Synthesis and in silico screening of a library of β-carboline- containing compounds

Article abstract of DOI:10.3762/bjoc.8.117

The synthesis of a library of tetrahydro-β-carboline-containing compounds in milligram quantities is described. Among the unique heterocyclic frameworks are twelve tetrahydroindolizinoindoles, six tetrahydrocyclobutanindoloquinolizinones and three tetrahydrocyclopentenoneindolizinoindolones. These compounds were selected from a virtual combinatorial library of 11,478 compounds. Physical chemical properties were calculated and most of them are in accordance with Lipinski's rules. Virtual docking and ligand-based target evaluations were performed for the β-carboline library compounds and selected synthetic intermediates to assess the therapeutic potential of these small organic molecules. These compounds have been deposited into the NIH Molecular Repository (MLSMR) and may target proteins such as histone deacetylase 4, endothelial nitric oxide synthase, 5-hydroxytryptamine receptor 6 and mitogen-activated protein kinase 1. These in silico screening results aim to add value to the β-carboline library of compounds for those interested in probes of these targets.

Full text of DOI:10.3762/bjoc.8.117

Synthesis and in silico screening of a library of
β-carboline-containing compounds
Kay M. Brummond*1, John R. Goodell1, Matthew G. LaPorte*1,
Lirong Wang2 and Xiang-Qun Xie*2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1048–1058.
1Department of Chemistry, Chemical Methodologies and Library
Development, University of Pittsburgh, Pittsburgh, Pennsylvania
15260, USA and 2Department of Pharmaceutical Sciences and
Computational Chemical Genomics Center, School of Pharmacy;
Drug Discovery Institute; Department of Computational Biology;
University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
doi:10.3762/bjoc.8.117
Received: 03 May 2012
Accepted: 20 June 2012
Published: 10 July 2012
This article is part of the Thematic Series "Recent developments in
chemical diversity".
Email:
Kay M. Brummond* - kbrummon@pitt.edu; Matthew G. LaPorte* -
mgl12@pitt.edu; Xiang-Qun Xie* - xix15@pitt.edu
Guest Editor: J. A. Porco Jr.
* Corresponding author
© 2012 Brummond et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
β-carboline; biological activity; chemical diversity; diversity-oriented
synthesis; in silico screening
Abstract
The synthesis of a library of tetrahydro-β-carboline-containing compounds in milligram quantities is described. Among the unique
heterocyclic frameworks are twelve tetrahydroindolizinoindoles, six tetrahydrocyclobutanindoloquinolizinones and three tetra-
hydrocyclopentenoneindolizinoindolones. These compounds were selected from a virtual combinatorial library of 11,478 com-
pounds. Physical chemical properties were calculated and most of them are in accordance with Lipinski’s rules. Virtual docking and
ligand-based target evaluations were performed for the β-carboline library compounds and selected synthetic intermediates to assess
the therapeutic potential of these small organic molecules. These compounds have been deposited into the NIH Molecular Reposi-
tory (MLSMR) and may target proteins such as histone deacetylase 4, endothelial nitric oxide synthase, 5-hydroxytryptamine
receptor 6 and mitogen-activated protein kinase 1. These in silico screening results aim to add value to the β-carboline library of
compounds for those interested in probes of these targets.
Introduction
Identification of a comprehensive set of small organic mole- cules is largely occupied by in-house libraries and commer-
cules capable of selectively modifying the function of bio- cially available compounds. The NIH Roadmap initiative was
logical targets tremendously impacts modern medical research established to address a recognized limitation of current com-
and drug discovery efforts [1]. Currently, this set of small mole- pound diversity resulting in the Molecular Libraries Probe
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Beilstein J. Org. Chem. 2012, 8, 1048–1058.
Centers Network (MLPCN) which has, since its inception, imposed by the β-carboline moiety, and the number of building
garnered a library of over 370,000 chemically diverse small blocks available for the diversifying elements R1 and R2.
molecules in a central molecule repository [2]. This supply of
compounds has been made possible by researchers across the The syntheses of tetrahydro-β-carbolines 6{1–16} were accom-
disciplines, but largely by synthetic chemists who are preparing plished in a manner entirely analogous to that reported previ-
compounds with an eye towards biologically relevant targets. ously (Table 1, entries 1–16) [4]. For example, the allenic
Another goal of the NIH Roadmap is the development of methyl ester of tryptophan 4 was reacted with a number of alde-
enabling methods for the synthesis of these structurally diverse hydes 5{1–15} under acidic conditions to produce the corres-
compound libraries; amongst these methods, skeletal diversifi- ponding products in yields ranging from 54–89%. A range of
cation strategies have emerged as particularly efficient for aldehydes were accommodated in the Pictet–Spengler reaction,
maximizing structural diversity [3].
including formaldehyde (Table 1, entry 1), alkyl aldehydes
(Table 1, entries 2 and 3), aryl aldehydes with electron-with-
Previous work in the Brummond laboratory has demonstrated drawing and electron-donating groups (Table 1, entries 4–7, 14
that an allene-containing β-carboline provided a good starting and 15), heteroaromatic aldehydes (Table 1, entries 8–13) and
point for synthesizing six novel types of hetero-frameworks, all glyoxalates (Table 1, entry 16). Moreover, useful quantities of
skeletally unique [4]. Moreover, scope and limitation studies β-carboline-containing products were obtained (43–100 mg).
contributed to an understanding of chemistries that would pos- For entries 2–15, mixtures of two diastereomers were obtained.
sess the robustness necessary for library preparation. Informa- Since the mixtures could not be readily separated by column
tion gained from these experiments was then utilized in the chromatography, diastereomeric ratios were determined by
construction of a virtual library of 11,748 compounds. A diver- 1H NMR and were advanced without further purification. Reac-
sity analysis was performed using B (Burden) C (CAS) UT tion of allene 6 under the silver-nitrate-mediated cyclization
(Pearlman at the University of Texas) metrics and Tanimoto conditions afforded the desired fused pyrrolines 1. However, in
coefficients (Tc) and this virtual compound library was mapped the initial phases of this cyclization process, a color change was
onto the existing chemical space of the NIH Molecular noted during the purification process. Indeed, when NMR
Libraries Small Molecule Repository (MLSMR) [4]. When stability studies were performed on the syn- and anti-pyrrolines
considering the physical properties most important to bimolec- 1{5}, decomposition of both diastereomers was evident.
ular interactions, atomic Gasteiger–Hückel charges, polarizabil- Although it was generally difficult to isolate the individual dia-
ities, and hydrogen-bond acceptors, these virtual compounds stereomers, they could be separated by column chromatog-
were found to occupy new chemical space when compared to raphy. It was found that anti-1{5} decomposed more rapidly
the 327,000 compounds in the MLSMR. A small subset of these than syn-1{5} during the 1H NMR stability studies, when
compounds was subsequently identified as ones representing a compared to an internal standard. These results combined with
maximally diverse chemical space. The synthesis of a modified previously reported skeletal reorganization processes of func-
subset of this virtual compound library is described within, tionalized β-carbolines, led to concerns about the long-term
where modifications were mainly driven by studies of com- storage of these compounds and their inclusion in the MLSMR
pound stability. Furthermore, a high throughput, in silico [5].
screening analysis of this library identified a number of poten-
tial biological targets for the compounds.
To increase the stability of this class of compounds, a toluene-
sulfonyl group was added to the indole nitrogen of 1{1–7} to
give N-tosyl-tetrahydro-β-carbolinepyrroline derivatives
Results and Discussion
Scaffolds 1, 2 and 3 (Figure 1) were chosen for library prepar- 7{1–7}. These tosylated derivatives exhibited improved stability
ation based upon favorable Tanimoto coefficient (Tc) scores as evidenced by 1H NMR (Table 1, entries 1–7, and Supporting
when compared to the MLSMR, conformational constraints Information File 1, S76–S81). Incorporation of the tosyl group
Figure 1: Tetrahydro-β-carboline containing scaffolds 1–3.
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Beilstein J. Org. Chem. 2012, 8, 1048–1058.
Table 1: Library of N-tosyltetrahydro-β-carbolinepyrrolines 7{1–7}.
entry
R1
yield of 6a (%)
anti:synb
yield of 7a (%)
purityc
1
2
5{1}
68 6{1}
74 6{2}
NA
28 7{1}
98%
98%
5{2}
5{3}
2.5:1
17 syn-7{2}
3
4
5
6
81 6{3}
73 6{4}
75 6{5}
74 6{6}
2.1:1
2.4:1
2.4:1
1.3:1
23 syn-7{3}
98%
11 anti-7{4}
28 syn-7{4}
98%
98%
5{4}
5{5}
5{6}
34 anti-7{5}
17 syn-7{5}
98%
98%
35 anti-7{6}
10 syn-7{6}
98%
98%
12 anti-7{7}
17 syn-7{7}
98%
98%
7
8
9
5{7}
5{8}
5{9}
54 6{7}
89 6{8}
78 6{9}
2.7:1
2.3:1
1.2:1
NDd
NDe
10
11
5{10}
5{11}
80 6{10}
70 6{11}
1:1.1
1.3:1
NDd
NDe
12
13
5{12}
5{13}
80 6{12}
63 6{13}
3.5:1
1:1.4
NDe
NDe
14
5{14}
58 6{14}
2.3:1
NDd
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Beilstein J. Org. Chem. 2012, 8, 1048–1058.
Table 1: Library of N-tosyltetrahydro-β-carbolinepyrrolines 7{1–7}. (continued)
15
16
5{15}
5{16}
80 6{15}
88 6{16}
2.3:1
1.4:1
NDd
8 syn-1{16}
99%
aIsolated yields; bdr determined by 1H NMR; cpurity established by LCMS/ELS; dcompound 6 detected; ecompound 6 not detected.
also eased the chromatographic separation of the syn- and anti- 5–8). During optimization of the conditions for the [2 + 2]
isomers for entries 2–7, thus compounds 7{2–7} were obtained cycloaddition reaction (Method A), it was found that reducing
as single diastereomers. Low to moderate yields for this two- the reaction temperature from 225 °C to 160 °C afforded
step reaction sequence were attributed to a problematic tosyla- cyclobutene 2{1,3} in 73% yield (Table 2, entry 3). Similarly,
tion due to the sterically hindered nature of the indole nitrogen allene-yne 9{1,5} was subjected to the lower reaction tempera-
atom. Moreover, unforeseen limitations were encountered for ture (Method A) to produce cyclobutene 2{1,5} in 57% yield
the heteroaromatic and naphthyl-containing β-carboline inter- (Table 2, entry 5).
mediates (Table 1, entries 8–15). While in some cases the inter-
mediate pyrrolines 1 were observed (Table 1, entries 8, 10, 14, For the final library scaffold, a small subset of α-methylenecy-
15), the corresponding tosylated products were not obtained. clopentenone-containing tetrahydro-β-carbolines was synthe-
The heteroaromatic examples (Table 1, entries 9, 11–13), did sized. These compounds contain a general substructure that has
not undergo cyclization upon treatment with silver nitrate. For recently been shown to inhibit DNA damage checkpoints [8].
these cases, it was assumed that competing coordination of the Allene-ynes 9{1,3}–9{1,4} undergo Pauson–Khand cyclocar-
heteroatom to the silver ion was an issue; however, attempts bonylation reactions when treated with molybdenum hexacar-
were not made to alter the reaction conditions for these bonyl in DMSO/toluene solutions (Table 3). Allene-yne 9{1,2}
substrates. Furthermore, conversion of the naphthalene- afforded a mixture of four compounds comprising two dia-
containing analogues 1{14} and 1{15} to their corresponding stereomers of 3{1,2}, the 4-alkylidene cyclopentenone, resulting
tosylates was not successful.
from the cyclocarbonylation reaction with the distal double of
the allene, and a fourth compound, which could not be identi-
Next, compounds possessing the cyclobutene-fused β-carboline fied (see spectral data in Supporting Information File 1). Aryl-
skeleton were assembled from the versatile allenyl intermediate substituted alkynones 9{1,5}–9{1,8} were not available for the
6. For this subset of compounds, acylation of the sterically molybdenum-mediated cyclocarbonylation process due to
hindered amine of 6{1} with the ynoic acids 8{1–8}, by using competing [2 + 2] cycloaddition reactions (Table 2).
bromo-tris-pyrrolidino-phosponium hexafluorophosphate
(PyBroP), provided the requisite allene-yne substrates The majority of these β-carboline-containing products exhibit
9{1,2}–9{1,8}. For the coupling reaction of the ynoic acids with acceptable calculated physical–chemical properties in accor-
an aryl group on the terminus of the alkyne 8{5–8}, the desired dance with Lipinski’s rule of five (Figure 2) [9,10]. These
allene-ynes 9{1,5}–9{1,8} were afforded along with the [2 + 2] favorable properties and structural novelty make these valuable
cycloadducts 2{1,5}–2{1,8} (Table 2, entries 5–8). Previous candidates for deposition in the MLSCN for biological activity
studies with related tryptophan-substituted allene-ynes, required evaluation.
much higher temperatures (225 °C versus rt) to give the [2 + 2]
cycloadducts, albeit none of these examples possessed two Diversity-oriented synthesis (DOS) has been employed to
radical stabilizing groups on the alkyne. Because the calcula- generate thousands of the organic compounds that have been
tions performed by Tantillo [6] regarding the thermal [2 + 2] deposited in the NIH molecular repository for medicinal chem-
cycloaddition reaction suggest that the energy barrier for this istry research. Deciphering the therapeutic potential of this
reaction should not be effected by the presence of two radical many compounds is a continuing challenge. By combining
stabilizing groups over one, it was postulated that this cycload- chemogenomics databases, such as Protein Data Base (PDB)
dition process was facilitated by exposure to incident light [7]. and ChEMBL, it is possible to map new compounds into
Thus, the mixtures of compounds 2 and 9 were reconstituted in existing chemical space and to predict protein targets for new
CH2Cl2 and placed in front of two 6 W UV lamps for 16 h at rt compounds, for which there are two complementary strategies
to afford the desired cyclobutenes (Method B, Table 2, entries that can be implemented. One is a structure-based docking
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Beilstein J. Org. Chem. 2012, 8, 1048–1058.
Table 2: Library of tetrahydro-β-carbolinecyclobutenes 2{1,3}–2{1,8}.
entry
R2
yield of 9a (%)
methodb
yield of 2a (%)
purityc
1
2
3
8{1}
0 9{1,1}
—
A
—
—
8{2}
8{3}
64 9{1,2}
75e 9{1,3}
NDd
—
A
73 2{1,3}
99%
4
5
8{4}
8{5}
71 9{1,4}
A
57 2{1,4}
99%
99%
9{1,5}
2{1,5}
A
B
57f 2{1,5}
40 2{1,5}
9{1,6}
2{1,6}
6
7
8{6}
8{7}
B
B
41 2{1,6}
30 2{1,7}
99%
99%
9{1,7}
2{1,7}
8
8{8}
9{1,8}
B
33 2{1,8}
99%
aIsolated yield; bmethod A: μW, 160 °C, DMF, 10 min; method B: Placed in front of two 6 W UV lamps (245 nm), CH2Cl2, rt, 16 h, no stirring; cpurity
established by LCMS/ELS; dND = not detected; eμW, 225 °C, DMF, 7 min, (39%); fseparated 9{1,5} (57% yield) from 2{1,5} (18% yield) after the
coupling reaction then submitted 9{1,5} to method A to give 2{1,5} in 68% yield. This compound was recombined with the previously isolated 2{1,5} to
afford a combined 57% yield.
strategy, in which a query compound is fit into a series of a collection of bioactive compounds are identified. In the
protein binding pockets to identify favorable compound–protein present study, both of these strategies were used to predict
interactions. A second approach is a ligand-based strategy in potential targets of the newly synthesized library of β-carboline-
which the structural similarities between a query compound and containing compounds.
Table 3: Synthesis of α-methylenecyclopentenone library 3{1,3}–3{1,4}.
entry
R2
9{1,3}
9{1,4}
yield of 3a (%)
purityb
1
48 3{1,3}
46 3{1,4}
99%
99%
2
aIsolated yields; bpurity determined by LCMS/ELS.
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Beilstein J. Org. Chem. 2012, 8, 1048–1058.
Figure 2: Library of tetrahydro-β-carboline containing compounds 1–7 and calculated properties (amolecular weight; bhydrogen-bond donor/accep-
tors; ccLogP; dpolar surface area (PSA)).
High-throughput docking studies for protein-
607 proteins defined as “druggable” targets, in order to reduce
target prediction of newly synthesized com-
pounds
Molecular docking studies were performed with the 34 newly
synthesized compounds, represented by scaffolds 1, 2, 3, and
allenyl precursors 4, 6{1–16}, 9{1–4} to identify potential
protein targets [11]. Protein structures were downloaded from
the PDB [12] and the analysis was limited to a selection of the
computational time [13]. (The complete listing of these proteins
and their PDB IDs are provided in Supporting Information
File 2). The Surflex-dock module of the Sybyl software was
employed for protein preparation and docking of the β-carbo-
line library [14,15]. Water molecules and ligands were removed
from the protein structures and the active site of each protein
was defined by the corresponding residues around the cocrystal-
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Beilstein J. Org. Chem. 2012, 8, 1048–1058.
lized ligands. In-house algorithms were used to evaluate ligand- A portion of the protein-scoring matrix is illustrated in Figure 3.
docking efficiency, and docking scores were used to assess and Several interesting results emerged from this in silico analysis:
rank the protein targets.
(1) Twenty of the new compounds have docking scores greater
Figure 3: Results of high-throughput docking analysis. Top: A docking-score matrix arranged by compound IDs and PDB IDs; bottom: Structures of
known ligands HR2 and TGF and the newly synthesized compounds 2{1,5} and 2{1,7}. Docking scores larger than 7.0 are red colored and can be
mapped to Kd values less than 100 nM. The corresponding protein names of PDB IDs and the full docking-score matrix are listed in Supporting Infor-
mation File 1.
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Beilstein J. Org. Chem. 2012, 8, 1048–1058.
than 7.0, a number that can be mapped to Kd values less than this study, structural similarities were calculated between the
100 nM, for several protein targets; (2) six compounds, 7{7} compounds of the β-carboline library and the bioactive com-
and 2{1,4–1,8}, are predicted to be ligands for a single protein, pounds in the well-annotated database, ChEMBL version 13,
human HDAC4 (PDBID:2vqq); (3) compounds 2{1,5} and the largest publicly available compound-target database,
2{1,7} are predicted to be high-affinity ligands for 3-hydroxy-3- containing 1,143,682 distinct compounds, 8,845 targets and
methylglutaryl-coenzyme A, reductase (PDBID:2q6b) and 6,933,068 bioactivity entries from 44,682 publications and
HDAC4, respectively, even though they are structurally PubChem bioassays [18,19]. The Openbabel FP2 fingerprint
different from the corresponding cocrystallized ligands HR2 was used as a descriptor to assess similarities between mole-
and TGF; and (4) compounds 2{1,6} and 6{10} are predicted to cules [20]. Tanimoto coefficients were calculated between the
be ligands for a total of 15 protein targets. This high number of compounds of the β-carboline library and the ChEMBL data-
potential protein targets may be due to the electronegative base, and only β-carboline compounds with a Tc greater than
trifluoromethyl group on 2{1,6} and the effect it would have on 0.60 were considered for bioactivity analysis. A lower Tc
the α,β-unsaturated amide and the purported bioactivity of the threshold was used to identify a larger number of bioactivity
pyrazole group of 6{10}.
targets. Table 4 lists the most promising bioactive targets for the
newly synthesized β-carbolines together with the structurally
similar lead compounds in ChEMBL along with their reported
Ligand-based strategy for target prediction
Ligand-based target prediction algorithms have been developed potency and literature citations. Several interesting results
based upon an established medicinal chemistry principle that emerge from the comparison study performed, including a
structurally similar compounds, with comparable physical prop- number of targets that the compounds should be screened
erties, should convey related biological properties [16,17]. In against, such as C–C chemokine receptor type 3, gamma-
Table 4: Potential targets of β-carbolines based upon bioactivity data in ChEMBL.
target
CHEMBL compound
bioactivity
type and reference
our compound
similarity
score
C–C chemokine
receptor type 3
IC50 = 325 nM [21]
0.79
CHEMBL33838
A
Leishmania donovani
IC50 = 1.42 µM [22]
0.80
4
CHEMBL55830
Acanthocheilonema
viteae
Activity = 94% [23]
0.86
CHEMBL44573
6{5}
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Beilstein J. Org. Chem. 2012, 8, 1048–1058.
Table 4: Potential targets of β-carbolines based upon bioactivity data in ChEMBL. (continued)
Gamma-aminobutyric
acid receptor subunit
gamma-2
IC50 = 250 nM [24]
0.84
CHEMBL358326
6{1}
5-Hydroxytryptamine
receptor 6
Ki = 271.3 nM [25]
0.69
CHEMBL370935
7{1}
3-Hydroxyacyl-CoA
dehydrogenase type-2
Potency = 31.6 µM
PubChem AID:893
0.64
CHEMBL1382101
7{7}
Benzodiazepine
receptors
Ki = 510 nM [26]
0.72
CHEMBL11901
CHEMBL148616
CHEMBL1089460
1{16}
Angiotensin-converting
enzyme
IC50 = 500 nM [27]
0.71
9{1,3}
Antithrombotic potency
IC50 = 8.56 nM [28]
0.69
9{1,4}
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Beilstein J. Org. Chem. 2012, 8, 1048–1058.
Table 4: Potential targets of β-carbolines based upon bioactivity data in ChEMBL. (continued)
Mitogen-activated
protein kinase 1
Potency = 0.794 µM
PubChem AID:995
0.82
CHEMBL44295
6{4}
Breast
adenocarcinoma cells
Inhibition = 78% [29]
0.79
CHEMBL1650665
6{6}
Potency = 1.78 µM
PubChem
DNA polymerase iota
0.85
AID:588590
CHEMBL1360719
6{7}
aminobutyric acid receptor subunit gamma-2, breast adenocar- library, by directing them to appropriate biological assays. Such
cinoma cells, 5-hydroxytryptamine receptor 6, angiotensin- strategies can also be used to explore the mechanisms of a bio-
converting enzyme, and DNA polymerase iota. Moreover, nine logically active compound in bioassays whose molecular target
of the twelve compounds are represented by allene precursors, is as of yet unidentified.
ones that were not originally considered in the diversity
analysis.
Supporting Information
Conclusion
Supporting Information File 1
A library of 34 β-carboline-containing compounds was
synthesized utilizing a skeletal diversification strategy. High-
throughput docking and ligand-based protocols were imple-
mented to predict potential biological targets of the newly
synthesized β-carbolines. The docking approach uses a struc-
ture-based technology to predict preferred interactions between
compounds and protein targets, whereas the ligand-based
method uses ligand similarity coefficients to identify potential
biological targets. The complementary nature of these two
protocols is evidenced by the fact that there was no overlap in
the predicted biological targets. Furthermore, the in silico
screening of these compounds is intended to add value to the
Experimental procedures and spectral data for compounds
1{5}, 1{16}, 2{1,3–8}, 3{1,2–4}, 4, 6{1–10}, 6{12–13},
6{15}, 7{1–7}, 9{1,2–4}.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-117-S1.pdf]
Supporting Information File 2
The complete listing of the proteins and their PDB IDs
(Targets Docking Score Matrix).
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-117-S2.xls]
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Beilstein J. Org. Chem. 2012, 8, 1048–1058.
19.Heikamp, K.; Bajorath, J. J. Chem. Inf. Model. 2011, 51, 1831–1839.
doi:10.1021/ci200199u
Acknowledgements
The authors are grateful to the NIH P50 GM067082 (118220)
for generous financial support. This work is also partially
supported by NIH R21HL109654 (Xie). We thank Drs. Lei
Wang and Tom Jones at Tripos Company and Professor Peter
Wipf at the University of Pittsburgh for professional discus-
sions. Finally, the analytical support provided by Mr. Pete G.
Chambers is very much appreciated.
Heikamp et al. carried out a large-scale similarity search investigation
on 266 well-defined compound activity classes extracted from the
ChEMBL database using molecular fingerprints. In 203 of 266 test
cases (~76%), a compound recovery rate of at least 50% was
observed.
20.Guha, R.; Howard, M. T.; Hutchison, G. R.; Murray-Rust, P.; Rzepa, H.;
Steinbeck, C.; Wegner, J.; Willighagen, E. L. J. Chem. Inf. Model.
2006, 46, 991–998. doi:10.1021/ci050400b
21.Dhanak, D.; Christmann, L. T.; Darcy, M. G.; Jurewicz, A. J.;
Keenan, R. M.; Lee, J.; Sarau, H. M.; Widdowson, K. L.; White, J. R.
Bioorg. Med. Chem. Lett. 2001, 11, 1441–1444.
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