Libraries from libraries: A series of sulfonamide linked heterocycles derived from the same scaffold

Article abstract of DOI:10.1016/j.tetlet.2013.06.003

A libraries from libraries approach is described for the synthesis of five different sulfonamide linked scaffolds. Four of the scaffolds are sulfonamides linked to heterocycles; piperazine, thiourea, cyclic guanidine, and dimethyl cyclic guanidine. The fifth scaffold is a polyamine linked sulfonamide. Three different diversity positions were effectively incorporated into each scaffold providing a number of different compounds with good yields and purity.

Full text of DOI:10.1016/j.tetlet.2013.06.003

Accepted Manuscript
Libraries from Libraries: A Series of Sulfonamide Linked Heterocycles Derived
from the Same Scaffold
Ginamarie Debevec, Wenteng Chen, Yongping Yu, Richard A. Houghten, Marc
A. Giulianotti
PII:
S0040-4039(13)00947-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.06.003
TETL 43056
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Accepted Date:
10 May 2013
3 June 2013
Please cite this article as: Debevec, G., Chen, W., Yu, Y., Houghten, R.A., Giulianotti, M.A., Libraries from
Libraries: A Series of Sulfonamide Linked Heterocycles Derived from the Same Scaffold, Tetrahedron Letters
(2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.06.003
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Title
Libraries from Libraries: A Series of Sulfonamide Linked Heterocycles Derived from the Same Scaffold
Authors
†
Ginamarie Debevec†, Wenteng Chen‡ , Yongping Yu‡, Richard A. Houghten†, and Marc A. Giulianotti†*
†Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie FL 34987
‡Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058,
P. R. China
*Corresponding Author: mgiulianotti@tpims.org Tel: 772-345-4729; Fax: 772-345-3649
Abstract
A libraries from libraries approach is described for the synthesis of five different sulfonamide linked
scaffolds. Four of the scaffolds are sulfonamides linked to heterocycles; piperazine, thiourea, cyclic
guanidine, and dimethyl cyclic guanidine. The fifth scaffold is a polyamine linked sulfonamide. Three
different diversity positions were effectively incorporated into each scaffold providing a number of
different compounds with good yields and purity.
Graphical Abstract
Keywords
piperazine; positional scanning; sulfonamide; urea; guanidine; libraries from libraries
The innovation of mixture-based combinatorial chemistry has proven to be a valuable tool in drug
discovery. In particular positional scanning synthetic combinatorial libraries (PS-SCL) allow for the rapid
biological evaluation of thousands to trillions of compounds from hundreds of samples in order to
identify active compounds for a variety of biological targets1-3. PS-SCL that are comprised of
oligonucleotides, peptides, low molecular weight acyclic and heterocyclic compounds offer a diversity of
structures for high-throughput screening while simultaneously requiring exponentially fewer samples to
screen4-5.

In nature, heterocyclic structures play an essential role as structural and reactive components in many
biologically relevant ligands. In particular, the heterocyclic ring offers medicinally relevant properties
that can increase hydrogen bonding possibilities and polarity, and generate ligands for specific biological
targets6. A number of heterocyclic motifs show efficacy as therapeutics and are found incorporated into
approved drugs. Heterocyclic thioureas have shown activity in growth inhibition of pathogenic
bacteria7, while a number of marketed drugs contain piperazines such as imatinib, quetiapine, and
eszopiclone and are used to treat cancer, behavioral disorders, and insomnia.
In medicinal chemistry, the sulfonamide moiety is widely used because of its widespread biological
activity. Marketed drugs containing a sulfonamide group can be divided into two classes: nonantibiotic
and antibiotic. Antibiotics containing a sulfonamide have a long history, starting with Prontosil in the
1930’s. Additionally, there are many other marketed drugs not used as antimicrobials in the United
States that contain the sulfonamide moiety, including acetazolamide, bumetanide, valdecoxib,
celecoxib, dorzolamide, glyburide, sumatriptan, sultiame, and celecoxib. These drugs are used for such
diverse applications as diuretics, anti-inflammatories, anti-glaucoma, anti-diabetics, anti-migraines,
anticonvulsant s, and COX-2 inhibitors8. Research indicates that compounds that include a sulfonamide
structure could be a powerful tool in combating the progression of Alzheizmer’s disease by potentially
inhibiting the BACE1 enzyme, which is a key enzyme in the progression of the disease9. Sulfonamides
have shown anticancer potential by being effective against human tumor cells as well10.
A library in which the core scaffold includes these two biologically active motifs thus holds great promise
for drug discovery efforts. In our continuing endeavor to synthesis biological relevant libraries and
utilizing the proven “libraries from libraries” approach11, five scaffolds were synthesized. This method
allows the modification of existing libraries to create diverse libraries that have different physical and
chemical characteristics. Herein we report the efficient solid phase synthetic approach used to obtain
these diverse libraries.
Multiple sequences that contained a variety of amino acids and sulfonyl chlorides were first selected for
synthesis. In order to be further utilized for a synthetic mixture library, the method must be robust to
sequences with diverse chemical properties. The core sulfonamide product 3 from which the libraries
are derived is generated by the solid phase synthetic scheme described below (scheme 1). Starting with
MBHA resin, Boc protected amino acids were coupled to the resin using standard DIC/ HOBt protocol for
2 hours at room temperature, followed by washes DMF (2X) and DCM (2X). After removal of the Boc
protecting group using 55% trifluoroacetic acid in DCM for 30 minutes, followed by washes with
DCM(2X), IPA(2X), and DCM (2X) the amino acid coupling was repeated to obtain a resin bound
dipeptide 1. After Boc removal sulfonyl chlorides at 8 eq in 0.1M anhydrous DCM were coupled to the
resin bound dipeptide using DIEA (10 eq) overnight to obtain the sulfonamide structure 2. Each coupling
reaction was monitored by the use of the ninhydrin test to ensure the coupling was complete. Resin
bound 2 was reduced by exhaustive borane reduction followed by piperidine treatment to yield 3. The
resin bound thiourea heterocyclic sulfonamide product 5 was obtained by cyclization with
thiocarbonyldiimidazole in 0.1M anhydrous DCM overnight at room temperature followed by cleavage
from the resin with HF (1.5 hours). Reacting 3 with phosgeniminium chloride (3 eq in 0.1M anhydrous
DCM, 3 eq DIEA) for 4 hours at room temperature followed by removal from the solid support with HF

yielded a dimethyl cyclic guanidine attached to the sulfonamide 6. A similar scaffold 7, a cyclic guanidine
sulfonamide, was achieved by cyclization using 5 eq cyanogen bromide in 0.1M anhydrous DCM
overnight at room temperature followed by treatment with HF. The piperzine ring attached to the
sulfonamide was obtained with similar ease; however it did require extra steps. The 2-Oxopiperazine
ring structure 8 is first achieved by reaction of 3 with bromoacetic acid at 5eq in 0.1M anhydrous DCM
overnight at room temperature. Next 8 underwent an exhaustive borane reduction followed by
treatment with piperidine producing the resin bound piperazine attached to a sulfonamide 9. The
desired product 10 is released from the resin by HF cleavage (7 hours). In all cases before analysis the
final products were extracted from their HF vessels with 95% acetic acid and then underwent three
successive rounds of freezing, lyophilizing, and resuspending with 50% acetonitrile/water. The samples
were analyzed by reverse phase LCMS. Diverse sequences were obtained which showed good purity and
yields. The results are presenting in Table 1. Additionally selected compounds were purified and
characterized by H1 NMR12.
In a continuing effort to create diverse mixture libraries and utilizing the libraries from library approach
the synthetic methodologies described above have been expanded to include a wide range of
substituents in the R1, R2 and R3 position. The work done to establish the positional scanning libraries for
the cyclic guanidine sulfonamide (7) and piperazine sulfonamide (10) has already been completed and is
the subject of a previous publication13. We are currently applying this same methodology to produce
positional scanning libraries for 4, 5, and 6 that will each contain 18,360 compounds. These libraries will
be immediately used in work directed at the identification of novel antinociceptives and efflux pump
inhibitors. In summary, this is an efficient approach to create five distinct sulfonamide scaffolds through
the use of solid phase chemistry.
Acknowledgments
This work was supported by NIH Grant 1R01DA031370, DOD Contract HDTRA1-13-C-005, Arthritis &
Chronic Pain Research Institute, and the State of Florida, Executive Office of the Governor's Department
of Economic Opportunity.
References and Notes
1.
2.
Houghten, R.A.; Pinilla, C.; Appel, J.R.; Blondelle, S.E.; Dooley, C.T.; Eichler, J.; Nefzi, A.; Ostresh,
J.M. J. Med Chem. 1999, 42, 3743-3778.
Houghten, R.A.; Pinilla, C.; Giulianotti, M.A.; Appel, J.R.; Dooley, C.T.; Nefzi, A.; Ostresh, J.M.; Yu,
Y.; Maggiora, G.M.; Medina-Franco, J.L.; Brunner, D.; Schneider, J. J. Comb. Chem. 2008, 10, 3-19.
Pinilla, C.; Appel, J.R.; Borras, E.; Houghten, R.A. Nature Medicine. 2003, 9, 118-122.
Lopez-Vallejo, F.; Giulianotti, M. A.; Houghten, R. A.; Medina-Franco, J. L. Drug Discovery Today
2012, 17, 718-726.
3.
4.
5.
6.
Medina-Franco, J.L.; Giulianotti, M.A.; Welmaker, G.S.; Houghten, R.A. Drug Discovery Today
2013, 18,495-501.
Walsh, C.T.; Malcolmson, S. J.; Young, T. S. ACS Chem Bio. 2012, 7, 429-442.

7.
8.
Suhas, R.; Chandrashekar, D.; Gowda C. European Journal of Medicinal Chemistry. 2012, 48, 179-
191.
Ovais. S.; Bashir, R.; Yaseen S.; Rathore, P.; Samim, M.; Javed, K. Med Chem Res. 2013, 22, 1378-
1385.
9.
Kang, J.E; Cho J.K; Curtis-Long, M.J. Molecules. 2012, 18, 140-153.
10.
Ferrari, S.; Ingrami M.; Sorgani, F.; Wade, R.C.; Costi M.P. Bioorganic & Medicinal Chemistry
Letters. 2013, 23, 663-668.
11.
12.
Nefzi, A.; Ostresh, J.M.; Yu, Y.; Houghten, R.A. Journal of Organic Chemistry 2004, 69, 3603-9
H1 NMR of sample 4f (S)-3-phenyl-N2-(((S)-1-(phenylsulfonyl)pyrrolidin-2-yl)methyl)propane-1,2-
diamine (400Hz, CDCl3): δ 7.83(2H,d) 7.56(3H,sex) 7.32-7.18(5H, m) 3.66 (1H,s) 3.20 (1H,quin)
2.95-2.89 (8H,m) 2.81 (3H,quin) 1.73 – 1.4 (4H, m).H1 NMR of sample 5f (S)-5-benzyl-1-(((S)-1-
(pehnylsulfony)pyrrolidin-2yl)methyl)imidazolidine-2-thione (400MHz, DMSO): δ 7.70(2H,d)7.66-
7.62 (3H, m) 7.26-7.23 (5H, m) 4.37 -3.59 (4H, m) 3.41 (1H, quin) 3.28–3.27 (4H, m) 2.63 (1H, q)
2.51 (1H, s) 1.90-1.33 (4H, m). H1NMR of sample 6j N-(1-(5-benzyl-2-(dimethylamino)-4,5-
dihydro-1H-imidazol-1-yl)-3-phenylpropan-2-yl)-4-bromobenzenesulfonamide (400MHz, DMSO):
δ 8.46 (1H, s) 7.58 (4H, q) 7.49-7.48 (5H, m) 7.25 (3H, quin) 6.91 (2H, d) 4.06 (1H, q) 3.73 (2H, t)
3.27 (2H, quin) 2.93 (6H, s) 2.93-2.76 (3H,m) 2.52 -2.28 (2H, m). H1NMR of sample 7j N-((S)-1-((S)-
5-benzyl-2iminoimidazolidin-1-yl)-3-phenylpropan-2-yl)-4-bromobenzenesulfonamide (400MHz,
DMSO): δ 8.46 (1H,s) 7.50 (2H,d) 7.39 – 7.27 (5H,m) 7.22 -7.01 (6H, m) 4.22 (1H,s) 3.68 (2H, t)
3.32 (1H, d) 3.26 (2H, q) 2.94( 1H, q) 2.67 -2.50 (3H, m) spectrum previously reported13. H1NMR
of
sample
10h
N-((S)-1-((S)-2-benzylpiperazin-1-yl)-3-(4-hydroxyphenyl)propan-2-
yl)benzenesulfonamide H1 NMR of 10H (400MHz, DMSO): δ 7.69 (2h, t) 7.55 – 7.43 (4H, m)
7.27- 6.92 (10H, m) 3.37 (3H, q) 2.80 (2H, q) 2.78-2.51 (4H, m) 2.49 – 2.18 (6H, m) spectrum
previously reported13.
13.
Giulianotti, M. A.; Debevec, G.; Santos, R. G; Maida, L.; Chen, W.; Ou, L.; Yu, Y.; Dooley, C.;
Houghten, R.A. ACS Combinatorial Science. 2012, 14, 503-512.

Table 1
Individual compound purities and yields for compounds from scaffolds 4, 5, 6, 7 and 10.
ID
R1
R2
R3
4
5
6
7
10
Yield
%
Purity
%
K’
Yield
%
Purity
%
K’
Yield
%
Purity
%
K’
Yield
%
Purity
%
K’
Yield
%
Purity
%
K’
38
43
97
98
2.95
3.02
70
46
75
80
6.18 N/A
N/A
5
N/A 114
3.76 107
99
90
3.90
3.70
99
95
95
90
3.65
3.53
A
B
5.50
6.05
30
20
OH
48
98
3.50
79
65
25
4.05 113
98
4.00
4.55
94
85
90
3.95
C
OH
52
43
85
98
4.30
3.70
75
69
50
75
7.10
6.90
23
42
10
90
5.88 109
4.40 114
95
95
60
90
4.45
4.20
D
4.32 105
E
F
68
40
42
99
99
99
3.35 104
80
75
6.43
5.50
30
61
90
50
4.10 106
3.64 127
95
85
95
4.10 109
3.75 119
4.38 107
90
92
98
3.95
3.50
4.24
N
H
OH
3.05
3.97
86
51
G
H
80% 6.81 N/A
N/A
N/A
82
75
S
47
55
60
75
99
97
3.95
4.20
4.30
56
51
61
85
75
75
6.80
7.15
7.22
54
55
49
75
95
95
4.35
95
98
98
4.25 104
75
95
75
4.25
4.45
4.50
I
J
Br
4.65 100
4.55
4.50
92
81
I
4.75
4.87
94
95
K
55
99
4.45
53
65
7.37
50
90
95
4.70
89
98
4.70
L

a Crude yields
b Purity of crude product before purification based on the UV peak at 214nm.
N/A: not available
K’: Samples analyzed on Shimadzu Prominence liquid chromatograph (Solvent A: water with 0.1% formic
acid, solvent B: acetonitrile with 0.1% formic acid), Shimadzu Prominence UV Detector (wavelength 214
and 254nm) and Shimadzu LCMS-2010 (positive mode scanning 175-1000 m/z). Samples are run in
reverse phase mode with a flow rate of 0.5mL/min and a gradient of 5-95% over 6 minutes on a
Phenomenex Luna C18 5μ 100A 50 X 4.60mm column.
Scheme 1. Reagents and conditions (a) 55%TFA/DCM (30min); 3x5%DIEA (b) Sulfonyl chloride (8 equiv
0.1M anhydrous DCM), DIEA (10 equiv) rt overnight; (c) BH3 –THF, 65°C 100 hours; (d) piperidine, 65°C
24hours; (e) Thiocarbonyldiimidazole (5 equiv in 0.1M anhydrous DCM) overnight rt; (f) HF, 0°C
1.5hours; (g)Phosgeniuminium chloride (3 equiv in 0.1M anhydrous DCM) rt 4 hours; (h) cyanogen
bromide (5 equiv in 0.1M DCM) rt overnight; (i) HF, 0°C 7 hours; (j) bromoacetic acid (5 equiv in 0.1M
anhydrous DCM) rt overnight.