Pyridine C3-arylation of nicotinic acids accessible via a multicomponent reaction: an entry to all-substituted-3,4-diarylated pyridines

Article abstract of DOI:10.1039/c6ra28299g

An efficient route for the synthesis of penta-substituted/functionalized-3,4-diarylated pyridines, biologically important templates, via pyridine C3-arylation of nicotinic acids has been developed. The poly-substituted nicotinic acid precursors were prepared by an established multicomponent condensation approach. This route shows an excellent opportunity for introducing versatile (hetero)aryls and other substituents/functionalities into the pyridine ring. Several of the synthesized compounds exhibited significant anti-proliferative properties.

Full text of DOI:10.1039/c6ra28299g

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PAPER
Pyridine C3-arylation of nicotinic acids accessible
via a multicomponent reaction: an entry to all-
substituted-3,4-diarylated pyridines†
Cite this: RSC Adv., 2017, 7, 8323
a
a
b
b
Sankar K. Guchhait,* Neha Hura, Kanchan Sinha and Dulal Panda
An efficient route for the synthesis of penta-substituted/functionalized-3,4-diarylated pyridines,
biologically important templates, via pyridine C3-arylation of nicotinic acids has been developed. The
poly-substituted nicotinic acid precursors were prepared by an established multicomponent
condensation approach. This route shows an excellent opportunity for introducing versatile (hetero)aryls
and other substituents/functionalities into the pyridine ring. Several of the synthesized compounds
exhibited significant anti-proliferative properties.
Received 16th December 2016
Accepted 18th January 2017
DOI: 10.1039/c6ra28299g
www.rsc.org/advances
Diheteroarylpyridin-2-carboxamide derivative is a selective A2B
Introduction
6
adenosine receptor antagonist. 2-Amino-4,6-diarylpyridines have
7
Poly-substituted/functionalized pyridines are omnipresent in been found to be potent ligands for estrogen receptor. There are
natural products, bioactive compounds, and functional mate- numerous bioactive natural products that contain polyarylated
1
8
rials. In particular, aryl or poly-aryl substituted pyridine deriva- pyridines. Nosiheptide has 1,5,6-triarylated 3-hydroxypyridine
9
tives have attracted considerable synthesis attention because they and promothiocin A has 5,6-diarylated pyridine-1-carboxamide
are oen found as a valuable structural motif in a wide range of and both are potent antibiotics. 2,6-Diarylpyridine-carboxylic
10
pharmaceutically active compounds (Fig. 1). Etoricoxib that ester is useful as a uorescent chemosensor.
contains the 2,3-diarylpyridine motif is a COX-2 selective inhib-
In recent times, as a part of current momentum of exploring
2,3
itor. 2,4,6-Triarylated pyridine compounds exhibit topoisomer- new useful organic functional/bioactive materials, the synthesis of
4
ase inhibition (Fig. 1). Perampanel is a 1,3,5-triarylated pyridine compounds that possess not only important heterocyclic scaf-
5
derivative that acts as an AMPA-receptor antagonist. 5,6- fold(s) but also structurally resembles in whole molecular skeleton
to drugs/bioactive agents has become a valuable research area to
11
organic chemists. In this direction, late stage functionalization of
12
drugs has also attracted signicant attention. The incorporation
of trimethoxyphenyl moiety in target organic compounds is valu-
able, since it plays role as an important pharmacophoric motif in
13
exhibiting biological properties and is present in natural prod-
1
4
15
ucts. Keeping these aspects in mind, we were interested in the
synthesis of 3,4-diarylated pyridines which contain structural
features, 3,4,5-trimethoxyphenyl as an aryl motif, and resemblance
16
17
to a nifedipine drug and biologically important nicotinic acid.
Over the years, numerous synthetic strategies have been
developed to access poly-functionalized pyridines.
1
8,19
They
involve majorly a pyridine-forming step of appropriately func-
2
0
tionalized precursors or the sequential introduction of
Fig. 1 Selected bioactive agents containing the poly-arylated pyridine
structure.
21
substituents on the preformed pyridine ring. The rst strategy
is limited to accessibility of particularly-functionalized
precursor, while the later strategy includes mainly aromatic
a
22
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education substitutions, direct metallation, or metal halogen-exchange
and Research (NIPER), S. A. S. Nagar, Mohali-160062, India. E-mail: skguchhait@
23
reactions. Here we report a novel route for synthesis of all-
niper.ac.in; Fax: +91 172 2214692; Tel: +91 172 2214683
b
substituted/functionalized pyridines containing 3,4-diaryl
moieties via one-pot pyridine-3-arylation of nicotinic acid skel-
eton that is easily accessible by an established multicomponent
reaction approach.
Department of Biosciences and Bioengineering, Indian Institute of Technology
Bombay, Powai, Mumbai 400076, India
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c6ra28299g
1
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Results and discussion
At the outset, we investigated for preparation of nicotinic acid
precursor (5a) by a Hantzsch multicomponent condensation of
aryl aldehyde (1a), ethyl acetoacetate (2a) and ammonium
acetate to construct dihydropyridine (3a), its dehydrogenative Scheme
3
Optimized reaction condition for one-pot proto-
decarboxylation–bromination–Suzuki coupling.
aromatization to product 4a, and mono-hydrolysis of di-ester
(
Scheme 1). Hantzsch reaction by a reported method was
24
good yielding.
Dehydrogenative aromatization reactions
25
utilizing different conditions were performed (see ESI, Table developed a Pd-catalyzed C3-selective arylation of unsubstituted
28
1
†). Highest yield was obtained using Mn(OAc)
room temperature. Initially, the mono-hydrolysis of pyridine- substituted/functionalized pyridine 6a with bromo- or iodoto-
,5-diesters 4a was found to be difficult. Both the ester func- luene using Ye's conditions provided 3-arylated pyridine (8a) in
tionalities underwent simultaneously the hydrolysis. A survey of poor yields (8% and 10% yields, respectively). A Pd-catalyzed 3-
3
and AcOH at pyridine with bromoarenes. Carrying out C3-arylation of
3
29
various conditions revealed that 2 equiv. NaOH in 2 mL of arylation of pyridine with aryl tosylates was reported by Dai.
EtOH–H O (3 : 1) was most effective for promoting mono- This methodology did not promote the reaction of compound
2
hydrolysis to produce nicotinic acid 5a (see ESI, Table 2†).
6a with p-tolyl tosylate. We explored previously a Pd-catalyzed
Next, we investigated to explore decarboxylative arylation of regioselective C6–H arylation of 3-aminoimidazo[1,2-a]pyr-
nicotinic acid 5a, with the goal of nding a convenient method azine that underwent via concerted metalation–deprotonation
30
for synthesis of penta-substituted/functionalized pyridines process. This method promoted the C3–H arylation of pyri-
containing 3,4-diaryl moieties (Route A, Scheme 2). Several dine derivative 6a, but the method as well as the variation of its
26
methods of decarboxylative arylation known for other scaf- conditions could not improve the product's yield more than
folds were investigated for the reaction of compound 5a. The 20%. Majorly, the substrate remained intact. The poor conver-
desired product was obtained, but the yield more than 8% could sion and yields in the C3-arylation of pyridine 6a by reported
not be accomplished by the methods as well as variation in methods might be due to signicant steric hindrance by 4-aryl
27
reported conditions. We envisaged that protodecarboxylation,
moiety to inhibit the substrate to undergo the C3-palladation
and subsequent C3–H bond arylation could afford C3-arylated with arylpalladium complex. With aim of obtaining the C-3
pyridine (Route B, Scheme 2). The protodecarboxylation of
compound 5a underwent via Ag-carboxylate on treatment with
a
ꢀ
Table 1 Evaluation of reagents and conditions
AgOAc (1 equiv.), K CO (30 mol%) in DMA (anhyd.) at 140 C
2 3
for 12 h and the product 6a was obtained in 80% yield. Next, the
C3–H arylation reactions of compound 6a following the re-
ported pyridine-arylation methods were performed. Ye
b
Entry
Variable
Yield
Catalyst (10 mol%), Na
2
CO
Pd(PPh
Pd(dppf)Cl
Pd(PPh Cl
Pd(OAc) + PPh
Pd(PPh
3
(5 equiv.), TBAB (1 equiv.), DMA–H
2
O (1 : 1)
70
55
NR
NR
1
2
3
3 4
)
2
3
)
2
2
c
4
2
3
d
5
3
)
4
40
Pd(PPh
3
)
4
(10 mol%), base (5 equiv.), TBAB (1 equiv.), DMA–H
CO
Cs CO
PO
Na CO
2
O (1 : 1)
60
55
40
45
Scheme 1 Synthesis of nicotinic acid derivative 5a.
6
7
8
K
2
3
2
3
K
3
4
e
9
2
3
4 2 3
Pd(PPh3) (10 mol%), Na CO (5 equiv.), TBAB (1 equiv.), solvent
10
11
12
EtOH–H
DMA
EtOH
2
O (1 : 1)
60
55
45
f
a
ꢀ
Reagents and conditions: PhB(OH)
2
(1.5 equiv.), 100 C, Ar, 2 h;
b
0
.5 mmol scale. Yield for maximum conversion in optimum time.
c
d
e
PPh
3 3 4 2 3
(40 mol%). Pd(PPh ) (5 mol%). Na CO (2.5 equiv.).
f
ꢀ
Reaction temperature: 80 C.
Scheme 2 Strategies towards synthesis of polysubstituted 3,4-diary-
lated pyridines.
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arylated product, we then investigated for an alternate approach
involving protodecarboxylation, C3-bromination and Suzuki
31
coupling sequentially (Scheme 3). C3-Bromination of pyridine
a leading to product 7a was found to be nearly quantitative
95%). Therefore, we were interested to explore one-pot condi-
tions for bromination–Suzuki coupling. A Pd(OAc) -catalyzed
6
(
2
32
method reported by Liu for Suzuki reaction of N-heteroaryl
halides was followed in the one-pot reaction of pyridine 6a with
phenylboronic acid, however, the desired product was obtained
33
in 25% yield only. Christakakou's reaction conditions yielded
the product 8a in 40% yield only. Gratifyingly, one-pot bromi-
nation and Suzuki coupling of pyridine 6a with phenylboronic
3 4 2 3 2
acid using Pd(PPh ) catalyst, Na CO , TBAB in DMA–H O
provided 3,4-diaryl-pyridine 8a in 70% yield (Table 1, entry 1).
However, further variation in conditions did not improve yield
of the product. Incomplete conversion and inferior yield (15%)
were obtained for the reaction carried out in the presence of
open air, indicating requirement of non-aerobic conditions for
a,b a
Scheme 4 Substrate scope.
a (1 mmol), AgOAc (1 equiv.), K
2 h; then, NBS (1.1 equiv.), p-TsOH (0.1 equiv.), DMA–H
0 min; then, RB(OH) (1.5 equiv.), Pd(PPh (10 mol%), TBAB (1 equiv.),
Substrates, reagents and conditions:
5
1
3
2
CO
3
(30 mol%), DMA (anhyd., 2 mL),
O (1 : 1, 4 mL),
2
2
3 4
)
ꢀ
b
Pd(0)-catalysis. The reaction without TBAB resulted in reduced Na CO (5 equiv.), 140 C, 1–12 h; yield for maximum conversion in
2
3
optimum time.
yield (40%). Other palladium sources were evaluated (Table 1,
entries 2–4). Pd(PPh was found to be best. Reducing the Pd-
catalyst loading (entry 5) was not benecial. Among various
bases investigated, Na CO provided best result (entries 6–8).
3 4
)
2
3
Decreasing the equivalence of sodium carbonate below to 5
equiv. resulted in reduced yield (Table 1, entry 9). DMA or EtOH
was found effective solvent for bromination, however, they were
inferior for promoting the Suzuki coupling in one-pot. Among
various solvents and their mixture with water, DMA–H O was
2
found to be most effective for promoting bromination–arylation
in one-pot (entries 10–12).
Fig. 2 Reported diarylated pyridines with potent anticancer activity.
We then investigated protodecarboxylation of nicotinic acid
5
a, bromination and Suzuki coupling sequentially in one-pot.
Amazingly, it worked well in one-pot with overall yield of 55%
Scheme 3). The one-pot multi-reactions synthesis of a target
molecule is considered as a useful approach in synthetic
synthesized in the present work have potential of exhibiting
versatile bioactivities especially the antiproliferative properties.
We extended our developed method applicable to the
synthesis of 3,4-diarylated pyridines with relevant substitutions
that are present in CA-4 and the diarylated pyridines synthe-
sized and bio-evaluated by Simoni and Zhang.
(
34
organic chemistry. The present work illustrates an important
example of one-pot three-reaction process.
With the optimized procedure, we next investigated to
explore its substrate scope and synthesize various substituted
pyridines. We were pleased to nd that the method was found to
be exible in introducing into pyridine at C3 a variety of (hetero)
aryls (Scheme 4). Aryls containing electron-withdrawing or
donating functionalities were incorporated. The biologically
relevant (hetero)aryl motifs were also introduced easily at C3-
position of pyridine derivatives. In the established route, diffi-
culty for pyridine C3-arylation due to steric hindrance by pres-
ence of a multi-substituted aryl (3,4,5-trimethoxyphenyl) at C4-
position was circumvented.
Ethyl 5-(3-hydroxy-4-methoxyphenyl)-2,6-dimethyl-4-(3,4,5-
trimethoxyphenyl)nicotinate (8r) was prepared via an
approach (Scheme 5) involving C3-bromination of precursor 6a,
boronation of 7a with bispinacolatodiborane, and Suzuki
coupling with 5-bromo-2-methoxyphenol. This prompted us to
synthesize compound 8t with switch in aryl substitutions of
37
On survey of literature, we found that Simoni demonstrated an
attractive prole of cytotoxicity and apoptosis-inducing activity of
2
-(3,4,5-trimethoxyphenyl)-3-(3-hydroxy-4-methoxyphenyl)-pyri-
35
dine (compound A, Fig. 2). Zheng documented that 2-(3-
hydroxy-4-methoxyphenyl)-6-(3,4,5-trimethoxyphenyl)-pyridine
(
B) inhibited cell survival and growth, comparable to a clinical
36
agent, combretastatin A-4 (CA-4). These representative classes
of compounds reveal that 3,4-diarylated pyridine derivatives
Scheme 5 Synthesis of ethyl 5-(3-hydroxy-4-methoxyphenyl)-2,6-
dimethyl-4-(3,4,5-trimethoxyphenyl)nicotinate (8r).
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spectra were taken on a 400 MHz spectrometer. Data were re-
ported in sequence of chemical shis in ppm from tetrame-
thylsilane as an internal standard in CDCl /CD OD, integration,
3
3
multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m
¼
¼
multiplet, dt ¼ doublet of triplet, dd ¼ doublet of doublet, br
13
broad), and coupling constants (Hz). C NMR spectra were
recorded on a 100 MHz spectrometer with protons-decoupling.
High-resolution mass spectra (HRMS) were recorded on a high-
resolution LCMS/MS instrument with “QTOF” mass analyzer.
Scheme 6 Synthesis of ethyl 4-(3-hydroxy-4-methoxyphenyl)-2,6- Thin-layer chromatography (TLC) analysis was done using
dimethyl-5-(3,4,5-trimethoxyphenyl)nicotinate (8t).
commercially received pre-coated TLC plates (silica gel 60
GF434, 0.43 mm). Column chromatography silica gel 100–200
compound 8r. We began the preparation of compound 8t via (silica gel 100–200 mesh, neutral, spherical) was used for puri-
similar strategy, utilizing 5-(ethoxycarbonyl)-4-(3-hydroxy-4- cation of products. The starting materials and solvents were
methoxyphenyl)-2,6-dimethylnicotinic acid as the precursor, used as received from commercial sources without further
but bromination did not take place. We anticipated that purication.
bromination was problematic due to presence of free hydroxyl
Representative experimental procedure for the synthesis of
group in the precursor. So, benzylation of the hydroxyl group diethyl
was done to circumvent this problem, and we carried out the pyridine-3,5-dicarboxylate (Scheme 1, 3a). 3,4,5-Trimethoxy-
synthesis of compound 8t utilizing benzyloxy-aryl derivative of benzaldehyde 1a (1 mmol, 196 mg), ethyl acetoacetate 2a
2,6-dimethyl-4-(3,4,5-trimethoxyphenyl)-1,4-dihydro-
24
nicotinic acid (5b). One-pot protodecarboxylation–bromina- (2 mmol, 260 mg, 2 eq.), NH OAc (2 mmol, 154 mg, 2 eq.), and
4
tion–Suzuki coupling was done to afford compound 8s, which PhB(OH) (0.1 mmol, 12 mg, 0.1 eq.) were taken in a round
2
on debenzylation resulted in compound 8t (Scheme 6).
bottom ask and reuxed in EtOH (2 mL) for 5 h. The reaction
A set of signicantly varied 3,4-diarylated pyridine derivatives mixture was poured into ice cold H O. It was then extracted with
2
(
8a–8t) were prepared in the developed approach. Purity (HPLC) EtOAc (2 ꢁ 10 mL). The organic solution was washed with brine,
of all the compounds were found to be >95%. Next anti- dried over Na SO , and concentrated under vacuum. The crude
2
4
proliferative activity was tested. All compounds were screened for product was puried by recrystallization from EtOH, which
inhibition of cell proliferation in HeLa cells as a representative provided 1,4-dihydropyridine 3a in 70% yield.
cancer cell line at 5 mM concentration (see ESI, Table 3†). Several
Representative experimental procedure for the synthesis of
%
of them were found to exhibit considerable antiproliferative diethyl
activity. Four most potent compounds (pyridines 8b, 8f, 8j, 8p) dicarboxylate (Scheme 1, 4a).
2,6-dimethyl-4-(3,4,5-trimethoxyphenyl)pyridine-3,5-
25a
Diethyl 1,4-dihydro-2,6-
were further evaluated for in vitro tubulin polymerization inhi- dimethyl-4-(3,4,5-trimethoxyphenyl)pyridine-3,5-dicarboxylate
bition (see ESI, Fig. 1†). The non-activity revealed that the anti- (3a) (1 mmol, 253 mg), manganese triacetate (2 mmol, 536 mg, 2
tubulin may not be the pathway for exhibiting cytotoxicity.
eq.) and acetic acid (5 mL) were taken in a round bottom ask.
The reaction mixture was stirred at room temperature till the
completion of reaction. Manganese diacetate was ltered
through celite bed and the mixture was poured into ice-cold
Conclusions
In conclusion, we have developed an efficient route for synthesis of water. Ice-cold aqueous NaHCO solution was added dropwise
3
all-substituted/functionalized pyridines containing 3,4-diaryl to neutralize the mixture. It was then extracted with dichloro-
moieties. It involves the preparation of nicotinic acids via multi- methane (2 ꢁ 10 mL) and dried over anhydrous sodium sulfate.
component condensation and their pyridine C3-arylation via one- The solution was concentrated under reduced pressure. The
pot protodecarboxylation–bromination–Suzuki coupling. A wide resulting crude mixture on crystallisation from ethanol
range of (hetero)aryls, including especially the biologically provided pure product 4a in 90% yield.
important aryl-motifs can be easily introduced in this route. The
Representative experimental procedure for the synthesis of
structural features of the products, structural resemblance to 2,6-dimethyl-5-(ethoxycarbonyl)-4-(3,4,5-trimethoxyphenyl)nico-
pharmacologically important agent as well as drug and the pres- tinic acid (Scheme 1, 5a). Aqueous solution of KOH (2 mmol,
ence of a biologically important motif 3,4,5-trimethoxyphenyl as 112 mg, 2 eq.) in 0.5 mL water was added to a solution of
one aryl ring, indicate that these functionalized 3,4-diarylpyridines compound 4a (1 mmol, 417 mg) in ethanol (1.5 mL). The
ꢀ
have potential application in nding of versatile bioactive agents. mixture was reuxed (80 C) till completion of the reaction as
Several of the synthesized compounds were found to exhibit indicated by TLC (7 h). The solvent was evaporated and the
signicant anti-proliferative activity.
crude mass obtained was redissolved in methanol. It was then
neutralised to pH 7 with dropwise addition of ice-cold meth-
anolic HCl. The organic solution was concentrated under
reduced pressure. The column chromatographic purication of
crude mass on silica gel eluting with MeOH–EtOAc (1 : 9)
Experimental
Chemistry
General information. ATR & IR (KBr) Microscope spectrom- provided the product 5a in 67% yield.
1
eter was used to record Infrared (IR (KBr)) spectra. H NMR
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Representative experimental procedure for synthesis of 2,6- 1H), 6.42 (s, 1H), 4.15–4.12 (m, 2H), 3.95 (s, 3H), 3.84 (s, 3H),
dimethyl-3-(ethoxycarbonyl)-5-phenyl-4-(3,4,5-trimethoxyphenyl)- 3.59 (s, 3H), 2.57 (s, 3H), 2.26 (s, 3H), 1.03 (t, J ¼ 7.1 Hz,
1
3
1
pyridine (Scheme 4, entry 1) (8a). Monoacid 5a (1 mmol, 389 3H) ppm; C{ H} NMR (100 MHz, CDCl ): d 168.9, 157.5, 155.1,
3
mg), AgOAc (1 mmol, 167 mg, 1 eq.) and K
1.5 mg, 0.3 eq.) were taken under nitrogen in an oven-dried 126.8, 126.3, 122.7, 108.3, 61.2, 61.1, 60.9, 56.1, 24.2, 23.0,
2 3
CO
(0.30 mmol, 152.3, 151.7, 148.4, 142.3, 135.7, 133.6, 130.6, 127.9, 127.6,
4
sealed tube equipped with a rubber septum and magnetic bar. 13.7 ppm; IR (KBr): nmax 2978, 2935, 2850, 1726, 1586, 1485,
ꢂ1
+
DMA (anhyd., 2 mL) was added under nitrogen. The tube was 1264, 1096 cm ; HRMS (ESI) m/z: calcd for C25
H28NO
5
[M + H]
ꢀ
then sealed. The mixture was stirred at 140 C. Upon comple- 422.1967, found: 422.1958.
tion of reaction as indicated by TLC (12 h), N-bromosuccinimide
(
2,6-Dimethyl-3-(ethoxycarbonyl)-5-(p-tolyl)-4-(3,4,5-trimethoxy-
1.1 mmol, 196 mg, 1.1 equiv.), p-TsOH (0.1 mmol, 17 mg, 0.1 phenyl)pyridine (8b). White solid; 252 mg, 58%; mp 123 C; H
ꢀ
1
eq.) and water (2 mL) were added in the reaction tube. Aer NMR (400 MHz, CDCl
completion of the bromination reaction aer 30 min, sodium 7.7 Hz, 2H), 6.54 (s, 1H), 6.44 (s, 1H), 4.15–4.09 (m, 2H), 3.94 (s,
): d 7.07 (d, J ¼ 7.1 Hz, 2H), 7.00 (d, J ¼
3
carbonate (5 mmol, 530 mg, 5 eq.), tetrabutyl ammonium 3H), 3.84 (s, 3H), 3.60 (s, 3H), 2.57 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H)
1
3
1
bromide (1 mmol, 322 mg, 1 eq.), phenylboronic acid 1.02 (t, J ¼ 7.1 Hz, 3H) ppm; C{ H} NMR (100 MHz, CDCl
3
):
(
1.5 mmol, 182 mg, 1.5 eq.) and Pd(PPh ) (0.1 mmol, 115 mg, d 168.9, 157.5, 155.1, 152.1, 151.8, 148.6, 142.2, 136.3, 133.7, 132.6,
3
4
0
.1 eq.) were added to the reaction tube under nitrogen. The 130.5, 128.4, 127.8, 126.3, 122.8, 108.2, 61.1, 61.0, 60.9, 56.1, 24.2,
ꢀ
tube was then sealed. The mixture was stirred at 140 C till the 23.1, 21.2, 13.7 ppm; IR (KBr): nmax 2925, 2854, 1724, 1587, 1488,
ꢂ1
+
completion of reaction monitored by TLC (2 h). Then, resultant 1263, 1087 cm ; HRMS (ESI) m/z: calcd for C26
H
30NO
[M + H]
5
mixture was allowed to cool to room temperature, diluted with 436.2124, found: 436.2124.
ethyl acetate (20 mL). The organic layer was washed with
aqueous solution of ammonia (3 ꢁ 5 mL) and brine (5 mL), trimethoxyphenyl)pyridine (8c). White solid; 271 mg, 60%; mp >
2,6-Dimethyl-3-(ethoxycarbonyl)-5-(4-methoxyphenyl)-4-(3,4,5-
ꢀ
1
dried over Na SO and the organic layer was concentrated under 200 C; H NMR (400 MHz, CDCl
3
): d 7.12 (d, J ¼ 7.8 Hz, 2H),
2
4
reduced pressure. The column chromatographic purication of 6.75 (d, J ¼ 8.4 Hz, 2H), 6.53 (s, 1H), 6.44 (s, 1H), 4.15–4.09 (m,
crude mass on silica gel eluting with EtOAc–hexane (1 : 3) 2H), 3.94 (s, 3H), 3.84 (s, 3H), 3.77 (s, 3H), 3.58 (s, 3H), 2.58 (s,
1
3
1
provided
trimethoxyphenyl)pyridine 8a in 55% overall yield.
Products (8b–8t) were also prepared following this repre- 142.3, 133.7, 131.7, 127.9, 127.4, 126.4, 122.7, 113.1, 108.2, 61.2,
2,6-dimethyl-3-(ethoxycarbonyl)-5-phenyl-4-(3,4,5- 3H), 2.30 (s, 3H), 1.02 (t, J ¼ 7.1 Hz, 3H) ppm; C{ H} NMR (100
MHz, CDCl ): d 168.9, 158.3, 157.6, 155.1, 152.1, 151.8, 148.7,
3
sentative procedure.
61.1, 60.9, 56.1, 55.1, 24.3, 23.1, 13.7 ppm; IR (KBr): nmax 2930,
Diethyl 2,6-dimethyl-4-(3,4,5-trimethoxyphenyl)-1,4-dihydro- 2850, 1725, 1586, 1488, 1262, 1245, 1096 cm ; HRMS (ESI) m/z:
ꢂ1
38
+
pyridine-3,5-dicarboxylate (3a). Yellow solid; 293 mg, 70%; mp calcd for C26
H
30NO
6
[M + H] 452.2073, found: 452.2068.
2,6-Dimethyl-3-(ethoxycarbonyl)-5-(3-methoxyphenyl)-4-(3,4,5-
.98 (s, 1H), 4.17–4.08 (m, 4H), 3.79 (s, 9H), 2.34 (s, 6H), 1.25 (t, J trimethoxyphenyl)pyridine (8d). White solid; 248 mg, 55%; mp
ꢀ
40 C; H NMR (400 MHz, CDCl ): d 6.52 (s, 2H), 5.77 (s, 1 NH),
3
1
1
4
1
3
1
ꢀ
1
¼
7.1 Hz, 6H) ppm; C{ H} NMR (100 MHz, CDCl
3
): d 167.7, 116 C; H NMR (400 MHz, CDCl
52.6, 143.9, 143.4, 105.0, 103.9, 60.8, 59.8, 55.9, 19.6, 14.4 ppm; 7.7 Hz, 1H), 6.84–6.78 (m, 2H), 6.74–6.71 (m, 1H), 6.55 (s, 1H),
3
): d 7.13 (dd, J ¼ 7.8 Hz, J ¼
1
ꢂ1
IR (KBr): nmax 3354, 2987, 1650, 1232, 1123, 1006 cm
.
6.46 (s, 1H), 4.15–4.12 (m, 2H), 3.95 (s, 3H), 3.84 (s, 3H), 3.65 (s,
Diethyl 2,6-dimethyl-4-(3,4,5-trimethoxyphenyl)pyridine-3,5- 3H), 3.63 (s, 3H), 2.57 (s, 3H), 2.29 (s, 3H), 1.03 (t, J ¼ 7.1 Hz,
ꢀ
1
13
1
3
dicarboxylate (4a). White solid; 375 mg, 90%; mp 130 C; H 3H) ppm; C{ H} NMR (100 MHz, CDCl ): d 168.9, 158.9, 157.6,
NMR (400 MHz, CDCl ): d 6.51 (s, 2H), 4.08 (q, J ¼ 7.1 Hz, 4H), 3.86 154.9, 152.3, 151.7, 148.5, 142.3, 137.0, 133.5, 128.5, 127.7, 126.3,
3
13
(
{
1
2
s, 3H), 3.83 (s, 6H), 2.60 (s, 6H), 0.99 (t, J ¼ 7.1 Hz, 6H) ppm;
C
123.3, 122.6, 115.9, 112.9, 108.2, 61.2, 61.1, 61.0, 56.1, 55.1, 24.2,
1
H} NMR (100 MHz, CDCl ): d 168.0, 155.4, 152.9, 145.7, 138.1, 22.9, 13.8 ppm; IR (KBr): nmax 2927, 2852, 1724, 1586, 1462, 1274,
3
ꢂ1
+
31.9, 126.8, 105.5, 61.5, 60.9, 56.2, 22.8, 13.7 ppm; IR (KBr): nmax 1259, 1088 cm ; HRMS (ESI) m/z: calcd for C26
987, 1719, 1585, 1232, 1123, 1006 cm ; HRMS (ESI) m/z: calcd 452.2073, found: 452.2068.
H
30NO
6
[M + H]
ꢂ1
+
for C22
H28NO
7
[M + H] 418.1866, found: 418.1858.
5-(3,4-Dimethoxyphenyl)-2,6-dimethyl-3-(ethoxycarbonyl)-
2
,6-Dimethyl-5-(ethoxycarbonyl)-4-(3,4,5-trimethoxyphenyl)
4-(3,4,5-trimethoxyphenyl)pyridine (8e). Pale yellow solid;
nicotinic acid (5a). Off white solid; 260 mg, 67%; mp charred at 313 mg, 65%; mp 135 C; H NMR (400 MHz, CDCl ): d 6.84–
3
ꢀ
1
ꢀ
1
2
4
2
25 C; H NMR (400 MHz, CDCl ): d 7.03 (s, 1H), 6.58 (s, 2H), 6.79 (m, 2H), 6.74 (d, J ¼ 8.2 Hz, 1H), 6.55 (s, 1H), 6.46 (s, 1H),
3
.14 (q, J ¼ 7.2 Hz, 2H), 3.88 (s, 3H), 3.87 (s, 6H), 2.60 (s, 3H), 4.18–4.11 (m, 2H), 3.95 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.67
1
3
1
.59 (s, 3H), 1.06 (t, J ¼ 7.2 Hz, 3H) ppm; C{ H} NMR (100 (s, 3H), 3.62 (s, 3H), 2.56 (s, 3H), 2.29 (s, 3H), 1.05 (t, J ¼
13 1
MHz, CDCl
3
3
): d 169.2, 158.7, 155.0, 153.3, 148.2, 138.2, 134.3, 7.1 Hz, 3H) ppm; C{ H} NMR (100 MHz, CDCl ): d 168.9,
1
(
25.8, 120.8, 105.1, 61.4, 60.9, 56.2, 24.5, 22.8, 13.8 ppm; IR 157.7, 154.8, 152.1, 151.8, 148.7, 147.9, 147.7, 142.3, 133.6,
ꢂ1
KBr): nmax 3423, 2970, 1718, 1582, 1249, 1122, 1010 cm
;
128.2, 127.5, 126.4, 123.1, 122.5, 114.1, 110.3, 108.3, 61.2,
+
HRMS (ESI) m/z: calcd for C20
90.1547.
,6-Dimethyl-3-(ethoxycarbonyl)-5-phenyl-4-(3,4,5-
trimethoxyphenyl)pyridine (8a). White solid; 232 mg, 55%; mp
H24NO
7
[M + H] 390.1553, found: 61.1, 60.9, 56.1, 55.7, 24.3, 22.9, 13.8 ppm; IR (KBr): nmax 2924,
ꢂ1
3
2853, 1726, 1586, 1463, 1248, 1086 cm ; HRMS (ESI) m/z:
+
2
calcd for C26
H
32NO
7
[M + H] 482.2179, found: 482.2181.
5-(Benzo[d][1,3]dioxol-5-yl)-2,6-dimethyl-3-(ethoxycarbonyl)-
20 C; H NMR (400 MHz, CDCl ): d 7.20–7.19 (m, 5H), 6.56 (s, 4-(3,4,5-trimethoxyphenyl)pyridine (8f). White solid; 293 mg,
ꢀ
1
1
3
ꢀ
1
6
3%; mp 115 C; H NMR (400 MHz, CDCl ): d 6.73–6.67 (m,
3
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3
3
1
H), 6.52 (s, 1H), 6.49 (s, 1H), 5.92 (s, 2H), 4.16–4.09 (m, 2H),
2,6-Dimethyl-3-(ethoxycarbonyl)-5-(4-(triuoromethoxy)phenyl)-
.94 (s, 3H), 3.83 (s, 3H), 3.63 (s, 3H), 2.58 (s, 3H), 2.34 (s, 3H), 4-(3,4,5-trimethoxyphenyl)pyridine (8k). White solid; 227 mg, 45%;
1
3
1
ꢀ
1
.02 (t, J ¼ 7.1 Hz, 3H) ppm; C{ H} NMR (100 MHz, CDCl ): mp 130 C; H NMR (400 MHz, CDCl ): d 7.24 (d, J ¼ 7.6 Hz, 2H),
3
3
d 168.8, 157.6, 155.3, 152.2, 151.8, 148.6, 146.9, 146.3, 142.2, 7.06 (d, J ¼ 8.1 Hz, 2H), 6.57 (s, 1H), 6.36 (s, 1H), 4.16–4.11 (m, 2H),
1
1
2
33.7, 129.4, 127.3, 126.3, 124.3, 122.5, 111.1, 108.1, 107.7, 3.95 (s, 3H), 3.85 (s, 3H), 3.62 (s, 3H), 2.58 (s, 3H), 2.27 (s, 3H), 1.03
13
1
00.8, 61.2, 61.1, 60.9, 56.1, 24.3, 23.1, 13.7 ppm; IR (KBr): nmax (t, J ¼ 7.1 Hz, 3H) ppm; C{ H} NMR (100 MHz, CDCl ): d 168.7,
3
925, 2851, 1723, 1586, 1481, 1455, 1262, 1233, 1123, 1081 157.8, 155.3, 152.6, 151.6, 148.0, 142.3, 134.5, 133.6, 132.1, 126.4,
ꢂ1
+
cm ; HRMS (ESI) m/z: calcd for C26
found: 466.1866.
H
28NO
7
[M + H] 466.1866, 126.3, 122.5, 120.4 (q, JC–F ¼ 255 Hz), 120.1, 108.3, 61.2, 61.1, 60.9,
56.1, 24.1, 23.1, 13.8 ppm; IR (KBr): n
max
2935, 2850, 1725, 1586,
ꢂ1
2
,6-Dimethyl-3-(ethoxycarbonyl)-4,5-bis(3,4,5-trimethoxyphenyl)- 1484, 1251, 1161, 1082, 1005 cm ; HRMS (ESI) m/z: calcd for
1
+
pyridine (8g). Yellow semisolid; 332 mg, 65%; H NMR (400 MHz, C H F NO [M + H] 506.1790, found: 506.1787.
2
6
27
3
6
CDCl ): d 6.57 (s, 1H), 6.51 (s, 2H), 6.47 (s, 1H), 4.18–4.12 (m, 2H),
2,6-Dimethyl-3-(ethoxycarbonyl)-5-(4-(triuoromethyl)phenyl)-
.95 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.68 (s, 9H), 2.56 (s, 3H), 2.31 4-(3,4,5-trimethoxyphenyl)pyridine (8l). White solid; 235 mg,
3
3
1
3
1
ꢀ
1
(
s, 3H), 1.06 (t, J ¼ 7.1 Hz, 3H) ppm; C{ H} NMR (100 MHz, 48%; mp 147 C; H NMR (400 MHz, CDCl ): d 7.47 (d, J ¼ 8 Hz,
3
CDCl
3
): d 168.8, 157.7, 154.6, 152.4, 152.2, 151.6, 148.6, 142.3, 136.8, 2H), 7.35 (d, J ¼ 7.3 Hz, 2H), 6.57 (s, 1H), 6.38 (s, 1H), 4.18–4.12
133.4, 131.1, 127.6, 126.4, 122.2, 108.3, 108.2, 61.3, 61.11, 61.09, (m, 2H), 3.95 (s, 3H), 3.85 (s, 3H), 3.61 (s, 3H), 2.58 (s, 3H), 2.28 (s,
1
3
1
6
0.9, 56.1, 56.0, 24.2, 22.8, 13.9 ppm; IR (KBr): nmax 2931, 2852, 1726, 3H), 1.04 (t, J ¼ 7.1 Hz, 3H) ppm; C{ H} NMR (100 MHz, CDCl ):
3
ꢂ1
1586, 1464, 1262, 1127, 1103, 1008 cm ; HRMS (ESI) m/z: calcd for d 168.7, 157.8, 155.4, 152.8, 151.6, 147.9, 142.3, 139.7, 133.6,
+
C H NO [M + H] 512.2284, found: 512.2280.
131.1, 128.8 (q, JC–C–F ¼ 32 Hz), 126.4, 126.2, 124.52, 124.49, 124.2
-(4-Chlorophenyl)-2,6-dimethyl-3-(ethoxycarbonyl)-4-(3,4,5- (q, JC–F ¼ 270 Hz), 122.4, 108.4, 61.3, 61.1, 61.0, 56.1, 24.2, 23.1,
trimethoxyphenyl)pyridine (8h). White solid; 250 mg, 55%; mp 13.8 ppm; IR (KBr): n
2935, 1725, 1586, 1322, 1260, 1121, 1084,
2
8
34
8
5
max
ꢀ
1
ꢂ1
+
>
200 C; H NMR (400 MHz, CDCl
3
26 27 3 5
): d 7.19–7.14 (m, 4H), 6.54 1065, 1005 cm ; HRMS (ESI) m/z: calcd for C H F NO [M + H]
(s, 1H), 6.42 (s, 1H), 4.15–4.12 (m, 2H), 3.94 (s, 3H), 3.84 (s, 3H), 490.1841, found: 490.1841.
3
3
1
1
1
1
+
.59 (s, 3H), 2.58 (s, 3H), 2.31 (s, 3H), 1.03 (t, J ¼ 7.2 Hz,
5-(4-Acetylphenyl)-2,6-dimethyl-3-(ethoxycarbonyl)-4-(3,4,5-
1
3
1
H) ppm; C{ H} NMR (100 MHz, CDCl
3
): d 168.7, 157.7, 155.3, trimethoxyphenyl)pyridine (8m). White solid; 208 mg, 45%;
ꢀ
1
52.5, 151.6, 148.2, 142.3, 134.2, 133.5, 132.7, 132.0, 127.8, mp 121 C; H NMR (400 MHz, CDCl ): d 7.81 (d, J ¼ 8 Hz, 2H),
3
26.41, 126.36, 122.6, 108.3, 61.2, 61.1, 60.9, 56.1, 24.2, 22.9, 7.34 (d, J ¼ 7.3 Hz, 2H), 6.56 (s, 1H), 6.41 (s, 1H), 4.19–4.12 (m,
3.7 ppm; IR (KBr): n
2934, 2851, 1724, 1585, 1483, 1261, 2H), 3.95 (s, 3H), 3.85 (s, 3H), 3.60 (s, 3H), 2.58 (s, 3H), 2.57 (s,
max
ꢂ1
13
1
084, 1005, 827 cm ; HRMS (ESI) m/z: calcd for C25
H
27NO
6
[M 3H), 2.27 (s, 3H), 1.05 (t, J ¼ 7.1 Hz, 3H) ppm; C{ H} NMR
+
H] 456.1570, found: 456.1588.
(100 MHz, CDCl ): d 198.0, 168.7, 157.8, 155.3, 152.8, 151.6,
3
2,6-Dimethyl-3-(ethoxycarbonyl)-5-(4-uorophenyl)-4-(3,4,5- 148.0, 142.3, 141.1, 135.3, 133.5, 130.9, 127.7, 126.5, 126.3,
trimethoxyphenyl)pyridine (8i). White solid; 220 mg, 50%; mp 122.5, 108.4, 61.3, 61.11, 61.06, 56.1, 26.6, 24.3, 23.1, 13.8 ppm;
ꢀ
1
1
(
4
2
45 C; H NMR (400 MHz, CDCl
3
): d 7.20–7.17 (m, 2H), 6.91 IR (KBr): nmax 2924, 2853, 1725, 1683, 1586, 1462, 1262, 1136,
ꢂ1
dd, J ¼ 8.5 Hz, J ¼ 8.4 Hz, 2H), 6.55 (s, 1H), 6.41 (s, 1H), 4.17– 1085, 1005 cm ; HRMS (ESI) m/z: calcd for C H NO [M +
2
7
30
6
+
.10 (m, 2H), 3.95 (s, 3H), 3.84 (s, 3H), 3.59 (s, 3H), 2.58 (s, 3H), H] 464.2073, found: 464.2082.
1
3
1
.30 (s, 3H), 1.03 (t, J ¼ 7.2 Hz, 3H) ppm; C{ H} NMR (100
5-(3-Acetylphenyl)-2,6-dimethyl-3-(ethoxycarbonyl)-4-(3,4,5-
MHz, CDCl
3
): d 168.8, 161.7 (d, JC–F ¼ 244 Hz), 157.7, 155.2, trimethoxyphenyl)pyridine (8n). White solid; 199 mg, 43%; mp
ꢀ
1
1
1
52.4, 151.7, 148.3, 142.3, 133.7, 132.3 (d, JC–C–C–F ¼ 8 Hz), 129 C; H NMR (400 MHz, CDCl ): d 7.84 (s, 1H), 7.80–7.77 (m,
3
31.6 (d, JC–C–C–C–F ¼ 4 Hz), 126.7, 126.3, 122.6, 114.6 (d, JC–C–F 1H), 7.46 (d, J ¼ 6.9 Hz, 1H), 7.32 (dd, J ¼ 7.7 Hz, J ¼ 7.6 Hz 1H),
21 Hz), 108.3, 61.2, 61.1, 60.9, 56.1, 24.2, 23.1, 13.8 ppm; IR 6.58 (s, 1H), 6.43 (s, 1H), 4.19–4.14 (m, 2H), 3.96 (s, 3H), 3.86 (s,
KBr): nmax 2959, 2928, 2870, 1716, 1586, 1487, 1257, 1093, 3H), 3.62 (s, 3H), 2.56 (s, 3H), 2.46 (s, 3H), 2.27 (s, 3H), 1.07 (t, J
¼
(
ꢂ1
13
1
1
082, 1006 cm ; HRMS (ESI) m/z: calcd for C H FNO [M + ¼ 7.1 Hz, 3H) ppm; C{ H} NMR (100 MHz, CDCl ): d 198.1,
2
5
27
5
3
+
H] 440.1873, found: 440.1860.
168.7, 157.8, 155.1, 152.6, 151.6, 148.0, 142.3, 136.4, 136.2,
2,6-Dimethyl-3-(ethoxycarbonyl)-5-(3-uorophenyl)-4-(3,4,5- 135.4, 133.6, 131.2, 127.9, 126.6, 126.48, 126.45, 122.5, 108.4,
trimethoxyphenyl)pyridine (8j). White solid; 211 mg, 48%; mp 61.3, 61.1, 61.0, 56.1, 26.6, 24.2, 22.9, 13.8 ppm; IR (KBr): n
max
ꢀ
1
ꢂ1
1
6
4
2
14 C; H NMR (400 MHz, CDCl
.96 (m, 1H), 6.91–6.86 (m, 1H), 6.54 (s, 1H), 6.44 (s, 1H), 4.15– HRMS (ESI) m/z: calcd for C H NO [M + H] 464.2073,
.10 (m, 2H), 3.95 (s, 3H), 3.84 (s, 3H), 3.62 (s, 3H), 2.58 (s, 3H), found: 464.2064.
3
): d 7.18–7.13 (m, 1H), 6.98– 2934, 2850, 1723, 1684, 1584, 1261, 1137, 1083, 1012 cm
;
+
2
7
30
6
1
3
1
.30 (s, 3H), 1.03 (t, J ¼ 7.2 Hz, 3H) ppm; C{ H} NMR (100
2,6-Dimethyl-3-(ethoxycarbonyl)-5-(3-hydroxyphenyl)-4-(3,4,5-
MHz, CDCl ): d 168.7, 162.2 (d, J
1
1
¼ 243 Hz), 157.8, 155.3, trimethoxyphenyl)pyridine (8o). Pale yellow solid; 175 mg, 40%;
3
C–F
ꢀ
1
52.6, 151.6, 148.1, 142.3, 137.9 (d, JC–C–C–F ¼ 8 Hz), 133.6, mp 169 C; H NMR (400 MHz, CDCl ): d 7.05 (s, 1H), 6.79–6.72
3
29.0 (d, JC–C–C–F ¼ 8 Hz), 126.6, 126.4, 126.3, 122.4, 117.6 (d, (m, 2H), 6.64 (d, J ¼ 7.9 Hz, 1H), 6.53 (s, 1H), 6.48 (s, 1H), 4.14–
J
5
1
C–C–F ¼ 21 Hz), 113.7 (d, JC–C–F ¼ 21 Hz), 108.3, 61.2, 61.1, 61.0, 4.08 (m, 2H), 3.94 (s, 3H), 3.83 (s, 3H), 3.61 (s, 3H), 2.55 (s, 3H),
1
3
1
6.1, 24.2, 23.1, 13.8 ppm; IR (KBr): nmax 2955, 2927, 2852, 2.27 (s, 3H), 1.01 (t, J ¼ 7.1 Hz, 3H) ppm; C{ H} NMR (100 MHz,
ꢂ1
724, 1584, 1482, 1260, 1129, 1084, 1014 cm ; HRMS (ESI) m/ CDCl ): d 168.8, 157.4, 155.5, 154.9, 152.3, 151.7, 148.8, 142.3,
3
+
z: calcd for C25
H
27FNO
5
[M + H] 440.1873, found: 440.1869.
137.1, 133.3, 128.8, 127.6, 126.5, 122.9, 117.8, 114.2, 108.2, 61.3,
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3
1
6
2
1.1, 61.0, 56.1, 23.8, 22.6, 13.7 ppm; IR (KBr): nmax 3395, 2936, (s, 3H), 2.34 (s, 3H), 1.12 (t, J ¼ 7.1 Hz, 3H) ppm; C{ H}
ꢂ1
851, 1726, 1592, 1448, 1280, 1133, 1096 cm ; HRMS (ESI) m/z: NMR (100 MHz, CDCl ): d 168.7, 157.8, 154.6, 152.6, 148.8,
3
+
calcd for C H NO [M + H] 438.1916, found: 438.1916.
146.5, 144.7, 136.8, 136.0, 132.6, 129.9, 126.8, 122.7, 115.6,
2
5
28
6
2,6-Dimethyl-3-(ethoxycarbonyl)-5-(4-(hydroxymethyl)phenyl)- 112.2, 106.9, 61.3, 60.9, 56.1, 56.0, 24.2, 22.8, 13.9 ppm; IR
4
4
6
3
7
1
1
1
1
+
-(3,4,5-trimethoxyphenyl)pyridine (8p). White solid; 203 mg, (KBr): nmax 3453, 2961, 2935, 2840, 1725, 1587, 1499, 1260,
ꢀ
1
ꢂ1
5%; mp 152 C; H NMR (400 MHz, CDCl
3
): d 7.23–7.17 (m, 4H), 1125, 1083, 1018 cm ; HRMS (ESI) m/z: calcd for C26
H
30NO
7
+
.54 (s, 1H), 6.44 (s, 1H), 4.64 (s, 2H), 4.15–4.12 (m, 2H), 3.94 (s, [M + H] 468.2022, found: 468.2015.
H), 3.84 (s, 3H), 3.59 (s, 3H), 2.56 (s, 3H), 2.26 (s, 3H), 1.03 (t, J ¼
1
3
1
3
.1 Hz, 3H) ppm; C{ H} NMR (100 MHz, CDCl ): d 168.7, 157.5,
Biology
55.2, 152.3, 151.7, 148.5, 142.2, 139.4, 134.9, 133.6, 130.8, 127.5,
26.4, 126.2, 122.7, 108.2, 64.9, 61.2, 61.1, 60.9, 56.1, 24.2, 22.9,
Cell-based screening assay. Synthesized penta-substituted/
3.8 ppm; IR (KBr): n
3395, 2980, 2936, 2850, 1725, 1588, 1488, functionalized-3,4-diarylated pyridine compounds 8a–8t used
max
ꢂ1
267, 1136, 1094 cm ; HRMS (ESI) m/z: calcd for C26
H] 452.2073, found: 452.2073.
H
30NO
6
[M in this study were dissolved in 100% DMSO (cell culture grade,
Himedia). The compounds were serially diluted in Dulbecco's
+
2
,6-Dimethyl-3-(ethoxycarbonyl)-5-(3-pyridinyl)-4-(3,4,5-trime- Modied Eagle (DMEM) cell culture medium to maintain the
thoxyphenyl)pyridine (8q). White solid; 177 mg, 42%; mp 107 C; DMSO concentration less than 0.1% for analyzing its cell
ꢀ
1
H NMR (400 MHz, CDCl
3
): d 8.48 (s, 1H), 8.42 (dd, J ¼ 4.8 Hz, J ¼ proliferation inhibiting potency in HeLa cell line. Briey, 5 ꢁ
3
15b
1
4
3
7
1
1
1
1
.5 Hz, 1H), 7.53 (d, J ¼ 7.6 Hz, 1H), 7.15 (dd, J ¼ 7.6 Hz, J ¼ 10 cells were seeded in 96 well plate. Aer 16 h compounds
.9 Hz, 1H), 6.58 (s, 1H), 6.43 (s, 1H), 4.18–4.09 (m, 2H), 3.96 (s, (5 mM) were added and incubated with cells for 24 h. Subse-
H), 3.86 (s, 3H), 3.64 (s, 3H), 2.57 (s, 3H), 2.30 (s, 3H), 1.03 (t, J ¼ quently, cells were xed with TCA and processed for sulfo-
1
3
1
39
.1 Hz, 3H) ppm; C{ H} NMR (100 MHz, CDCl
): d 168.6, 157.9, rhodamine B (SRB) assay.
3
55.5, 152.9, 151.8, 151.3, 147.9, 147.7, 142.3, 138.0, 133.9, 131.7,
Effects of diarylated pyridine compounds on in vitro tubulin
26.4, 123.8, 122.6, 122.5, 108.4, 61.3, 61.1, 61.0, 56.1, 24.3, 23.1, assembly. Tubulin was puried from goat brain using 1 M
4
0,41
3.8 ppm; IR (KBr): nmax 2978, 2936, 2848, 1725, 1586, 1465, 1385, glutamate as described earlier.
Tubulin concentration was
ꢂ1
42
267, 1139, 1095, 1003 cm ; HRMS (ESI) m/z: calcd for determined by Bradford method. Puried tubulin (12 mM) in
+
C H N O [M + H] 423.1920, found: 423.1918.
PEM buffer (25 mM PIPES pH 6.8, 3 mM MgCl
,6-Dimethyl-3-(ethoxycarbonyl)-5-(3-hydroxy-4-methoxy- EGTA) was incubated in the absence and presence of 20 mM of
phenyl)-4-(3,4,5-trimethoxyphenyl)pyridine
(8r). White compounds (8b, 8f, 8j and 8p) for 10 min on ice and then,
solid; 210 mg, 45%; mp 148 C; H NMR (400 MHz, CDCl
): DMSO (nal concentration 10%) and 1 mM GTP was added to
d 6.85 (s, 1H), 6.68–6.65 (m, 2H), 6.51 (s, 1H), 6.49 (s, 1H), the reaction mixtures. Subsequently, the assembly kinetics was
2
and 1 mM
2
4
27 2 5
2
ꢀ
1
3
ꢀ
ꢀ
5
(
.61 (s, 1H), 4.14–4.09 (m, 2H), 3.93 (s, 3H), 3.84 (s, 3H), 3.83 monitored at 37 C by 90 light scattering (350 nm) using
e
s, 3H), 3.62 (s, 3H), 2.57 (s, 3H), 2.32 (s, 3H), 1.01 (t, J ¼ Spectramax M2 . The extent of inhibition of polymerization was
13 1
7
1
1
6
3
.1 Hz, 3H) ppm; C{ H} NMR (100 MHz, CDCl
3
): d 168.8, measured aer 30 min of assembly. The light scattering data of
57.5, 155.2, 152.1, 151.9, 148.8, 145.6, 144.8, 142.2, 133.7, only compounds (20 mM) were also recorded and subtracted
28.9, 127.4, 126.3, 122.7, 122.6, 117.0, 109.9, 108.1, 61.1, from their respective data set. Three independent set of exper-
1.0, 60.9, 56.1, 55.8, 24.2, 23.0, 13.7 ppm; IR (KBr): nmax iments were performed.
ꢂ1
410, 2935, 2838, 1721, 1586, 1488, 1250, 1087, 1015 cm
;
+
7
HRMS (ESI) m/z: calcd for C26H30NO [M + H] 468.2022,
Acknowledgements
found: 468.2013.
4
-(3-(Benzyloxy)-4-methoxyphenyl)-2,6-dimethyl-3-(ethoxycar-
bonyl)-5-(3,4,5-trimethoxyphenyl)nicotinate (8s). Yellow solid;
ꢀ
50 mg, 45%; mp 120 C; H NMR (400 MHz, CDCl ): d 7.46 (d, J
3
We gratefully acknowledge nancial support from CSIR, New
Delhi for this investigation. NH is thankful to DST, NewDelhi
for her DST-INSPIRE fellowship. DP is thankful to DAE,
Government of India for DAE-SRC fellowship.
1
2
¼
8.6 Hz, 2H), 7.38 (dd, J ¼ 8.6 Hz, J ¼ 7.1 Hz, 2H), 7.32 (dd, J ¼
7
4
3
.2 Hz, J ¼ 7.0 Hz 1H), 6.98 (s, 1H), 6.83 (s, 1H), 6.49 (s, 3H),
.04–4.02 (m, 2H), 3.96 (s, 3H), 3.81 (s, 3H), 3.67 (s, 6H), 2.57 (s,
1
3
1
H), 2.34 (s, 3H), 1.01 (t, J ¼ 7.2 Hz, 3H) ppm; C{ H} NMR (100
Notes and references
MHz, CDCl
3
): d 168.8, 157.9, 154.7, 152.7, 149.4, 148.8, 147.1,
36.9, 136.7, 135.8, 133.6, 129.3, 128.6, 127.9, 127.4, 126.7, 122.7,
14.8, 113.4, 106.9, 71.1, 61.3, 60.9, 56.2, 56.0, 24.3, 22.9,
1
1
1
1
5
1 (a) A. O. Plunkett, Nat. Prod. Rep., 1994, 11, 581; (b) J. Daly,
H. Garaffo and T. Spande, Alkaloids, 1993, 43, 185; (c)
A. R. Pinder, Nat. Prod. Rep., 1992, 9, 491; (d) G. D. Henry,
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2 D. Riendeau, M. D. Percival, C. Brideau, S. Charleson,
D. Dube, D. Ethier, J.-P. Falgueyret, R. W. Friesen,
R. Gordon, G. Greig, J. Guay, J. Mancini, M. Ouellet,
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max
ꢂ1
+
122, 1079 cm ; HRMS (ESI) m/z: calcd for C H NO [M + H]
3
3
36
7
58.2492, found: 558.2476.
,6-Dimethyl-3-(ethoxycarbonyl)-4-(3-hydroxy-4-methoxy-
phenyl)-5-(3,4,5-trimethoxyphenyl)pyridine (8t). White
solid; 350 mg, 75%; mp > 200 C; H NMR (400 MHz, CDCl ):
d 6.94 (s, 1H), 6.82 (s, 1H), 6.51–6.48 (m, 3H), 5.78 (br s, 1H),
.18–4.13 (m, 2H), 3.96 (s, 3H), 3.80 (s, 3H), 3.67 (s, 6H), 2.56
2
ꢀ
1
3
4
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