Parallel synthesis of an oligomeric imidazole-4, 5-dicarboxamide library

Article abstract of DOI:10.1021/cc1000105

A library of oligomeric compounds was synthesized based on the imidazole-4, 5-dicarboxylic acid scaffold along with amino acid esters and chiral diamines derived from amino acids. The final compounds incorporate nonpolar amino acids (Leu, Phe, Trp), polar amino acids (Ser, Asp, Arg), and neutral amino acids (Gly, Ala), and were designed to be useful in screening for inhibitors of protein-protein interactions. Many of the protected and deprotected oligomers show evidence of conformational isomers persistent at room temperature in aqueous solution. A total of 317 final oligomers, out of 441 targeted compounds, were obtained in high analytical purity and of sufficient quantity to submit them for high-throughput screening as part of the NIH Roadmap.

Full text of DOI:10.1021/cc1000105

248
J. Comb. Chem. 2010, 12, 248–254
Parallel Synthesis of An Oligomeric Imidazole-4,5-dicarboxamide
Library
Zhigang Xu,† John C. DiCesare,‡ and Paul W. Baures*,†
Department of Chemistry and Biochemistry, The UniVersity of Tulsa, 800 South Tucker DriVe, Tulsa,
Oklahoma 74104, and Department of Chemistry, Georgia Southern UniVersity, P.O. Box 8064,
Statesboro, Georgia 30460
ReceiVed January 19, 2010
A library of oligomeric compounds was synthesized based on the imidazole-4,5-dicarboxylic acid scaffold
along with amino acid esters and chiral diamines derived from amino acids. The final compounds incorporate
nonpolar amino acids (Leu, Phe, Trp), polar amino acids (Ser, Asp, Arg), and neutral amino acids (Gly,
Ala), and were designed to be useful in screening for inhibitors of protein-protein interactions. Many of
the protected and deprotected oligomers show evidence of conformational isomers persistent at room
temperature in aqueous solution. A total of 317 final oligomers, out of 441 targeted compounds, were obtained
in high analytical purity and of sufficient quantity to submit them for high-throughput screening as part of
the NIH Roadmap.
Introduction
that were based on the comparable distance between carbon
atoms of the imidazole-4,5-dicarboxamide (I45DC) substit-
uents with the spacing of side chains in a critical R-helix
within the PPI.24,25 These first-generation oligomeric I45DCs
were symmetric and utilized two L-amino acids as well as a
N,N′-dialkylalkanamine in their design and synthesis.26
Selected oligomers were effective as inhibitors of the CD81-
hepatitis C glycoprotein E2 interaction, thereby supporting
our design hypothesis.24
The design and preparation of compound libraries for
application in high-throughput screening is a well-known
approach to hit identification in drug discovery research.1,2
The library design criteria are generally target dependent,
with the choice of scaffold or building blocks determined
by considering known bioactive compounds or hypothesis
or both.3–5
Protein-protein interactions (PPI) are significant events
in signaling within and between cells, and as such are
potential targets for intervention by small molecules to
modulate or treat diseases related to these signals.6–10 The
design of inhibitors for PPIs has, in the past, been considered
intractable because of the size and flatness of the associating
surfaces. Yet, most buried interfaces rely on “hot spots” that
require relatively few residues to obtain the majority of the
thermodynamic driving force for the PPI.11,12 Thus, targeting
a PPI “hot spot” is a practical approach to reduce the overall
size and molecular weight of a potential PPI inhibitor.
The second-generation oligomeric I45DCs in this project
likewise anticipate the distance between substituents on each
I45DC to match the distance between side chains found along
the length of an R-helix or adjacent along one side of a
ꢀ-strand.25 The total of four amino acid side chains per
oligomer in this design is expected to be a significant
improvement and doubles the number of pharmacophoric
side chains as compared with the first-generation oligomers.
Although only a few amino acids are often involved in a
PPI hot spot,11,12 we nonetheless reason the oligomers in
this project have greatly improved odds of yielding inhibitors
of PPIs when employed in high-throughput screening.
Good progress toward the design and discovery of inhibi-
tors of PPIs has been reported in recent years by generating
a suitable mimic of one of the two protein surfaces.13–18 In
general, these inhibitors mimic secondary structures, such
as ꢀ-turns,3,10 ꢀ-strands,19 or an R-helix,9,10,20 to accurately
display important residues or “hot spots” of the PPI in a
proper orientation. This approach can yield compounds with
drug-like or nearly drug-like features;21,22 therefore, the use
of inhibitors of PPIs as therapeutic agents is anticipated.23
The number and type of amino acid building blocks that
we employed for these oligomeric I45DCs was based on a
compromise between those amino acids expected to be
important in PPI hot spots and the number of compounds
we could reasonably synthesize, purify, and characterize in
parallel. Also guiding our selection was the knowledge that
aromatic, polar, and ionic amino acid side chains were of
equal or greater significance to hydrophobic interactions in
manyPPIs,suchasthoseinantibody-antigenorenzyme-protein
inhibitor interactions.27,28 The oligomeric design uses com-
binations of two ethylenediamines along with two L-amino
acids. Two of the three ethylenediamines used are chiral with
Ala and Leu side chains and were synthesized from their
L-amino acids. The seven L-amino acids we chose included
We have previously employed the imidazole-4,5-dicar-
boxylic acid scaffold in the design of CD81 proteomimetics
* To whom correspondence should be addressed. E-mail: paul-baures@
utulsa.edu.
† The University of Tulsa.
‡ Georgia Southern University.
10.1021/cc1000105  2010 American Chemical Society
Published on Web 02/19/2010

Oligomeric I45DC Libraries
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 249
Scheme 1
amino acids 1{2-3} were converted to their respective
methyl esters, 2{2-3}, by slight modification of a known
procedure,31 converted to amides 3{2-3} with an NH4OH
solution,32 and subsequently reduced to the chiral diamines
4{2-3} with BH3 · S(CH3)2 in THF.33 These intermediates
were not purified but first were protected with Cbz-Cl to
give 5{2-3}, following purification.30 Deprotection of the
Boc group in 5{2-3} with CF3CO2H in CH2Cl2 yielded
6{2-3}. Likewise, Cbz-L-amino acids, 7{2-3}, were start-
ing materials for the chiral diamines 12{2-3} as shown in
Scheme 3. The synthesis again proceeded through methyl
esters 8{2-3}, amides 9{2-3}, reduced intermediates
10{2-3}, and the differentially protected chiral diamines
11{2-3}. Hydrogenation then produced the final chiral
diamines 12{2-3} needed for oligomer synthesis.
Table 1. N-Boc and Cbz-Protected Amino Acids, 1{2-3} and
7{2-3}, Respectively, Used in Library Synthesis
The oligomeric design uses the two chiral, monoprotected
diamine chemsets 6 and 12 that were synthesized from amino
acid amides, along with the two L-amino acid chemsets 14
and 18. The two halves of the oligomers come from chemsets
16 and 20 that are independently synthesized with orthogonal
protecting groups in order to allow selective deprotection of
these monomeric building blocks (Scheme 4).
Synthesis of the monomeric building blocks begins with
the pyrazine diacid chloride, 13, which is prepared from
imidazole-4,5-dicarboxylic acid as previously reported.34 The
amino acid ester-substituted pyrazine chemsets 15 and 19
were likewise prepared by following methods previously
reported, generally giving good to excellent yields of product
(Table 3).26,35
The monomeric building blocks with a Cbz-protected
amino group, chemset 16, were prepared by reacting pyrazine
chemset 15 with the Cbz-protected diamine chemset 6 in
CH2Cl2 at room temperature from 5-120 h. These products
were purified by column chromatography with EtOAc/
hexanes as the eluant. Product was not obtained for 16{2,7}
and 16{3,7}. The reason for reagent failure, as well as
identification of the reaction products, for these two reactions
was not determined. These reactions were attempted more
than once with the same results. Reaction yields for the
remaining chemset compounds of 16 ranged from 30-80%
and averaged 58%.
Cmpd
R1
cmpd
R2
1{2}
1{3}
CH3
CH2CH(CH3)2
7{2}
7{3}
CH3
CH2CH(CH3)2
two aromatic residues (Trp and Phe), two hydrophobic
residues (Leu and Ala), two charged residues (Asp and Arg),
and one polar residue (Ser). The monomeric I45DCs were
also differentially protected to allow selective deprotection
of the amino and carboxylic acid termini before coupling in
parallel to create a maximum of 441 unique oligomeric
I45DCs. A total of 317 of these pure oligomeric I45DCs
have been characterized and were obtained in sufficient
quantity for submission to the Molecular Library Small
Molecule Repository (MLSMR) for use in high-throughput
screening as part of the NIH Roadmap.
Results and Discussion
Ethylenediamine was monoprotected to yield 12{1}, as
shown in Scheme 1, by following a literature procedure.29
This compound was further protected with a known proce-
dure30 to give 11{1} and then selectively deprotected to give
6{1} as the free amine, thereby providing the two differen-
tially monoprotected ethylenediamines, 6{1} and 12{1}
needed for oligomer synthesis. The other chiral diamines used
in this project were synthesized from L-amino acids bearing
either N-Boc or N-Cbz protecting groups as shown in Table
1. Boc-L-amino acids, 1{2-3}, were the starting materials
for the chiral diamines 6{2-3} as shown in Scheme 2. The
Likewise, monomeric building blocks with a benzyl ester-
protecting group, chemset 20, were prepared by reacting
pyrazine chemset 19 with the N-Boc protected diamine
Scheme 2

250 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Xu et al.
Scheme 3
Scheme 4
chemset 12 in CH2Cl2 at room temperature from 1 to 72 h.
These products were likewise purified by column chroma-
tography with EtOAc/hexanes as the eluant. Product was not
obtained for 20{3,5} and the reason for this was not further
investigated. Reaction yields for the remaining chemset
compounds of 20 ranged from 25-89% and averaged 66%.
The Cbz and benzyl ester, respectively, for isolated
chemset intermediates 16 and 20 were deprotected with 1

Oligomeric I45DC Libraries
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 251
Table 2. Protected Amino Acids, 14{1-7} and 18{1-7},
Respectively, Used in Library Synthesis
chromatography with a gradient ranging from EtOAc/hexanes
to EtOAc/MeOH as the eluents, affording chemset 22.
Out of the 361 possible combinations for which mono-
meric chemset intermediates 17 and 21 were available, a total
of 323 products were purified and yields determined, which
were generally good (Table 4). The compounds of the
protected oligomer chemset 22 were characterized by
combined LC-MS and 1H NMR spectroscopy (see Support-
ing Information). In a few cases, a library member was
identified by LC-MS but was not completely characterized
or carried forward because of insufficient amounts of material
or contamination with impurities.
Quantitative deprotection of products of chemset 22 was
done with 25% CF3CO2H in CH2Cl2 at room temperature
over 2-18 h, using LC-MS analysis to determine when the
reaction was complete.
Following removal of the solvents, the trifluoroacetate salt
was exchanged for chloride by dissolving the deprotected
oligomer chemset 23 in 0.90 mL of 10% aqueous MeOH
with gentle heat as needed for solubilization and adding 100
µL of 1 M HCl. The solutions were immediately frozen in
liquid N2 before lyophilizing to dryness.
Interestingly, we observed two significant signals in the
LC-MS analysis of 45 of the protected oligomer library
compounds. In all cases both signals have an identical MS
spectra that is consistent with the proposed structure. We
hypothesize that this is evidence of two conformers that are
stable under the conditions of the analysis. Indeed, confor-
mational isomers have been reported for comparable oligo-
mers containing two N-methylimidazole-4,5-dicarboxylic
acid rings.37 A majority of the hypothesized conformational
isomers that are observed have hydrophobic amino acid side
chains located in both substituent amides of chemset 21, such
as combinations of leucine or phenylalanine (see Supporting
Information). However, we do not observe such conforma-
tional isomers in the protected oligomers containing tryp-
tophan in chemset 21. It is possible that this is the result of
a preference for one conformer with the larger tryptophan
substituent as compared with leucine or phenylalanine or that
these conformational isomers simply do not resolve in the
LC-MS for those examples.
Table 3. Pyrazines Substituted with Amino Acid Esters
amino
acid ester
amino
acid ester
compound
yield (%) compound
yield (%)
15{1}
15{2}
15{3}
15{4}
15{5}
15{6}
15{7}
14{1}
14{2}
14{3}
14{4}
14{5}
14{6}
14{7}
76
72
85
99
70
64
89
19{1}
19{2}
19{3}
19{4}
19{5}
19{6}
19{7}
18{1}
18{2}
18{3}
18{4}
18{5}
18{6}
18{7}
71
84
84
98
67
34
NDa
a ND ) yield was not determined, and the member was used without
purification.
atm. H2 and 5% Pd/C in MeOH. The reactions were stirred
at room temperature from 4.5-29 h for chemset 16 and
11-30 h for chemset 20, at which point the reaction was
complete as determined by TLC analysis. The reaction
mixture was filtered through Celite, and the solvent removed
under vacuum to afford chemsets 17 and 21, respectively,
from chemsets 16 and 20, minus members 17{2,7}, 17{3,7},
and 21{3,5} for which starting materials were unavailable.
The yields for chemset 17 ranged from 84-99% and
averaged 94%, whereas the yields for chemset 21 ranged
from 65-100% and averaged 89%. All of the products were
suitable for use without further purification.
Our hypothesis of conformational isomers in protected
oligomer chemset 22 is further supported by the fact that
1
many compounds show broad and poorly defined H NMR
spectra, whereas others have comparably well-defined sig-
1
nals. Figure 1 compares part of the LC-MS and H NMR
spectra for 22{2,1,2,2} with 22{2,1,3,2}. Oligomer
22{2,1,2,2} showed only a single peak in the LC-MS analysis
while 22{2,1,3,2} shows two peaks hypothesized to be the
conformational isomers. The 1H NMR spectra in the aliphatic
region for 22{2,1,2,2} is considerably more defined than the
comparable region for 22{2,1,3,2}. The broadness of the 1H
NMR spectra for 22{2,1,3,2} is therefore hypothesized to
result from the presence of conformational isomers having
The protected oligomer chemset 22, excluding those
examples where monomeric intermediates 17{2,7}, 17{3,7},
and 21{3,5} were unavailable, were prepared in CH2Cl2 at
room temperature over 20 h by coupling chemsets 17 and
21 with the water-soluble carbodiimide, EDC · HCl, and
dimethylaminopyridine.36 The reaction mixtures were con-
centrated under vacuum and the product purified by column
1
overlap in their H NMR chemical shifts or the relative
dynamics of the compound on the NMR time scale or both.
It is noted, however, that a broad 1H NMR spectrum did not
necessarily mean that the oligomer showed two peaks in the
LC-MS analysis, since there are examples of this behavior

252 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Table 4. Yields of Protected Oligomer Chemset 22a
Xu et al.
a Areas shaded in gray indicate regions of chemset space for which intermediates were not obtained.
also. Among the potential explanations for this differing
behavior include overlap in the retention time of persistent
conformers in the LC conditions or that the change in solvent
from aqueous CH3CN (LC-MS) versus CDCl3 (1H NMR)
alters the conformational behavior between the analyses.
One concern was that the two signals in the LC-MS
analysis represent diasteromeric oligomers resulting from
epimerization of a stereocenter under the coupling conditions.
We did not expect the coupling conditions to cause in
significant epimerization, and note that we observe two
signals only in select cases for any given set of hydrophobic
amino acids. This variability in behavior is strong evidence
against epimerization as the explanation for our results.
As with the protected oligomers, two significant LC-MS
signals were observed in 54 of final compounds of chemset
23. Again, the general trend appears to be related to the
presence of two hydrophobic amino acids in chemset 21,
although there are exceptions in the deprotected oligomers
just as there were for the protected oligomers. Importantly,
some protected oligomers with two conformers did not show
two conformers when deprotected (e.g., 23{2,2,3,2} and
23{2,2,3,3}), while others did not show two conformers until
the oligomer was deprotected (e.g., 23{1,2,3,4} and
23{1,3,3,4}). This is yet further evidence against the forma-
tion of diasteromers in the coupling reactions, as diastere-
omeric compounds of chemset 22 would yield diastereomeric
compounds of chemset 23.
As additional evidence in support of the conformational
hypothesis, we performed variable-temperature LC-MS on
four deprotected oligomers (23{1,2,3,3}, 23{1,3,3,4},
23{2,5,3,3}, and 23{1,6,3,3}) that show evidence of two
peaks in the LC-MS analysis (see Supporting Information).
The analysis was run from 25 to 65 °C, and showed a steady
decline in the relative amounts of the lesser conformer as
compared to the major conformer. While we did not observe
coalescence of the two conformers at 65 °C, it is possible
that hydrophobic interactions could continually stabilize the
conformations in an aqueous environment. Nonetheless, the
differing relative amounts of the two peaks support our
hypothesis that these are conformational isomers rather than
diastereomers.
It is commonplace to use VT-NMR spectroscopy to
examine conformational isomerism in solution. We know
from our previous experience with monomeric derivatives
that self-association occurs at or above 1 mM in CDCl3 and
above 10 mM in DMSO-d6.39 Thus, VT-NMR was per-
formed from 30 to 70 °C in DMSO-d6 for 22{2,1,2,2} and
22{2,1,3,2} at 3 mM (see Supporting Information), resulting
1
in similar H NMR spectra observed for both compounds
across the range of temperatures. We are unable to assign

Oligomeric I45DC Libraries
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 253
1
Figure 2. Partial H NMR spectrum of 22{2,1,3,2} recorded at 3
mM in DMSO-d6 at 30 °C. The imidazole NHs, amide NHs
(intramolecular hydrogen bonded as well as free amide) and
carbamate NH are labeled and indicate the presence of conforma-
tional isomers. Also shown in the 2-CH of the imidazole (e) at 7.8
ppm. Two intramolecularly hydrogen bonded conformations of
22{2,1,3,2} that differ about the I45DC acquired from chemset 21
are also shown (A and B). The arrows underneath each imidazole
indicate the direction of the intramolecular hydrogen bond from
donor to acceptor for that ring. The top conformer has the same
direction for each hydrogen bond and the bottom conformer has
opposing directions.
conformations in dissymmetrically disubstituted I45DCs and
provided evidence that the favored hydrogen bond donor
arose from increasing substitution adjacent the amide nitro-
gen.38 Moreover, we have shown in model I45DCs that the
intramolecular hydrogen bond is relatively strong and worth
least 14 ( 1 kcal/mol, as well as observed in an aqueous
environment.39 The two conformations for 22{2,1,3,2}
shown in Figure 2 are therefore real possibilities for
explaining the observed behavior in both the LC-MS analysis
and 1H NMR spectra. It is reasonable that 22{2,1,2,2} would
also adopt analogous intramolecularly hydrogen bonded
conformations, and the lack of a second hydrophobic side
chain may increase the dynamics of the conformational
exchange.
The expected intramolecular hydrogen bonding conforma-
tions were a valuable design criteria as they fix the distance
between amide substituents to approximate the separation
of nearby side chains in R-helices and ꢀ-strands.24,25 The
two different conformers would not affect that separation
but do alter the possible hydrogen bonding interactions with
the imidazole ring because the hydrogen bond donor and
acceptor groups on the ring have their relative positions
switched. One conformation about a single I45DC of the
oligomer, relative to the other I45DC conformer, may also
be valuable as the oligomers optimize binding interactions
at protein interfaces. In this way the conformational isomers
could be of added value in the use of these oligomers in
screening for inhibitors of protein-protein interactions.
Figure 1. Comparison of the LC-MS trace (boxed) and aliphatic
region in the 1H NMR spectra of 22{2,1,2,2} (left) with 22{2,1,3,2}
(right).
specific NHs to observed signals, but can nonetheless identify
the two imidazole NHs as those signals around 13 ppm, the
two amide NHs involved in intramolecular hydrogen bonding
as the signals around 11 ppm, the three remaining amide
NHs between 8 and 9 ppm, and the carbamate NH near 7
ppm, as shown in Figure 2 for 22{2,1,3,2}. From inspection
it is then clear that there are conformational isomers present
in the solution. For example, there are four signals for the
two intramolecular hydrogen bonded hydrogens (b). An
increase in temperature yields only modest changes on the
chemical shifts of the NHs over this entire region. This has
previously been reported for oligomeric I45DCs that form
conformation isomers observable in DMSO-d6 even at 100
°C.37 Cooling the NMR sample of 22{2,1,3,2} to 30 °C from
70 °C yields the same spectrum as first recorded at 30 °C,
indicating the stability of the compounds in a polar solvent
at high temperatures.
We suggest that the conformational isomers may result
from differing intramolecular hydrogen bonding interactions,
particularly around the I45DC from chemset 21, and perhaps
supported by the presence of hydrophobic interactions that
protect the hydrogen bond from fast exchange during the
Conclusion
1
LC-MS analysis and on the H NMR time scale. We have
A total of 317 final products in chemset 23 that were both
previously observed two intramolecularly hydrogen bonded
analytically pure and of sufficient quantity were submitted

254 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
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Supporting Information Available. General methods,
synthetic procedures, and characterization data for intermedi-
ates and final oligomers, tables of data for intermediates and
final oligomers, LC-MS and 1H NMR spectra for 53
protected oligomers in chemset 22, LC-MS data for 51
deprotected final compounds in chemset 23, variable tem-
perature LC-MS data for four conformationally promiscuous
final products in chemset 23, and VT-NMR data in DMSO-
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