 2 was prepared as
discrete compounds using the IRORI AccuTag-100 radio
frequency tagged solid-phase synthesis system and the
directed sorting split-pool method. Scaffolds 1 and 2 were
each coupled to eight amino acid-functionalized trityl-
Tentagel resins. Each scaffold-amino acid resin was then
used to prepare a 48-member sublibrary by reaction with
six isocyanates and eight carboxylic acids. Several of the
amino acid building blocks contained acid-labile protecting
groups. These protecting groups were removed concomi-
tantly with cleavage of the final product from the solid
support. In total, 16 48-member sublibraries were prepared.
Library analysis by LC/MS showed that 90% of the library
products were produced in >80% purity.9
a
Reagents and conditions: (a) 20% piperidine/DMF, rt; (b) (1) or
(2), HATU, DIPEA, DMF, rt. HATU ) [O-(7-azabenzotriazol-1-yl)-
1,1,3,3-tetramethyluronium hexafluorophosphate].
Sch em e 4a
A new strategy for the construction of broad screening
libraries using a carbohydrate-based universal pharmacoph-
ore mapping library strategy has been described. This
strategy takes advantage of the unique molecular charac-
teristics of saccharides and the efficiency and speed of solid
phase chemistry. By employing a family of trifunctionalized
saccharide scaffolds in a combinatorial library strategy, it
is possible to rapidly define a pharmacophore map of a
biomolecular receptor.
Su p p or tin g In for m a tion Ava ila ble: The detailed experi-
mental procedures and characterization data for compounds 1-10,
15, and 18 and resin cleavage products of 12-14, 16, and 17,
including representative LC/MS data for library products (28
pages).
a
Reagents and conditions: (a) 0.5 M i-PrNCO/DMF, cat. Cu(I)Cl,
rt; (b) 20% piperidine/DMF, rt; (c) 4-nitrobenzoic acid, HATU, DIPEA,
DMF, rt; (d) 10% TFA/1,2-dichloroethane, rt.
J O980164M
TFA. The trifunctionalized scaffolds 157 and 188 were
(8) Compound 18: 1H NMR (300 MHz, CDCl3/DMSO-d6/D2O) δ 8.32 (br
d, 1), 8.0 (d, 1, J ) 9 Hz), 6.47 (dd, 1, J ) 9 Hz, 3 Hz), 6.36 (d, 1, J ) 3 Hz),
4.85 (dd, 1, J ) 9 Hz), 4.75 (br s, 1), 4.46 (m, 1), 4.43 (d, 1, J ) 7 Hz), 4.15
(m, 1), 3.83 (s, 3), 3.83 (m, 1), 3.74 (s, 3), 3.5 (s, 3), 3.45 (m, 1), 1.55 (m, 5),
1.2 (d, 1), 1.0 (m, 6), 0.9 (m, 8).
obtained in 100% and 70% yields, respectively. By LC/MS
(7) Compound 15: 1H NMR (300 MHz, CDCl3/DMSO-d6/D2O) δ 8.16 (d,
2, J ) 9.7 Hz), 8.0 (d, 2, J ) 9.7 Hz), 7.83 (d, 1, J ) 8.7 Hz), 4.85 (m, 2), 4.7
(br.s, 1), 4.4 (m, 2), 4.05 (d, 1, J ) 12 Hz), 3.75 (dd, 1, J ) 12 Hz), 3.5 (s, 3),
3.5 (m, 2), 3.3 (s, 3), 1.6 (m, 3), 1.25 (m, 1), 1.05 (m, 6), 0.8 (m, 6).
(9) Library building blocks and LC/MS data for representative library
products can be found in the provided Supporting Information.