Spiro heterocycles as potential inhibitors of SIRT1: Pd/C-mediated synthesis of novel N-indolylmethyl spiroindoline-3,2′-quinazolines

Article abstract of DOI:10.1016/j.bmcl.2012.12.089

Novel N-indolylmethyl substituted spiroindoline-3,2′-quinazolines were designed as potential inhibitiors of SIRT1. These compounds were synthesized in good yields by using Pd/C-Cu mediated coupling-cyclization strategy as a key step involving the reaction of 1-(prop-2-ynyl)-1′H- spiro[indoline-3,2′-quinazoline]-2,4′(3′H)-dione with 2-iodoanilides. Some of the compounds synthesized have shown encouraging inhibition of Sir 2 protein (a yeast homologue of mammalian SIRT1) in vitro and three of them showed dose dependent inhibition of Sir 2. The docking results suggested that the benzene ring of 1,2,3,4-tetrahydroquinazolin ring system of these molecules occupied the deep hydrophobic pocket of the protein and one of the NH along with the sulfonyl group participated in strong H-bonding interaction with the amino acid residues.

Full text of DOI:10.1016/j.bmcl.2012.12.089

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1351–1357
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Spiro heterocycles as potential inhibitors of SIRT1: Pd/C-mediated
synthesis of novel N-indolylmethyl spiroindoline-3,20-quinazolines
D. Rambabu a, Guttikonda Raja b, B. Yogi Sreenivas a, G. P. K. Seerapu a, K. Lalith Kumar a,
Girdhar Singh Deora a, Devyani Haldar a, , M. V.Basaveswara Rao c, , Manojit Pal a,
⇑
⇑
⇑
a Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500 046, India
b Department of Chemistry, Acharya Nagarjuna University, Guntur 522 510, AP, India
c Department of Chemistry, Krishna University, Machilipatnam 521 001, AP, India
a r t i c l e i n f o
a b s t r a c t
Novel N-indolylmethyl substituted spiroindoline-3,20-quinazolines were designed as potential inhibitiors
of SIRT1. These compounds were synthesized in good yields by using Pd/C–Cu mediated coupling-
cyclization strategy as a key step involving the reaction of 1-(prop-2-ynyl)-10H-spiro[indoline-3,20-
quinazoline]-2,40(30H)-dione with 2-iodoanilides. Some of the compounds synthesized have shown
encouraging inhibition of Sir 2 protein (a yeast homologue of mammalian SIRT1) in vitro and three of
them showed dose dependent inhibition of Sir 2. The docking results suggested that the benzene ring
of 1,2,3,4-tetrahydroquinazolin ring system of these molecules occupied the deep hydrophobic pocket
of the protein and one of the NH along with the sulfonyl group participated in strong H-bonding
interaction with the amino acid residues.
Article history:
Received 6 October 2012
Revised 12 December 2012
Accepted 25 December 2012
Available online 5 January 2013
Keywords:
Quinazoline
Indole
SIRT1
Cancer
Ó 2012 Elsevier Ltd. All rights reserved.
Pd/C
Indoles being the most abundant N-heterocycle in drugs, phar-
maceuticals, natural products, and agrochemicals have attracted
enormous attention over the years.1 Indeed, the indole framework
is considered as one of the most privileged structures in the area of
medicinal chemistry and drug discovery. The spiro heterocycles on
the other hand have gained particular attention because of their
interesting pharmacological properties in addition to their natural
occurrences. These include spiroindole based bioactive natural
products, for example, horsfiline (A), spirotryprostatin A (B), coe-
rulescine (C), etc. (Fig. 1).2,3 Recently, due to their wide range of
pharmacological properties4–6 spiroquinazolines have attracted
considerable interest in medicinal and pharmaceutical chemistry.
Thus spiroindoline-3,20-quinazolines possessing a N-indolylmethyl
substituent appeared to be an interesting class of heterocycles and
development of appropriate synthetic methodologies is desirable
for accessing these novel compounds.
the standard cytotoxic agents.7b The Sirtuins (class III NAD-depen-
dent deacetylases that catalyze NAD+ dependent removal of acetyl
group to generate deacetylated proteins, nicotinamide, and O-acetyl-
ADP-ribose) function in diverse biological processes such as
transcriptional silencing, regulation of apoptosis by deacetylation
of p53, fatty acid metabolism, cell cycle regulation, and aging.8
The mammalian sirtuin family consists of seven members, for
example, SIRT1–7 and among the seven human sirtuins, SIRT1
has been studied well which has several substrates such as p53,
Ku70, NF-j
B, forkhead proteins, etc.9 Sirtuins are being considered
as important targets for cancer therapeutics as they are up-regu-
lated in many cancers. Inhibition of sirtuins allows re-expression
of silenced tumor suppressor genes, leading to reduced growth of
cancer cells. Several small molecule inhibitors of sirtuins, such as
nicotinamide, sirtinol, splitomicin, cambinol, tenovins, and the in-
dole derivative EX52710 have been shown to induce cell death in
cancer cells. However, no sirtuin inhibitors except EX527 (which
is presently undergoing Phase 1a clinical trial for the treatment
of Huntington’s disease) have progressed into clinical trials as anti-
cancer agents. While indole derivates, for example, EX527 have
been explored as inhibitors of sirtuins earlier the sirtuin inhibiting
properties of indoles containing spiro heterocycles has not been
examined. Moreover, structural manipulations of a generic spiroin-
dole D via E followed by incorporating some of the structural fea-
tures of EX527 lead to spiro heterocycles F (Fig. 2). Indeed, the
design and selection of 1,2,3,4-tetrahydroquinazolin ring as a part
In view of traumatic side effects of existing anticancer drugs
there is an urgent need for the development of more specific and
relatively non toxic drugs to address the major health problem of
cancer worldwide.7a Epigenetic therapeutics of cancer such as
inhibitors of DNA methyltransferases and histone deacetylases
(class I and class II) are already being used in combination with
⇑
Corresponding authors. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581 (M.P.).
E-mail address: manojitpal@rediffmail.com (M. Pal).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.12.089

1352
D. Rambabu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1351–1357
O
O
O
O
N
Me
O
NH
N
O
O
N
N
NH2
Me
N
+
N
H
N
Amberlyst-15
MeCN, rt
NH2
MeO
O
O
96%
O
4
5
1
N
H
N
H
N
MeO
H
Scheme 2. Preparation of 1-(prop-2-ynyl)-10H-spiro[indoline-3,20-quinazoline]-
2,40(30H)-dione (1).
C
B
A
Figure 1. Examples of spiro heterocycle based bioactive natural products.
quinazoline]-2,40(30H)-dione 1 with N-(2-iodophenyl)methanesul-
fonamide (2a) in the presence of 10% Pd/C (0.026 equiv), PPh3
(0.20 equiv), CuI (0.05 equiv), and triethylamine (3.0 equiv) in var-
ious solvents. The corresponding results are summarized in Table 1.
The reaction was initially carried out in ethanol for 3 h when the
desired product, that is, 1-((1-(methylsulfonyl)-1H-indol-2-yl)-
methyl)-10H-spiro[indoline-3,20-quinazoline]-2,40(30H)-dione (3a)
was isolated in 80% yield (Table 1, entry 1). The increase of reaction
time did not improve the product yield further (Table 1, entry 2).
The use of other solvents such as MeOH, MeCN, 1,4-dioxane and
DMF was examined and found to be less effective in terms of prod-
uct yields (Table 1, entries 3–6). Since best result was achieved by
using EtOH as a solvent hence all other studies were carried out
using EtOH.
Having established the optimum reaction conditions for the
preparation of 3a we then used this methodology for the prepara-
tion of our other target compounds related to 3a. Thus, a variety of
2-iodoanilides (2) were employed under the reaction conditions
presented in entry 1 of Table 1 and the results are summarized
in Table 2.
of spiro heterocycles was supported by the docking studies
(homology modeling) performed using a series of molecules based
on F with human SIRT1 (hSIRT1) (see later for a discussion). This
prompted us to synthesize and evaluate the SIRT1 inhibiting prop-
erties11 of F and herein we report our preliminary results of this
study, that is, N-indolylmethyl substituted spiroindoline-3,20-quin-
azolines as potential inhibitors of SIRT1.
A large number of methods1,12,13 have been reported for the
construction of indole ring many of which are mediated by transi-
tion metal catalysts particularly palladium catalysts. The use of
Pd/C–CuI–PPh3 as a less expensive catalyst system for efficient
synthesis of various heterocyclic structures14 including indoles15,16
has been explored earlier. The catalyst Pd/C is stable and easy to
handle as well as separable from the product. Moreover, the
catalyst can be recycled.14 In view of simplicity, advantages and
versatility of this methodology we decided to adopt a similar Pd/C
based coupling-cyclization strategy as a key step for the synthesis
of our target compounds F (or 3) as shown in Scheme 1.
Thus, the reaction of 1-(prop-2-ynyl)-10H-spiro[indoline-3,20-
quinazoline]-2,40(30H)-dione 1 with 2-iodoanilides (2) in the pres-
ence of 10% Pd/C, CuI, PPh3 and Et3N in EtOH at 70 °C afforded the
corresponding N-indolylmethyl substituted spiroindoline-3,
20-quinazolines (3) via a tandem coupling-cyclization process in
the same pot. The key starting material, that is, the terminal alkyne
1 required for our study, was prepared by reacting 2-aminobenz-
amide (4) with 1-(prop-2-ynyl)indoline-2,3-dione (5) under
ultrasound irradiation at room temperature (Scheme 2). All the
2-iodoanilides (2) were prepared according to the procedure
described in the literature.15b,17 Initially, we chose to examine
the coupling reaction of 1-(prop-2-ynyl)-10H-spiro[indoline-3,20-
As evident from Table 2 that the reaction proceeded well with
other 2-iodoanilides (Scheme 1 and Table 2). Various groups such
as Cl (3d, 3k), F (3b, 3i), Br (3c, 3j), Me (3f, 3m) and CF3 (3e, 3l)
were tolerated. All the indole derivatives (3a–n) synthesized were
characterized by spectral data.
All the synthesized compounds were tested for sirtuin inhibi-
tory potential in vitro by using a yeast cell based reporter silencing
assay as a model system for primary screening. Compounds were
tested at the concentration of 50 lM for their ability to inhibit
yeast sirtuin family NAD-dependent histone deacetylase (HDAC)
Sir 2 protein (a yeast homologue of mammalian SIRT1). Splitomi-
O
HN
O
Cl
HN
NH
O
NH
O
H2N
N
H
O
N
H
N
O
N
EX527
F
E
N
Z
D
X
Figure 2. Design of novel spiro heterocycles F from coerulescine (C) and the known inhibitor EX527.
R
O
O
I
R
O
NH
NH
10%Pd/C
PPh3,CuI
O
HN
S
HN
N
O
O
+
N
H
N
O
N
R1
Et3N, EtOH
70 oC, 3.0 h
75-80%
S
O
R1
2
1
3
R1= CH3, tolyl
Scheme 1. Pd/C-mediated synthesis of N-indolylmethyl substituted spiroindoline-3,20-quinazolines (3).

D. Rambabu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1351–1357
1353
Table 1
Effect of solvents on Pd/C-mediated reaction of 1-(prop-2-ynyl)-10H-spiro[indoline-3,20-quinazoline]-2,40(30H)-dione (1) with N-(2-iodophenyl)methanesulfonamidea (2a)
O
NH
O
O
NH
10%Pd/C
PPh3,CuI
O
I
HN
N
+
N
H
N
Ms
N
Ms
N
H
Et3N, EtOH
70 oC,
2a
1
3a
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
EtOH
EtOH
MeOH
MeCN
1,4-Dioxane
DMF
3
6
3
10
3
80
80
75
60
65
60
3
a
All the reactions were carried out by using 1 (1.0 equiv), 2a (1.5 equiv), 10% Pd/C (0.026 equiv), PPh3 (0.20 equiv), CuI (0.05 equiv), and Et3N (3 equiv) in EtOH at 70 °C
under a nitrogen atmosphere.
b
Isolated yields.
Table 2
Pd/C-mediated synthesis of N-indolylmethyl substituted spiroindoline-3,20-quinazolines (3) (Scheme 1)a
Entry
2-Iodoanilides (2)
Product (3)b
Yieldc (%)
I
O
Ms
NH
O
N
H
2a
HN
HN
1
80
N
N
Ms
3a
F
I
F
O
O
O
O
Ms
NH
N
H
O
2
3
4
5
78
75
80
2b
2c
2d
2e
N
Ms
N
3b
Br
Cl
I
Br
Cl
Ms
Ms
NH
N
H
O
HN
HN
HN
N
Ms
N
3c
I
NH
N
H
O
N
Ms
N
3d
F3C
I
CF3
Ms
NH
N
H
O
75
N
N
Ms
3e
(continued on next page)

1354
D. Rambabu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1351–1357
Table 2 (continued)
Entry
2-Iodoanilides (2)
Product (3)b
Yieldc (%)
H3C
I
CH3
O
Ms
NH
N
H
O
HN
6
80
2f
N
Ms
N
3f
H3CO
I
OCH3
O
Ms
NH
N
H
O
HN
HN
7
8
9
75
78
75
2g
N
Ms
N
3g
I
O
Ts
NH
O
N
H
N
Ts
2h
N
3h
F
I
F
O
Ts
NH
N
H
O
HN
2i
N
Ts
N
3i
Br
I
Br
O
O
O
Ts
NH
N
H
O
HN
HN
HN
10
11
12
80
75
80
2j
2k
2l
N
Ts
N
3j
Cl
I
Cl
Ts
NH
O
N
H
N
Ts
N
3k
F3C
I
CF3
Ts
NH
N
H
O
N
Ts
N
3l
H3C
I
CH3
O
Ts
NH
O
N
H
HN
13
75
2m
N
Ts
N
3m

D. Rambabu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1351–1357
1355
Table 2 (continued)
Entry
2-Iodoanilides (2)
Product (3)b
Yieldc (%)
H3CO
I
OCH3
O
Ts
NH
O
N
H
HN
14
78
2n
N
N
Ts
3n
a
All the reactions were carried out by using 1 (1.0 equiv), 2 (1.2 equiv), 10% Pd/C (0.026 equiv), PPh3 (0.20 equiv), CuI (0.05 equiv), and Et3N (3 equiv) in EtOH at 70 °C
under a nitrogen atmosphere.
b
Identified by 1H NMR, IR, HPLC and MS.
Isolated yields.
c
Table 3
Table 4
Yeast based in vitro bioassay of N-indolylmethyl substituted spiroindoline-3,20-
quinazolines (3)
Dose dependent % inhibition shown by compounds 3g, 3k and 3n
Concentration (
l
M)
% Inhibitiona
Entry
Compounds (3)
% Inhibition @ 50 l
Ma
3g
3k
3n
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
13.9
30.3
38.5
30.9
39.6
40.9
43.5
36.5
15.2
16.4
40.9
38.4
1.2
1
10
30
50
100
9
20
29
39
67
18
30
37
41
56
12
25
32
41
61
a
Data represent the mean values of three independent determinations.
URA3 was inserted in the silenced telomeric region where it is
silenced by yeast Sir 2 protein. Inhibition of Sir 2 protein by an
inhibitor would allow the URA3 gene to be expressed thereby
resulting in death of the yeast cell in presence of 5-FOA through
the formation of toxic 5-fluorouracil. The toxicity of test com-
pounds can also be tested by using this assay. For example, the
cells when grown in the absence of 5-FOA should grow if the com-
pound is not toxic whereas in case of toxic compound yeast cells
would die. Nevertheless, the results of our studies using the yeast
based in vitro bioassay are summarized in Table 3. It is evident that
a substituent at C-5 position of the N-mesyl indole ring of 3 played
a key role in Sir 2 inhibition. For example increased activities were
observed when this position was occupied by F, Br, Cl, CF3, Me or
OMe (Table 3, entries 1 vs 2–7). A slightly different trend was
observed in case of N-tosyl derivatives (Table 3, entries 8–14)
where a compound without C-5 substitution on the indole ring
42.4
a
Data represent the mean values of three independent determinations. Spli-
tomicin was used as a reference compound.18a
cin,18a a known inhibitor of sirtuin, was used as a reference com-
pound in this assay. Various N-indolylmethyl substituted spiroind-
oline-3,20-quinazolines (3) were tested for their ability to inhibit
Sir 2 protein by estimating inhibition of growth of yeast strain con-
taining URA3 gene at telomeric locus, in presence of 5-fluoroorotic
acid (5-FOA).18b In this assay a yeast strain (TEL::URA3 strain
(MAT
leu2-
a
D
ura3-52 lys2-801 ade2-101 trp
1 TEL adh4::URA) was used in which, a reporter gene
D63 his3D200 leu3D200
Figure 3. Inhibition of Sir 2 protein mediated transcriptional silencing at the telomeric locus in yeast by 3k, 3n and 3g. (A) The growth inhibition of yeast in presence of 3k, 3n
and 3g which is due to inhibition of HDAC activity of Sir 2 protein. (B) Representative % growth inhibitory activity of the compound 3k, 3n and 3g.

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D. Rambabu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1351–1357
Figure 6. Binding interaction (H-bonding) and docked pose of 3g at the hSIRT-1
catalytic site.
Figure 4. Binding interaction (H-bonding) and docked pose of 3k at the hSIRT-1
catalytic site.
ing studies were performed, using FRED v3.0 implemented from
OpenEye Scientific Software (for docking studies with Sir 2,
see Supplementary data). The multi-conformer database of the
inhibitors along with known inhibitor splitomicin19 was generated
by OMEGA v1.7.7.20 The complexes formed by inhibitors with
hSIRT-1 catalytic pocket are presented in Figures 4–6. The docking
scores (Chemgauss4 score) summarized in Table 5 indicate that
these molecules bind well with the hSIRT1 protein.21 The study
suggested that the benzene ring of 1,2,3,4-tetrahydroquinazolin
ring system of these molecules occupied the deep hydrophobic
pocket of the protein. The hydrogen of N1 atom of 1,2,3,4-tetrahy-
droquinazolin ring and sulfonyl group, in all three molecules par-
ticipated in strong H-bonding interaction with oxygen of the
backbone carbonyl group of VAL 412 and nitrogen of the backbone
amino group of GLY 415, respectively (Fig. 7). These backbone H-
bond interactions could be an important factor for stabilization
of these inhibitors in the catalytic pocket of hSIRT1.
In conclusion, a series of novel N-indolylmethyl substituted spi-
roindoline-3,20-quinazolines were designed as potential inhibitors
of SIRT1. These compounds were synthesized in good yields by
using Pd/C–Cu mediated coupling-cyclization strategy as a key
step involving the reaction of 1-(prop-2-ynyl)-10H-spiro[indoline-
3,20-quinazoline]-2,40(30H)-dione with 2-iodoanilides. Some of the
compounds synthesized have shown encouraging inhibition of Sir
2 protein (a yeast homologue of mammalian SIRT1) when tested
using yeast based in vitro bioassay. Three of them showed dose
dependent inhibition of Sir 2. The docking results suggested that
the benzene ring of 1,2,3,4-tetrahydroquinazolin ring system of
these molecules occupied the deep hydrophobic pocket of the pro-
tein and one of the NH along with the sulfonyl group participated
in strong H-bonding interaction with the amino acid residues.
These interactions contributed towards the stabilization of these
inhibitors in the catalytic pocket of hSIRT1. Overall, the synthetic
strategy described here could be useful in constructing library of
small molecules based on N-indolylmethyl substituted spiroindo-
line-3,20-quinazoline framework. Additionally, the spiro heterocy-
clic framework presented here could be an attractive template
for the identification of novel and potent inhibitors of SIRT1.
Figure 5. Binding interaction (H-bonding) and docked pose of 3n at the hSIRT-1
catalytic site.
showed significant inhibition, for example, 3h. Moreover, com-
pound having F or Br or Me at C-5 was found to be inferior to
3h, for example, 3i, 3j and 3m. It is evident from Table 3 that
among all the compounds tested 3g, 3k and 3n showed significant
inhibition in the presence of 5-FOA (Fig. 3). None of these com-
pounds showed significant toxic effect as can be seen from yeast
growth in the absence of 5-FOA (Fig. 3). A dose response study
was performed using these three compounds the results of which
are summarized in Table 4.
In order to understand the preferred binding orientation of 3g,
3k and 3n at the catalytic site of hSIRT1 (human SIRT1), the dock-

D. Rambabu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1351–1357
1357
Table 5
Docking scores obtained after docking compounds 3k, 3n and 3g into SIRT1 protein
Molecules
Dock scorea
Steric
Protein desolvation
Ligand desolvation H-bond
Clash
Ligand desolvation
Hydrogen bond
Splitomicin
ꢀ9.9
ꢀ7.6
ꢀ7.9
ꢀ7.3
ꢀ13.9
ꢀ17.4
ꢀ17.0
ꢀ17.6
ꢀ3.9
7.5
6.0
ꢀ0.1
ꢀ0.9
ꢀ0.8
ꢀ0.8
0.2
0.9
0.8
0.9
0.3
3.6
4.1
3.8
ꢀ0.3
ꢀ1.4
ꢀ1.1
ꢀ1.5
3k
3n
3g
7.76
a
FRED Chemgauss4 score.
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Figure 7. Binding mode and orientation of 3k, 3n and 3g in hSIRT-1 catalytic
pocket. Surface area colored in grey represents the hydrophobic property and blue
the hydrophilic property.
Acknowledgments
12. Krüger, K.; Tillack, A.; Beller, M. Adv. Synth. Catal. 2008, 350, 2153.
13. Ackermann, L. Synlett 2007, 507.
14. For a review, see: Pal, M. Synlett 2009, 2896.
The authors thank management of ILS for encouragement and
support. D.H. and M.P. thank DBT, New Delhi, India for financial
support (Grant No. BT/PR13997/Med/30/310/2010).
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.12.
089.
17. Xiao, W. J.; Alper, H. J. Org. Chem. 1999, 64, 9646.
18. Splitomicin has been reported to inhibit yeast Sir2 with an IC50 value of 60 lM
in vitro, see: (a) Bedalov, A.; Gatbonton, T.; Irvine, W. P.; Gottschling, D. E.;
Simon, J. A. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 15113; (b) Grozinger, C. M.;
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References and notes
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