Novel purine-based fluoroaryl-1,2,3-triazoles as neuroprotecting agents: Synthesis, neuronal cell culture investigations, and CDK5 docking studies

Article abstract of DOI:10.1016/j.bmcl.2011.05.019

A series of novel purine-based fluoroaryl triazoles were synthesized using the Cu(I) catalyzed 1,3-dipolar cycloaddition reactions (click reactions), and assayed for their neuroprotective effects using fluorescence electron microscopy. Among these triazoles, o-fluorophenylmetyl-triazole, 7, has comparable neuroprotective effect as that of Flavopiridol (1) and Roscovitine (2), the state of the art CDK inhibitors, against the Aβ induced neurotoxicity. These results are substantiated using computer docking methods (DarwinDock/GenDock), which predict that Roscovitine and the triazole 7 bind to the ATP-binding site of CDK5/p25 with comparable binding energies, whereas the corresponding pentafluorophenylmethyl-triazole, 9, has dramatically reduced binding energy (in accordance with its lack of neuroprotection). These combined experimental and theoretical studies support the involvement of CDK5/p25 in the neuronal cell cycle re-entry.

Full text of DOI:10.1016/j.bmcl.2011.05.019

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3957–3961
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel purine-based fluoroaryl-1,2,3-triazoles as neuroprotecting agents:
Synthesis, neuronal cell culture investigations, and CDK5 docking studies
Nanditha Nair a, Wataru Kudo b, Mark A. Smith b, Ravinder Abrol c, William A. Goddard III c,
V. Prakash Reddy a,
⇑
a Department of Chemistry, Missouri University of Science and Technology, Rolla, MO 65409, United States
b Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, United States
c Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA 91125, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel purine-based fluoroaryl triazoles were synthesized using the Cu(I) catalyzed 1,3-dipolar
cycloaddition reactions (click reactions), and assayed for their neuroprotective effects using fluorescence
electron microscopy. Among these triazoles, o-fluorophenylmetyl-triazole, 7, has comparable neuroprotec-
tive effect as that of Flavopiridol (1) and Roscovitine (2), the state of the art CDK inhibitors, against the Ab
induced neurotoxicity. These results are substantiated using computer docking methods (DarwinDock/
GenDock), which predict that Roscovitine and the triazole 7 bind to the ATP-binding site of CDK5/p25 with
comparable binding energies, whereas the corresponding pentafluorophenylmethyl-triazole, 9, has dra-
matically reduced binding energy (in accordance with its lack of neuroprotection). These combined exper-
imental and theoretical studies support the involvement of CDK5/p25 in the neuronal cell cycle re-entry.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 10 April 2011
Revised 5 May 2011
Accepted 6 May 2011
Available online 14 May 2011
Keywords:
CDK5
Docking methods
ATP
Roscovitine
Flavopiridol
Purine triazoles
Cell cycle inhibitors
Neuroprotectors
The concept of abnormal neuronal cell cycle re-entry is gaining
increasing attention as a major causative factor for Alzheimer’s dis-
ease (AD). Neuronal cell cycle dysregulation leading to neuronal
apoptosis is accompanied by a variety of cascades including kinase
upregulation and DNA replication.1,2 Cyclin dependent kinases
(CDKs) are the protein kinases that regulate cell cycles, among
which CDK5 plays a major role in the neuronal cell death due to
abnormal cell cycle re-entry.3–7 Overactivation of CDK5, mediated
by amyloid b (Ab), results in tau-hyperphosphorylation, decreased
levels of synaptic markers, and cell cycle reactivation leading to
substantial neuronal loss.6,8–12
CDK5 in association with its principal activation protein p35 is
involved in such functions as neuronal differentiation and migra-
tion to synaptic transmission. Intracellular oxidative stress leads
to a rise in Ca2+ levels that activate calpain resulting in the cleavage
of p35 to p25.13 Recent reports show the involvement of CDK5/p25
complex in the phosphorylation of retinoblastoma, an early event
in the neuronal cell death.14 Thus selective inhibitors of CDK5/
p25 over CDK5/p35 are currently targeted, although there seems
to be little success in this regard.15–18 A variety of CDK5 inhibitors
are currently under development as potential therapeutics in AD
and neuronal disorders. Structurally diverse compounds including
indole,19–22 imidazole,16 and purine23–25 derivatives have been
tested as CDK5 inhibitors. Among these compounds, Flavopiridol
(1) and Roscovitine (2) are currently undergoing clinical trials as
therapeutics in AD.26–29
CH3
Ph
NH
N
N
N
CH3
OH
N
OH
OH
O
O
N
N
H
Cl
H3C CH3
OH
1
2
Fluorinated compounds are a major focus of current pharma-
ceutical interest. Introduction of a fluorinated aryl group into phar-
maceuticals results in major improvement in their therapeutic
efficacy, presumably due to the hydrogen bonding interactions of
⇑
Corresponding author. Tel.: +1 573 341 4768.
E-mail address: preddy@mst.edu (V.P. Reddy).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.05.019

3958
N. Nair et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3957–3961
the fluorines at the enzyme active sites.30–32 Further, fluorinated
drugs have additional advantages such as their enhanced solubili-
ties, metabolic stabilities and bioavailability.33–35 We have rea-
soned that a fluoroaryl group distant from the nucleoside moiety,
through optimal hydrophobic interactions at the enzyme active
site, could impart selective CDK5 inhibitory effect, effectively caus-
ing neuronal cell cycle suppression. With that goal, we have syn-
(Scheme 1). As expected, the products show high 1,4-regioselectiv-
ity in these cycloadditions. Reaction of the commercially available
2,6-dichloropurine (3) with benzylamine gave 2-chloro-6-benzyl-
aminopurine (4) using a reported procedure.25 Under our condi-
tions, the reaction was complete in 15 min at 60 °C instead of the
reported time of 3 h at 110 °C.
Propargylation of compound 4 using propargyl bromide in DMSO
under mild conditions gave 2-chloro-6-benzylamino-9-(2-propy-
nyl) purine (5) regioselectively in high yield. The Cu(I) catalyzed
azide-alkyne click reaction38 of the alkyne 5 with fluorinated benzyl
azides, prepared in situ from their corresponding benzyl bromides,
gave triazoles, 7–9. The isomeric homogeneity of the product tria-
zoles is readily verified through their 19F NMR spectra (Fig. 1). The
pentafluorophenylmethyl-triazole, 9, shows relatively shielded
thesized
a series of fluorinated purine-based triazoles and
assayed their protective effect against Ab-induced neurotoxicity
in hippocampal slice cultures.
Selective inhibition of CDK5/p25 over CD5/p35 and other CDK
kinases is a desired goal for the treatment of AD and other neuro-
logical disorders. Roscovitine is currently undergoing clinical trials
as kinase inhibitor in AD, although it is not a selective inhibitor of
CDK5.36 Similarly, a flavone-derived compound, Flavopiridol (1)
has also been shown to be effective as a broad-spectrum CDK
inhibitor.37 Perhaps due to this nonspecificity to selective CDKs,
it is more cytotoxic and has other harmful effects. It is therefore
desirable to design selective CDK inhibitors that show neuropro-
tective effects, without attendant harmful side effects. We have
anticipated that modulating the hydrophobicity effect of the
compounds by attaching the fluoroaryl rings to the Roscovitine
analogues through 1,2,3-triazole linkage might make these com-
pounds selective inhibitors of CDKs, which would attenuate the
otherwise harmful effects of the Flavopiridol (1) and related
compounds.
d
19F absorptions as compared to the o-fluorophenylmethyl- and
the 2,6-difluorophenylmethyl-triazoles, 7 and 8 respectively, in
accordance with similar observations for the monofluoro-, di-
fluoro-, and pentafluoro-toluenes.42
Ab has been known to overactivate CDK5 which results in the
tau-hyperphosphorylation, and cell cycle re-entry, leading to neu-
ronal apoptosis.1,6,18,43 Thus, we have used Ab oligomers as the
trigger of neurotoxicity in vitro for convenient assay of the neuro-
protective effects of the kinase inhibitors.
Mouse hippocampal slice cultures were treated with Ab oligo-
mers in the presence of PI as the staining agent. The degree of hip-
pocampal neuronal death was monitored by fluorescence electron
microscopic observation of the PI uptake. The intensities of the
fluorescence were conveniently analyzed using Scion images. The
intensity of the PI fluorescence reflects the relative number of
the dead cells, since PI cannot permeate the live cell membranes.
As shown in Figure 2, there is visible difference in the control (in
the absence of Ab oligomers) and the Ab oligomers-treated cell cul-
tures. Typically 48 h is required for the expression of the Ab toxic-
ity. These experiments were repeated using the established cell
cycle inhibitors, Roscovitine (2), Flavopiridol (1), and the triazoles,
6, 7, 8, and 9.
As can be seen in Figure 3, after 48 h of incubation time, Rosco-
vitine (2), Flavopiridol (1) and the o-fluorophenylmethyl-triazole,
compound 7, have neuronal cell survival rates comparable to those
of the control experiments, that is, those corresponding to the cul-
tures in the absence of the Ab oligomers. Interestingly, the penta-
fluorophenylmethyl-triazole (9) has virtually no neuroprotective
effect, and the 2,6-difluorophenylmethyl-triazole (8) and the non-
fluorinated- analogue (6) have only marginal effects. Thus the de-
gree of fluorination has a dramatic effect on the neuroprotective
effects of these compounds, implying that these compounds may
We have adopted Sharpless–Huisgen’s Click chemistry38–40 as a
convenient technique for tethering fluorinated and variously
substituted aryl moieties to purine derived alkynes, and investi-
gated the neuroprotective effects of these fluoroaryl substituted
purine based 1,2,3-triazoles along with those of Flavopiridol (1)
and Roscovitine (2), the current state-of-the-art pharmaceuticals41
for AD and related neurological diseases.
In this study, we have used a convenient assay for neuronal cell
death, which was induced by incubation with Ab oligomers in hip-
pocampal slice cultures. The binding of propidium iodide (PI) with
DNA of dead cells gives characteristic fluorescence that could be
followed by fluorescence electron microscopy. Since PI is imperme-
able to live cell membranes, the observed fluorescence is indicative
of the extent of dead cell populations. Using this technique, we
have found that incubation of hippocampal neuronal cells with
Ab results in significant neuronal cell death after a duration of
48 h (Fig. 2).
The triazole, 6, and its fluorinated derivatives, compounds 7–9,
were prepared by the Cu(I) catalyzed 1,3-dipolar cycloaddition
reactions of the corresponding alkyne and azide substrates
HN
Cl
N
HN
N
N
N
N
N
N
a
b
c
N
N
N
Cl
N
H
N
H
Cl
Cl
3
4
5
HN
N
N
6; n=0
7; n=1; o-fluoro-
8; n=2; 2,6-difluoro-
9; n=5
Fn
N
N
N
N
N
Cl
Scheme 1. Synthesis of purine-based fluoroaryl triazoles. Reagents and conditions: abenzylamine/Et3N/n-BuOH, 60 °C/15 min, 95%; bpropargyl bromide/K2CO3/DMSO, 0 °C/
1 h, 80%; cfluorophenylmethyl bromide (or phenylmethyl bromide)/sodium azide/Cu(I)Br/Et3N/DMSO, rt/30 min, 80% (6), 85% (7), 84% (8), 89% (9).

N. Nair et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3957–3961
3959
Figure 1. 19F spectra of compounds 7, 8, and 9.
Figure 2. (A) Fluorescence electron microscopy images showing the time-dependent PI uptake in hippocampal slices exposed to 5
l
M Ab oligomers. (B) The PI uptake
responses were quantitatively analyzed and shown as graphs. Data were expressed as the means SE (n = 4). Differences between groups were examined for statistical
significance using one-way analysis of variance with an unpaired Students t-test; the p value for statistical significance was set at <0.05 (⁄: p <0.05).
serve as substrates for CDK5/p25 complex which is responsible for
the cell cycle re-entry, eventually leading neuronal cell death.
The neurotoxicity of Ab peptide may arise primarily due to its
overactivation of CDK5/p25 complex followed by cell cycle re-en-
try.1,6,18,43 Thus selective reversible enzyme inhibitors for CDK5/
p25 would be the ideal target for designing neuroprotective agents.
Goddard’s molecular docking methods, DarwinDock/GenDock, are
ideally suited in the design of these selective inhibitors.44,45 We
have shown the validity of these calculations for CDK5/p25 by
reproducing the Roscovitine/CDK5-p25 cocrystal structure46 from
protein data bank (PDB; 1UNL). We have located three potential
binding regions (A, B, and C; Figure 4) in CDK5/p25 and showed
that all high scoring poses preferred region A which is consistent
with the binding site observed in the co-crystal, 1UNL. In addition,
the binding pose is within 0.17 Å (heavy atom RMSD) of the pose
observed in the co-crystal structure (1UNL). The predicted

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N. Nair et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3957–3961
Figure 3. (A) Fluorescence electron microscopy images showing the relative PI uptake in hippocampal slices incubated with various compounds (1
lM; 1 h) followed by Ab
oligomers (5 M; 48 h). (B) The PI uptake responses were quantitatively analyzed and shown as graphs. Data were expressed as the means SE (n = 4). Differences between
l
groups were examined for statistical significance using one-way analysis of variance with an unpaired Students t-test; the p value for statistical significance was set at <0.05
(⁄: p <0.05; #: p <0.05, ##: p <0.01).
Figure 5. Expanded view of the Roscovitine (2)–CDK5/p25 complex showing the X-
ray structure (1UNL) superimposed on the DarwinDock/GenDock simulated
structure.
Figure 4. Potential Roscovitine (2) binding regions in CDK5/p25 obtained from
DarwinDock/GenDock simulations; region A is the highest scoring site in accor-
dance with co-crystal structure, 1UNL.
Docking of compounds 7 and 9 to the three potential ligand
binding regions predicts that these inhibitors also prefer region
A. The closeup view of the binding site for compound 7 is shown
in Figure 6. The later site overlaps the Roscovitine site but the
structure superimposed on the experimental co-crystal structure
(1UNL) is shown in Figure 5.

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3961
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Figure 6. Expanded view of the compound 7–CDK5/p25 complex, showing
hydrogen bonds to Lys89, Ile10, Asn144 and Gln130.
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H-bonding interactions with Asn144, Lys89, backbone carbonyl
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Supplementary data (computational methodology, neuronal
cytotoxicity studies, and synthesis of compounds) associated with
this article can be found, in the online version, at doi:10.1016/
j.bmcl.2011.05.019.