Structure-based design, synthesis and biological evaluation of novel β-secretase inhibitors containing a pyrazole or thiazole moiety as the P3 ligand

Article abstract of DOI:10.1016/j.bmcl.2014.11.087

We describe structure-based design, synthesis, and biological evaluation of a series of novel inhibitors bearing a pyrazole (compounds 3a-h) or a thiazole moiety (compounds 4a-e) as the P3 ligand. We have also explored Boc-β-amino-l-alanine as a novel P2 ligand. A number of inhibitors have displayed β-secretase inhibitory potency. Inhibitor 4c has shown potent BACE1 inhibitory activity, K_i = 0.25 nM, cellular EC₅₀ of 194 nM, and displayed good selectivity over BACE2. A model of 4c was created based upon the X-ray structure of 2-bound β-secretase which revealed critical interactions in the active site.

Full text of DOI:10.1016/j.bmcl.2014.11.087

Bioorganic & Medicinal Chemistry Letters 25 (2015) 668–672
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure-based design, synthesis and biological evaluation of novel
b-secretase inhibitors containing a pyrazole or thiazole moiety as the
P3 ligand
Arun K. Ghosh a,b,c, , Margherita Brindisi a,b, Yu-Chen Yen d, Xiaoming Xu a,b, Xiangping Huang a,e
,
⇑
Thippeswamy Devasamudram c,f, Geoffrey Bilcer c,f, Hui Lei f, Gerald Koelsch a,e,f, Andrew D. Mesecar a,d
,
Jordan Tang a,e,g
a Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States
b Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, United States
c Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, United States
d Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, United States
e Protein Studies Program, Oklahoma Medical Research Foundation, United States
f CoMentis Inc, Oklahoma City, OK 73104, United States
g Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe structure-based design, synthesis, and biological evaluation of a series of novel inhibitors
Received 21 October 2014
Revised 26 November 2014
Accepted 28 November 2014
Available online 6 December 2014
bearing a pyrazole (compounds 3a–h) or a thiazole moiety (compounds 4a–e) as the P3 ligand. We have
also explored Boc-b-amino-L-alanine as a novel P2 ligand. A number of inhibitors have displayed
b-secretase inhibitory potency. Inhibitor 4c has shown potent BACE1 inhibitory activity, Ki = 0.25 nM,
cellular EC50 of 194 nM, and displayed good selectivity over BACE2. A model of 4c was created based upon
the X-ray structure of 2-bound b-secretase which revealed critical interactions in the active site.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
b-secretase
Alzheimer’s disease
Memapsin 2
BACE-1
Protease inhibitors
The development of effective treatment for Alzheimer’s disease
(AD) continues to be a formidable challenge in medicine.1,2 b-
Secretase (also known as memapsin 2 or BACE1) is the protease
responsible for the first cleavage of b-amyloid precursor protein
(APP) leading to the production of a 40/42 residue amyloid-b-pep-
tides (Ab), the major constituent of the brain amyloid plaques.3,4
The pathological hallmark of AD is the formation of amyloid
plaques and neurofibrillary tangles in the brain of AD patients,
which is generally believed to be derived from Ab accumulation
and intimately related to the pathogenesis of AD. Due to the central
role of b-secretase in the generation of Ab, inhibition of b-secretase
has become a major focus in the search for AD therapy.5–7 From a
therapeutic perspective, BACE1 inhibition has generated much
interest as a suitable target since BACE1 gene deletion in mice
showed only a mild phenotypic response.8,9 Despite the promise
of BACE1 as a target, the clinical development of a BACE1 inhibitor
has been quite slow and challenging.10 This is due to problems
associated with poor pharmacological properties of inhibitors, par-
ticularly the inability to cross the blood–brain-barrier and the lack
of inhibitor selectivity against other important human aspartic acid
proteases.11–13
Early reports from our laboratories demonstrated that a potent
BACE1 inhibitor can be designed by incorporating a nonhydrolyz-
able Leu-Ala hydroxyethylene dipeptide isostere at the cleavage
site.14,15 As shown, inhibitor 1 (OM99-2, Fig. 1) is quite potent.
We subsequently determined the X-ray crystal structure of 1-
bound BACE1 which provided insight into ligand-binding site
interactions and critical drug design templates.7 Inhibitor 1 did
not show selectivity over BACE2 or cathepsin D (Cat-D). We then
reported the design of potent and selective inhibitors. Peptidomi-
metic inhibitor 2 with a pyrazolemethyl urethane showed excel-
lent potency and selectivity over BACE2 (>3800-fold) and Cat-D
(>2500-fold).16 Based upon the X-ray crystal structure of 2-bound
b-secretase, we further explored amide-based P2–P3 ligands.
Herein we report our studies in which we have developed pyrazole
and thiazole-derived novel P3-ligands containing hydrogen bond
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.bmcl.2014.11.087
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

A. K. Ghosh et al. / Bioorg. Med. Chem. Lett. 25 (2015) 668–672
669
O
O
O
CO2H
Me
N
Me
N
H2N
a
NH
N
OH
Me
OCH3
O
H
N
H
H
N
N
Me
NH
Me
b,c
H2N
N
H
5
Me
6
Me
O
O
O
H
N
HO2C
Ph
1
(OM99-2), Ki = 1.6 nM
O
O
O
Me
and,
Me
N
N
O
N
CO2H
N
O
O
O
S
HN
HN
Me
Me
7b
Ts
Ts
Me
7a
Me
OH
Me
O
Me
H
H
N
(structure by X-ray)
N
N
O
N
H
N
O
O
d
d
O
NH
NH
Me
Me
2
Ki = 0.3 nM
O
O
O
Me
Me
N
N
O
S
N
N
OH
OH
O
O
Me
Me
OH
Me
Me
Me
Me
H
N
H
N
8
8
(S)-
(R)-
N
N
H
N
Me
O
O
O
O
O
3h
Ki = 192 nM
Ref 20
H3CO
OCH3
OCH3
O
O
R
10a
10b
9
R = Et
NH
R = i-Pr
OH
O
Me
e
H
H
N
10c R = i-Bu
N
N
N
H
Me
O
O
Me
N
Me
S
N
Me
O
O
O
NH
b-d
N
N
OCH3
OH
4c
Ki = 0.25 nM
R
R
Me
Me
(S)-
(S)-
12a
12b
11a
11b
R = Et
R = i-Pr
R = Et
R = i-Pr
Figure 1. Structures of BACE1 inhibitors 1, 2, 3h and 4c.
(S)-12c R = i-Bu
11c R = i-Bu
donor and acceptor groups to interact with residues in the S3
subsite. Asymmetric synthesis of these heterocyclic ligands as well
as the use of optically active (1S,2R)-1-tosyl-amino-2-indanol pro-
vided access to optically pure ligands.
O
Me
N
Me
N
a-d
N
OH
NH
Me
The synthesis of the pyrazole-derived ligands is shown in
Scheme 1. Reaction of 3,5-dimethyl pyrazole 5 and methyl methac-
rylate in a sealed tube at 180 °C for 6 h provided racemic Michael
addition product 6.17 Saponification of ester 6 with aqueous LiOH
at 23 °C for 10 h furnished the corresponding racemic acid. Esteri-
fication of the acid with (1S,2R)-1-tosyl-amino-2-indanol18,19 using
EDC and DMAP at 23 °C for 12 h afforded a diastereomeric mixture
(nearly 1:1 by 1H NMR analysis) of esters, 7a and 7b. The mixture
was separated by silica gel chromatography to provide pure diaste-
13
(S)-14
Scheme 1. Reagents and conditions: (a) methyl methacrylate, 6 h, 180 °C, sealed
tube, 59–61%; (b) LiOHꢁH2O, H2O/THF, 23 °C, 10 h, 73–80%; (c) (1S,2R)-(ꢀ)-cis-1-
tosyl-amino-2-indanol, EDC, DMAP, dry CH2Cl2, 23 °C, 12 h, 62–90%; (d) LiOHꢁH2O,
H2O/THF, 23 °C, 10 h, 54–60%: (e) 3,5-dimethyl-1H-pyrazole, 6 h, 180 °C, sealed
tube, 59–62%.
oxazolidinone 15a with NaHMDS in THF at ꢀ78 °C provided the
corresponding enolate.22 The enolate was reacted with known 4-
iodomethyl-2-methylthiazole 1623 at ꢀ78 °C to 23 °C for 1 h fur-
nishing alkylated product 17a diastereoselectively. Alkylation of
15b with iodide 16 provided alkylated product 17b. Subsequent
treatment of 17a,b with a mixture of aqueous LiOH and hydrogen
peroxide at 0 °C for 1 h afforded optically active ligand acids 18a
and 18b, respectively.
reomers, 7a and 7b. The absolute configuration of the
a-methyl
center of diastereomer 7a was determined by X-ray crystallo-
graphic analysis. Saponification of esters 7a and 7b using aqueous
LiOH at 23 °C for 10 h furnished optically active ligand acids (S)-8
and (R)-8.
For the synthesis of optically active ligands containing other
substitutions, dimethylmalonate
9 was converted to acrylate
derivatives 10a–c as described in the literature.20 These acrylate
derivatives were converted to pyrazole derivatives 11a–c by
Michael addition in the presence of 3,5-dimethyl pyrazole 5 as
described above. Saponification and subsequent esterification with
(1S,2R)-1-tosyl-amino-2-indanol afforded the diastereomeric mix-
ture of esters. Diastereomers were separated by silica gel chroma-
tography and the respective diastereomer with the lower Rf-value
turned out to be the isomer with the (S)-configuration at the
For the synthesis of isomeric ligand acids, commercially
available (4-methylthiazole-2-yl) methanol 19 was converted to
2-iodomethyl-4-methylthiazole 20 by treatment of 19 with mesyl
chloride and triethylamine followed by reaction of the resulting
mesylate with lithium iodide in acetone. Asymmetric alkylation
of oxazolidinone derivatives 15a–c with iodide 20 as described
above afforded alkylation products 21a–c, respectively. Removal
of the chiral auxiliary with alkaline hydrogen peroxide furnished
optically active ligand acids 22a–c.
a
-alkyl center. Further corroboration of stereochemistry of the a-
alkyl group was carried out by comparison of 1H NMR data with
diastereomer 7a. Saponification of esters provided optically active
ligand acids (S)-12a–c. Acid (S)-14, containing a 3-methylpyrazole
moiety, was prepared following the same procedures described for
(S)-8.
The synthesis of inhibitors is shown in Scheme 3. Commercially
available protected b-amino-L-alanine 23 was coupled with Leu-
Ala transition-state isostere derivative 24 in the presence of EDC,
HOBt and diisopropylethylamine at 23 °C for 15 h to provide amide
derivative 25 in good yield. Removal of the Cbz-group by catalytic
hydrogenation over Pearlman’s catalyst furnished amine 26 in near
quantitative yield. Coupling of this amine with ligand acid (S)-8
followed by removal of the TBS group by exposure to TBAF in
The synthesis of the thiazole acids is shown in Scheme 2. For
asymmetric alkylation, (R)-4-benzyl-2-oxazolidinone derivatives
15a,b were prepared as described previously.21 Treatment of

670
A. K. Ghosh et al. / Bioorg. Med. Chem. Lett. 25 (2015) 668–672
O
O
O
O
THF provided inhibitor 3a. Inhibitors 3b–f were synthesized by fol-
lowing a similar sequence of reactions as inhibitor 3a.
For the synthesis of inhibitors 3g,h, amine 24 was coupled with
commercially available N-Boc-L-methylcysteine 27 using EDC and
a
R
R
N
N
O
O
N
S
Me
Ph
, R = Me
, R = Et
Ph
HOBt to furnish the corresponding coupled product. Removal of
the Boc group by exposure to trifluoroacetic acid, followed by cou-
pling of the resulting amine with optically active ligand acid (S)-8
directly provided inhibitor 3g without needing the final TBS depro-
tection step. Oxidation of the sulfide with oxone furnished inhibi-
tor 3h in excellent yield.24 The synthesis of inhibitors 4a–e was
carried out by coupling amine 26 with thiazole-derived ligand
acids 18a,b and 22a–c to furnish the corresponding coupling prod-
ucts. Exposure of the coupling products to TBAF in THF as
described for inhibitor 3a, afforded inhibitors 4a–e.
The b-secretase inhibitory activity was determined against
recombinant b-secretase using our previously reported assay pro-
tocols.25 The structure and inhibitory potency of inhibitors 3a–h
and 4a–e are reported in Tables 1 and 2, respectively. As can be
observed, the activity data generated from the pyrazole-containing
inhibitors (Table 1) clearly outline a series of well-defined struc-
ture-activity relationships (SARs). First of all, the (S)-configuration
15a
15b
17a, R = Me
17b,
R = Et
b
O
N
I
OH
Me
Me
S
S
N
R
18a, R = Me
16
18b,
Me
R = Et
N
N
HO
I
c, d
Me
S
S
19
20
O
O
O
O
a
R
R
N
N
O
O
N
Me
S
Ph
Ph
15a
15b
, R = Me
21a
, R = Me
, R = Et
b
of the
a-alkyl group showed to be of critical importance for the
, R = Et
21b
O
inhibitory activity, as demonstrated by the dramatic drop in
15c, R = i-Pr
21c, R = i-Pr
S
potency (nearly 40-fold) for compound 3b with respect to 3a,
OH
bearing the
compounds also highlighted the efficacy of the small alkyl group
at the -position, as shown by the steady loss in inhibitory potency
with the increase of the steric bulk of the -alkyl group
(3a > 3c > 3e > 3d). Compound 3d, bearing the bulkier -isopropyl
a-methyl group with (R)-configuration. This series of
N
22a
R
, R = Me
, R = Et
22b
Me
22c, R = i-Pr
a
a
Scheme 2. Reagents and conditions: (a) NaHMDS (1 M in THF), 16 or 20, dry THF,
ꢀ78 °C to 23 °C, 1 h, 69–86%; (b) LiOHꢁH2O, 30% wt H2O2, H2O/THF, 0 °C, 1 h, 90–
95%; (c) CH3SO2Cl, TEA, dry CH2Cl2, 1 h, 0 °C; (d) LiI, acetone, 2 h, 23 °C, 82% (over
two steps).
a
group displayed a nearly 10-fold reduction of potency compared
to inhibitor 3a. The importance of both methyl groups on the pyr-
azole ring (3a) can be seen by comparison of its inhibitory activity
with that of inhibitor 3f. This evidence is in line with the molecular
insight obtained from the protein–ligand X-ray structure of the
pyrazole-bearing inhibitor 2.16 In this X-ray structure, both methyl
groups on the pyrazole ring appear to effectively fill the S3 hydro-
Boc
TBS
O
NH
OH
Me
H
N
H2N
+
N
Cbz
phobic pocket. The importance of Boc-b-amino-L-alanine as the P2
O
H
O
O
NH
a
24
ligand over methylsulfonyl- -alanine can be seen by comparison of
L
23
inhibitor 3a with 3h. Interestingly, methyl sulfide derivative 3g
turned out to be more potent in this series than methyl sulfone
derivative 3h.17
Thiazole containing compounds were also evaluated against b-
secretase and their inhibitory potencies are reported in Table 2.
O
O
TBS
NH
O
Me
H
H
N
N
R N
H
O
O
Compound 4a with a 2-methylthiazole moiety and a-methyl group
25 R = Cbz
26 R = H
O
NH
b
in the P3 ligand showed good BACE1 activity. However, compound
4c, bearing the 4-methylthiazole moiety in the P3 ligand turned
out to be a very potent inhibitor with over 120-fold improvement
over inhibitor 4a. The corresponding inhibitors bearing an ethyl
group or an isopropyl group (4d and 4e) were significantly less
active.
c,d
3a-f
4a-e
and
as defined in Tables 1 and 2
SMe
We have determined the cellular production of Ab in BE(2)-M17
human neuroblastoma cells (ATCCÒ CRL-2267™).26 Inhibitor 4c
displayed an EC50 value of 194 nM in this assay. It showed good
selectivity against memapsin 1 (Ki = 71 nM, selectivity >280-fold).
However, its selectivity over Cat-D was marginal (Ki = 1.25 nM, 5-
fold). As mentioned, blood–brain barrier (BBB) penetration repre-
sents a major issue for the development of BACE1 inhibitors.11–13
It appears that the lipophilicity of inhibitor 4c (clogP, 3.55) is
OH
24
+
N
H
27
Boc
O
a,e,f
Me
X
OH
Me
Me
O
H
N
H
N
N
N
N
H
Me
3g
O
O
O
NH
3g
Me
improved compared to urethane-derived inhibitor
2 (clogP,
X = S
2.21).27,28 Such improvement of lipid solubility may favor BBB pen-
etration of compound 4c over compound 2.
g
3hX = SO2
Scheme 3. Reagents and conditions: (a) EDCIꢁHCl, HOBtꢁH2O, DIPEA, dry CH2Cl2, dry
DMF, 23 °C, 15 h, 61%; (b) Pd(OH)2 20% on carbon, H2, MeOH, 3 h, 99%; (c)
appropriate carboxylic acid, EDCIꢁHCl, HOBtꢁH2O, DIPEA, DMF, 15 h, 23 °C, 45–52%;
(d) TBAF, THF, 23 °C, 12 h, 65–72%; (e) TFA, CH2Cl2, 2 h, 23 °C, 98%; (f) (S)-8,
HATU, HOAt, 2,4,6-collidine, DMF, 23 °C, 15 h, 68%; (g) Oxone, MeOH, water,
23 °C, 1.5 h, 99%.
To obtain molecular insight into specific ligand-binding site
interactions, we created an energy-minimized active site model
of inhibitor 4c based upon the crystal structure of inhibitor 2-
bound b-secretase.16 The conformation of 4c was optimized using
the CHARMM force field.29 A stereoview of the model is shown in

A. K. Ghosh et al. / Bioorg. Med. Chem. Lett. 25 (2015) 668–672
671
Table 1
Enzyme inhibitory activity of pyrazole-based inhibitors 3a–h
Table 2
Enzyme inhibitory activity of thiazole containing inhibitors 4a–e
Entry
Inhibitor
Ki (nM)
Entry
Inhibitor
Ki (nM)
O
O
O
O
O
O
O
O
O
O
O
NH
NH
OH Me
OH Me
Me
O
O
H
H
N
H
H
N
N
N
N
N
N
N
H
N
H
1
40
1
31.9
Me
O
Me
O
O
Me
O
S
O
NH
NH
NH
NH
NH
O
NH
NH
NH
NH
NH
3a
4a
Me
O
O
NH
NH
OH Me
OH Me
Me
O
O
O
H
H
N
H
H
N
N
N
N
N
N
N
H
N
H
2
1640
2
3
4
5
16.8
Me
O
O
O
Me
O
S
O
O
3b
4b
Me
O
O
NH
NH
OH Me
OH Me
Me
O
O
O
H
H
N
H
H
N
N
N
N
N
N
N
H
N
H
3
63.1
0.25
Me
O
S
S
S
Me
O
O
O
O
O
3c
4c
Me
O
O
NH
NH
OH Me
OH Me
O
O
Me
H
H
N
H
H
N
N
N
N
N
H
N
N
N
H
10.8
4
471
Me
O
O
O
O
O
O
Me
4d
3d
O
O
O
O
NH
NH
OH Me
OH Me
Me
H
H
N
H
H
N
N
N
N
5
147.7
N
H
N
N
N
H
28.9
Me
O
O
O
O
O
O
4e
3e
Me
O
NH
OH Me
O
O
H
H
N
N
6
7
8
201
N
N
N
H
in the S3 subsite of BACE1. Similarly, the (S)-methyl group occupies
a hydrophobic pocket surrounding Gly11, Ile110, Lys 107 and
Gln73. Preference for the (S)-configuration can be justified as the
alkyl group with (R)-configuration appears to bump into the P1-
leucine side chain, which may likely destabilize ligand binding site
interactions in the S3-pocket.
The P2 Boc-aminomethyl functionality appears to fit nicely in
the S2-subsite. As shown, the Boc-carbonyl oxygen can form a
hydrogen bond with the Gln73 side chain carboxamide. Also, the
Boc-NH and the urethane oxygen are well positioned to make a
water-mediated hydrogen bond with the backbone NH of Asn233
and the P3-ligand carbonyl oxygen. These interactions of the P2
and P3 ligands may be responsible for the observed selectivity of
inhibitor 4c over BACE2. The transition-state hydroxyl group of
inhibitor 4c forms a number of hydrogen bonds with the active site
aspartic acid residues Asp32 and Asp228. These interactions and
other inhibitor 4c-BACE1 interactions in the S10–S30 subsites are
similar to inhibitor 2.16
O
O
Me
O
NH
NH
3f
Me
Me
S
OH Me
Me
H
N
H
N
N
N
N
H
64.2
O
Me
O
O
3g
Me
O
O
S
Me
OH Me
Me
O
H
H
N
N
N
N
N
H
192.2
O
Me
O
O
NH
Me
3h
In summary, we have carried out structure-based design and
synthesis of novel P2–P3 ligands for BACE1 inhibitors containing
Leu-Ala hydroxyethylene isosteres. In particular, we have designed
pyrazole and thiazole-derived P3-ligands which contain hydrogen
bond donor and acceptor groups for specific interactions in the S3
subsite. We have developed a practical asymmetric synthesis of
Figure 2. As it appears, the P3-thiazole nitrogen is within proximity
to form a hydrogen bond with the Thr232 side chain hydroxyl
group. The P3-ligand carbonyl oxygen is also within hydrogen
bonding distance to the Thr232 backbone NH. The methyl group
on the thiazole ring seems to fill in the shallow hydrophobic pocket

672
A. K. Ghosh et al. / Bioorg. Med. Chem. Lett. 25 (2015) 668–672
Figure 2. Stereoview of the model of inhibitor 4c (green carbon chain) with b-secretase. Possible hydrogen bonds between the inhibitor and b-secretase are shown in black
dotted lines.
9. Cai, H.; Wang, Y.; McCarthy, D.; Wen, H.; Borchelt, D. R.; Price, D. L.; Wong, P. C.
Nat. Neurosci. 2001, 4, 233.
(1S,2R)-aminoindan-2-ol derivatives. We have also investigated
10. Ghosh, A. K.; Osswald, H. L. Chem. Soc. Rev. 2014, 43, 6765.
these heterocyclic ligands using readily available optically active
Boc-amino alanine and methylsulfonyl alanine as the P2-ligands.
The Boc-amino alanine ligand provided an inhibitor with enhanced
activity compared to inhibitors with a P2-methylsulfonyl deriva-
tive. Inhibitor 4c displayed excellent BACE1 inhibitory activity
and good selectivity over BACE2. Its cellular inhibitory potency in
neuroblastoma cells was in the micromolar range. An energy-min-
imized model of inhibitor 4c was created based upon the X-ray
structure of 2-bound b-secretase. This model has provided
important molecular insight into the ligand-binding site interac-
tions in the S2 and S3 subsites of b-secretase. Further design and
improvement of inhibitor properties are currently in progress.
11. Roberds, S. L.; Anderson, J.; Basi, G.; Bienkowski, M. J.; Branstetter, D. G.; Chen,
K. S.; Freedman, S. B.; Frigon, N. L.; Games, D.; Hu, K.; Johnson-Wood, K.;
Kappenman, K. E.; Kawabe, T. T.; Kola, I.; Kuehn, R.; Lee, M.; Liu, W.; Motter, R.;
Nichols, N. F.; Power, M.; Robertson, D. W.; Schenk, D.; Schoor, M.; Shopp, G.
M.; Shuck, M. E.; Sinha, S.; Svensson, K. A.; Tatsuno, G.; Tintrup, H.; Wijsman, J.;
Wright, S.; McConlogue, L. Hum. Mol. Genet. 2001, 10, 1317.
12. Fischer, F.; Molinari, M.; Bodendorf, U.; Paganetti, P. J. Neurochem. 2002, 80,
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13. Benes, P.; Vetvicka, V.; Fusek, M. Crit. Rev. Oncol. Hematol. 2008, 68, 12.
14. Ghosh, A. K.; Bilcer, G.; Harwood, C.; Kawahama, R.; Shin, D.; Hussain, K. A.;
Hong, L.; Loy, J. A.; Nguyen, C.; Koelsch, G.; Ermolieff, J.; Tang, J. J. Med. Chem.
2001, 44, 2865.
15. Ghosh, A. K.; Kumaragurubaran, N.; Hong, L.; Kulkarni, S. S.; Xu, X.; Chang, W.;
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16. Ghosh, A. K.; Kumaragurubaran, N.; Hong, L.; Lei, H.; Hussain, K. A.; Liu, C. F.;
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Acknowledgments
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Financial support by the National Institutes of Health and
Purdue University is gratefully acknowledged. Partial support by
the Walther Cancer Foundation (ADM) is also gratefully acknowl-
edged. J.T. held the J.G. Peuterbaugh Chair at the Oklahoma Medical
Research Foundation during the course of this work. We would
also like to thank Dr. Kalapala Venkateswara Rao (Purdue
University) and Ms. Heather Osswald (Purdue University) for
helpful discussions.
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