Ligand/PTC-free intramolecular Heck reaction: Synthesis of pyrroloquinoxalines and their evaluation against PDE4/luciferase/oral cancer cell growth in vitro and zebrafish in vivo

Article abstract of DOI:10.1039/c3ob41504j

A series of 1,3-disubstituted pyrrolo[2,3-b]quinoxalines has been designed for the potential inhibition of PDE4 without inhibiting luciferase. A ligand/PTC (phase transfer catalyst) free intramolecular Heck cyclization strategy was used to prepare these compounds, some of which showed significant inhibition of PDE4B (IC₅₀ ≈ 5-14 μM) and growth inhibition of oral cancer cells (CAL 27) but not inhibition of luciferase in vitro. They also showed acceptable safety profiles but no apoptosis in zebrafish embryos.

Full text of DOI:10.1039/c3ob41504j

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Ligand/PTC-free intramolecular Heck reaction:
synthesis of pyrroloquinoxalines and their evaluation
against PDE4/luciferase/oral cancer cell growth in vitro
and zebrafish in vivo†
Cite this: Org. Biomol. Chem., 2013, 11,
6680
P. Vijaya Babu,a,b Soumita Mukherjee,a Girdhar Singh Deora,a
Keerthana Sarma Chennubhotla,a,c Raghavender Medisetti,a,c Swapna Yellanki,a,c
Pushkar Kulkarni,a,c Shivashankar Sripelly,a Kishore V. L. Parsa,a Kiranam Chatti,a
K. Mukkantib and Manojit Pal*a
Received 22nd July 2013,
Accepted 2nd August 2013
DOI: 10.1039/c3ob41504j
www.rsc.org/obc
A series of 1,3-disubstituted pyrrolo[2,3-b]quinoxalines has been
designed for the potential inhibition of PDE4 without inhibiting
luciferase. A ligand/PTC (phase transfer catalyst) free intramolecu-
lar Heck cyclization strategy was used to prepare these com-
pounds, some of which showed significant inhibition of PDE4B
(IC50 ≈ 5–14 μM) and growth inhibition of oral cancer cells (CAL
27) but not inhibition of luciferase in vitro. They also showed
acceptable safety profiles but no apoptosis in zebrafish embryos.
Fig. 1 Design of PDE4 inhibitor
inhibitor A.
B via modification of known luciferase
Phosphodiesterases (PDEs), a superfamily of enzymes that
degrade cyclic adenosine monophosphate (cAMP) and cyclic
guanosine monophosphate (cGMP), are classified into 11
families e.g. PDE1–PDE11.1 One of them, e.g. the cAMP-
specific enzyme PDE4 has been targeted to treat several
inflammatory diseases including COPD, asthma and CNS
related disorders. However, recent literature has indicated that
PDE4 is widely expressed in tumour cells and thus inhibition
of PDE4 in cancerous cells could be a new therapeutic target
for cancer. For example, PDE4 inhibitors have been reported to
inhibit brain tumor cell growth,2,3 reduce proliferation and
angiogenesis of lung cancer cell lines4 and display the ability
for selective apoptosis of malignant cells without affecting
normal cells.5 Thus, targeting PDE4 can be beneficial in treat-
ing cancer. Due to our long term interest in PDE4 inhibitors,6
we now report the design and synthesis of 1,3-disubstituted
pyrrolo[2,3-b]quinoxalines as new and potential inhibitors of
PDE4. To the best of our knowledge this class of heterocycles
has not previously been explored as PDE4/cancer cell growth
inhibitors.
Recently, we reported the luciferase inhibiting properties of
a series of 2-substituted pyrrolo[2,3-b]quinoxalines A (Fig. 1)
that were originally designed for potential inhibition of PDE4.7
These molecules were identified as false positive hits when
tested against PDE4B in vitro by using a luciferase reporter
gene assay and were found to interact with luciferase preferen-
tially over the enzyme PDE4B. A subsequent docking study
revealed that factors governing the binding of these molecules
into the luciferase pocket include (i) the linear shape of A
which helped them to fit effectively inside the luciferase
pocket and (ii) the free pyrrole nitrogen which formed strong
H-bonds with the surrounding amino acid residues inside the
pocket. Based on this and to prevent the inhibition of lucifer-
ase we decided to make two major structural modifications i.e.
(i) changing the linear shape of A by shifting the substituent
from C-2 to the N-1 of the pyrrolo[2,3-b]quinoxaline ring,
thereby blocking the H-bonding property of the NH and (ii)
introduction of a small group at C-3 to disrupt the linearity of
the molecule further. We anticipated that these changes might
help the newly designed molecules B (Fig. 1) derived from A to
inhibit PDE4 effectively but not luciferase. Our hypothesis was
aDr Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli,
Hyderabad 500046, India. E-mail: manojitpal@rediffmail.com;
Tel: +91 40 6657 1500
bChemistry Division, Institute of Science and Technology, JNT University, Kukatpally,
Hyderabad 500072, India
cZephase Therapeutics (an incubated company at the DRILS), University of
Hyderabad Campus, Gachibowli, Hyderabad 500046, India
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, spectral data for all new compounds, results of in vitro/in vivo and
docking study. See DOI: 10.1039/c3ob41504j
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Scheme 2 Synthesis of N-benzyl-3-chloroquinoxalin-2-amine derivatives.
Fig. 2 Binding of designed molecule B (R = Me, Ar = Ph) in PDE4B pocket.
further supported by the docking studies, which showed that B
(R = Me, Ar = Ph) interacted more strongly with the PDE4B
pocket (Fig. 2) (Glide score −8.0) than luciferase (Glide score
−3.3).
Among the various methods reported for the synthesis of
pyrroloquinoxalines, the Pd-catalysed pyrrole ring formation
on the pyrazine motif of the quinoxaline ring appeared to be
attractive. Thus, Pd8,9 or Pd/C-mediated10 coupling–cyclization
of N-alkyl or N-aryl-3-chloroquinoxalin-2-amine with terminal
alkynes has been used to afford 1,2-disubstituted pyrrolo[2,3-b]-
quinoxalines. The synthesis of 1,3-disubstituted analogues has
also been reported via intramolecular Heck coupling of allyl-3-
haloquinoxalin-2-ylamines under Jeffery’s “ligand-free” con-
ditions.11 However, this method was limited to the synthesis
of N-alkyl substituted pyrroloquinoxalines only and its appli-
cation towards N-aryl derivatives has not been explored. We
adopted a similar but suitably modified strategy to synthesize
our target compounds e.g. 1,3-disubstituted N-aryl/alkyl
pyrrolo[2,3-b]quinoxalines B. Our strategy was based on Pd-
catalyzed intramolecular Heck coupling of allyl-3-chloroqui-
noxalin-2-ylamines in the absence of any ligand or phase
transfer catalyst (vide infra, Table 2).
Scheme 3 Synthesis of N-allyl-3-chloroquinoxalin-2-amines (7 and 8).
Table 1 Effect of reaction conditions on Pd-mediated cyclisation of 7aa
Entry
Pd-catalysts
Base
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
10% Pd/C
10% Pd/C
Et3N
Et3N
DMF
DMF
DMF
DMF
1,4-Dioxane
DMF
DMF
1,4-Dioxane
DMF
DMF
2
2
2
2
5
5
6
6
5
6
88
65c
91
90c
66
32
30
0
K2CO3
K2CO3
K2CO3
Et3N
K2CO3
Et3N
The starting amines 4a–g and 5a–f were synthesized via the
reaction of 2,3-dichloroquinoxalines 1 or 2 with aromatic
amines 3 in the presence of AlCl3 (Scheme 1) whereas the
N-benzyl-3-chloroquinoxalin-2-amine derivatives 4h and 5g
were prepared by reacting 1 and 2 with benzyl amine 6
(Scheme 2).9a The amines 4a–h and 5a–g were then allylated to
Et3N
K2CO3
0
0
10
a Reactions were carried out by using 7a (1.0 mmol), Pd-catalyst
(0.015 mmol), XPhos (0.15 mmol) and a base (3.0 mmol) in a solvent
(10 mL) at 100 °C under nitrogen. b Isolated yields. c Reaction was
carried in the absence of XPhos.
give N-allyl substituted amines 7a–h and 8a–g (Scheme 3). The
cyclization of a representative compound 7a was initially
studied by varying the reaction conditions (Table 1). The reac-
tion was performed using Pd(OAc)2 and Et3N in DMF in the
presence of XPhos as a ligand at 100 °C. The reaction was com-
pleted within 2 h affording the desired pyrrolo[2,3-b]quin-
oxaline 9a in 88% yield (entry 1, Table 1). While the product
yield was decreased considerably in the absence of XPhos
(entry 2, Table 1), an improvement in the product yield (91%)
Scheme 1 Synthesis of N-aryl-3-chloroquinoxaline-2-amines (4a–g, 5a–f).
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Table 2 Synthesis of 1,3-disubstituted pyrrolo[2,3-b]quinoxalinesa
Fig. 3 Structure of compound 10b and its regioisomer 10b’.
Entry
Amines
Products; R2 =
Yieldb (%)
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7h
8a
8b
8c
8d
8e
8f
9a, R2 = Ph
82
90
85
81
85
92
90
80
89
90
80
85
84
90
91
9b, R2 = p-Me-C6H4
9c, R2 = p-OMe-C6H4
9d, R2 = p-F-C6H4
9e, R2 = p-Cl-C6H4
9f, R2 = p-Br-C6H4
9g, R2 = m-F-C6H4
9h, R2 = PhCH2
9
10a, R2 = Ph
10
11
12
13
14
15
10b, R2 = p-Me-C6H4
10c, R2 = p-OMe-C6H4
10d, R2 = p-F-C6H4
10e, R2 = p-Br-C6H4
10f, R2 = m-F-C6H4
10g, R2 = PhCH2
8g
a Reactions were carried out by using amines 7 or 8 (1.0 mmol),
Pd(OAc)2 (0.015 mmol), and K2CO3 (3.0 mmol) in DMF (10 mL) at
100 °C under nitrogen. b Isolated yields.
was noticed when an inorganic base e.g. K2CO3 was used in
place of Et3N irrespective of the presence or absence of XPhos
(entries 3 and 4, Table 1). A change of solvent from DMF to
1,4-dioxane decreased the yield significantly in spite of the
Scheme 4 Proposed mechanism for the ligand/PTC-free intramolecular Heck
cyclization of 7 or 8.
presence of XPhos (entry 5, Table 1). The use of other Pd-cata- one 3-bond correlation for the other carbon B [with Hi (8.15 δ,
lysts along with XPhos was also studied. Compound 9a was d, J = 8.4 Hz)] (Fig. 3, see also ESI†). An opposite HMBC result
obtained in poor yield when Pd(PPh3)4 was used in the pres- was expected for the regioisomer 10b′, hence 10b appeared to
ence of Et3N or K2CO3 in DMF (entries 6 and 7, Table 1) and be the structure of the isolated product. Based on an earlier
no product formation was noticed in 1,4-dioxane even after 6 h report12 we propose a Pd(II)–Pd(IV) catalytic cycle instead of a
(entry 8, Table 1). The use of 10% Pd/C in the presence of Et3N classical Pd(0)–Pd(II) cycle for the present ligand free intra-
or K2CO3 in DMF was also found to be unsuitable (entries 9 molecular Heck reaction (Scheme 4). Thus the reaction pro-
and 10, Table 1). Overall, the best result was obtained with ceeds via generation of a Pd(II) complex E-1 in situ which
Pd(OAc)2 as a catalyst, K2CO3 as a base and DMF as a solvent undergoes oxidative addition with the proximal C–Cl bond of
in the presence of XPhos. However, since the omission of the 3-chloroquinoxaline moiety generating the Pd(IV) species
ligand gave an almost similar yield of 9a, further reactions E-2. The elimination of acetate group in the presence of K2CO3
were performed under the conditions of entry 4 of Table 1.
generates E-3. Subsequent reductive elimination of a Pd(II)
The scope and generality of the present reaction was then species from E-3 facilitates C–C bond formation in an intramo-
studied using a variety of amines e.g. 7a–h and 8a–g under the lecular fashion leading to E-4. The exocyclic double bond of
optimised reaction conditions (Table 2). Both N-aryl and E-4 undergoes a facile isomerisation to afford the thermodyna-
N-alkyl substituted 3-chloroquinoxaline-2-amines participated mically more stable compound 9 or 10. The Pd(II) species
well affording the 1,3-disubstituted pyrrolo[2,3-b]quinoxalines regenerates the Pd(OAc)2 to complete the catalytic cycle.
9a–h and 10a–g. The formation of 9 or 10 was indicated by the
Among all the synthesized compounds, nine were studied
appearance of a singlet near 7.4–7.9 δ due to the C-2 proton for PDE4B inhibition using an enzyme based assay13 (Table 3).
(though this singlet was merged with other aromatic protons Most of them showed significant PDE4B inhibition (>60%), at
in some cases) and disappearance of the CH2 protons of 7 or 8 30 μM, except 9h. The other compounds i.e. 9b, 9c, 9f and 10b
near 4.1–4.7 δ in their corresponding 1HNMR spectra (see showed solubility related issues in the medium used for the
ESI†). A Heteronuclear Multiple Bond Correlation (HMBC) assay. The active compounds were also tested7 for luciferase
study performed by using compound 10b indicated two inhibition separately where none of them showed significant
3-bond correlations for the ring junction carbon A [with Hh inhibition (Table 3) with 10g showing the highest inhibition of
(7.91 δ, s) and He (7.52 δ, dd, J = 8.4, 1.2 Hz) separately] and ∼14%. In a dose response study, 9a and 9d (which displayed
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Table 3 Inhibition of PDE4B and luciferase by 9 and 10 at 30μM
% Luciferase
inhibition
% PDE4B
Glide
Entry
Compound
inhibitionb
S.D.
scorea
1
2
3
4
5
6
7
8
9
9a
9b
9c
9d
9f
9h
10a
10b
10g
8.44
—
—
7.89
—
4.86
12.87
—
76.12
ND
ND
70.06
ND
46.88
63.04
ND
2.23
—
—
3.47
—
2.49
3.10
—
−8.02
−8.03
—
—
14.24
60.87
2.58
—
a For PDE4B. b S.D.: standard deviation. ND: not determined.
Fig. 5 Orientation of 9d in the Q-pocket of the PDE4B enzyme.
Phe 446 and Tyr 233 along with an H-bond with Gln 443; the
pyrrole ring was involved in a π–π stacking interaction with
Phe 414) (Fig. 5) and weak interactions with luciferase (see ESI,
Fig. S4†). Thus the introduction of an aryl group on the pyrrole
nitrogen increased selectivity for PDE4B over luciferase.
Some of the active pyrrolo[2,3-b]quinoxalines were tested
against oral cancer cell lines e.g. CAL 27 in vitro at 10 μM using
the sulphorhodamine B (SRB) assay14 (gemcitabine15 as a
reference compound), where 9a, 9d and 10g showed 23–25%
growth inhibition after 72 h of treatment. However, none of
them showed any effects on normal HEK 293 T cells [Human
Fig. 4 Dose-dependent curve for 9a and 9d.
>70% inhibition of PDE4B) showed IC50 = 14.0 and 5.1 μM, Embryonic Kidney 293 cells] when tested at 10 μM. Notably,
respectively (Fig. 4) comparable to rolipram’s IC50 of ∼1.0 μM.
gemcitabine16 showed >50% growth inhibition of CAL 27 cells
Further, in silico studies of 9a and 9d were performed using at 10 μM. To assess the safety profile of this class of hetero-
PDE4B and luciferase. The three divisions or pockets of the cycle two representative compounds i.e. 9a and 10a were tested
PDE4B binding site include the M- or metal binding pocket, for toxicity in zebrafish embryos17 (Fig. 6) in the range
S- or solvent filled side pocket and Q- or core pocket i.e. the 1.0–30 μM. None of them showed toxic effects at these concen-
hydrophobic clamp. The docking studies indicated that both trations (Fig. 7) with No Observed Adverse Effect Level
9a and 9d are tightly bound in the Q-pocket of PDE4B. The (NOAEL) ≥ 30 μM. Both the compounds showed no to mild
nitrogen of the quinoxaline ring of 9a was involved in an hepatotoxicity when tested at 1–30 μM in the same model.
H-bond with the Gln 443 and two π–π stacking interactions Notably, none of these compounds was found to be positive
with Phe 446 and Phe 414, whereas the pyrrole ring was compared to methotrexate18 when tested for apoptotic activity
involved in a π–π stacking interaction with Tyr 233 (see ESI, (Fig. 8) indicating that they induce cancer cell death by non-
Fig. S1†). Notably, except for a few weak hydrophobic inter- apoptotic mechanisms such as necrosis, senescence, auto-
actions 9a did not show any strong interactions when docked phagy and mitotic catastrophe.19
into the luciferase (see ESI, Fig. S3†). Similarly, 9d showed
In conclusion, we have described a unique strategy to
strong binding with PDE4B (two π–π stacking interactions with develop PDE4 inhibitors devoid of luciferase inhibition via a
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Fig. 6 Control embryo showing normal body; embryo treated with phenobar-
bital (positive control) at 3 mM showing severe abnormalities, body bent; com-
pound 9a and 10a showing no and slight abnormalities respectively at 30 μM.
Fig. 8 Images of the embryos treated with 9a and methotrexate for apoptosis.
quinoxaline based PDE4 inhibitors may be of further interest
as potential agents against oral cancer.
PVB thanks CSIR, India for a Research Fellowship. SM
thanks CSIR, India for a Research Associateship.
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