Total syntheses and antiproliferative activities of prenostodione and its analogues

Article abstract of DOI:10.1039/d1ob00897h

A high-yielding total synthesis of the indole alkaloid prenostodione was completed in 4 steps and 44% overall yield from 1H-indole-3-carboxylic acid. The expedient syntheses of prenostodiones containing distinct substituents at theparaposition of the phenyl frame underscored the scope of this methodology. The cytotoxic activities of thetert-butyl esters of prenostodione analogues were tested using six tumor cell lines. Preliminary structure-activity studies revealed the importance of the identity of the aromatic substituent at the C-4 position for cytotoxic activity. The IC₅₀values of these compounds were found to compare satisfactorily with those of the commercially available drugs etoposide and cisplatin. Furthermore, the compounds with, respectively, -OMe (14d) and -NO₂(14f) groups at C-4 were more selective than these control compounds in PC-3, K-562, and MCF-7 cells. Also, computational studies were carried out to determine the ADMET profiles and passive membrane permeabilities of the compounds. The results suggested the promise of14dand14fas hit compounds for the development of new anticancer agents.

Full text of DOI:10.1039/d1ob00897h

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DOI: 10.1039/D1OB00897H
ARTICLE
Total syntheses and antiproliferative activities of prenostodione
and its analogues
Aldahir Ramos Orea,a Teresa Ramírez-Apan,a Rosa M. Chávez-Santos,a Rodrigo Aguayo-Ortiz,b Clara
Received 00th January 20xx,
Accepted 00th January 20xx
Espitia,c Mayra Silva Miranda,c Rubén O. Torres-Ochoa*a and Roberto Martínez*a
DOI: 10.1039/x0xx00000x
A high-yielding total synthesis of the indole alkaloid prenostodione was completed in 4 steps and 44% overall yield from 1H-
indole-3-carboxylic acid. The expedient syntheses of prenostodiones containing distinct substituents at the para position of
the phenyl frame underscored the scope of this methodology. The cytotoxic activities of the tert-butyl esters of
prenostodione analogues were tested using six tumor cell lines. Preliminary structure-activity studies revealed the
importance of the identity of the aromatic substituent at the C-4 position for cytotoxic activity. The IC50 values of these
compounds were found to compare satisfactorily with those of the commercially available drugs etoposide and cisplatin.
Furthermore, the compounds with, respectively, -OMe (14d) and -NO2 (14f) groups at C-4 were more selective than these
control compounds in PC-3, K-562, and MCF-7 cells. Also, computational studies were carried out to determine the ADMET
profiles and passive membrane permeabilities of the compounds. The results suggested the promise of 14d and 14f as hit
compounds for the development of new anticancer agents.
it is the most commonly found pigment in cyanobacteria.4
Nostodione A (2), existing as a mixture of E- and Z-isomers
because of a tautomeric equilibrium, has been observed to
display antimitotic5 and proteasome inhibition,6 as well as anti-
Toxoplasma gondii activity7 beyond its UV-absorbing features.
It has been proposed that scytonemin (1) and nostodione A (2)
could be biosynthesized from prenostodione (3a).8
Introduction
Blue-green algae (cyanobacteria) form a remarkable source of
fascinating and noteworthy bioactive metabolites.1 Of these
metabolites, indole-based alkaloids constitute an outstanding
vast group of natural products, and especially attractive are
those in which a coumaric acid residue is bound at the C-2
position of the indole core, owing to the crucial role of the
resulting compounds in protecting cyanobacteria against highly
damaging UV radiation (Fig. 1).2
Prenostodione (3a) was originally isolated as a single E-isomer
by Carmeli in 2001 from a natural bloom of the cyanobacterium
Nostoc sp. in relatively low yield (0.002% from dry cell weight).8
Unlike the array of bioactivities described for scytonemin 1 and
nostodione A 2, no biological activities have to the best of our
knowledge been documented for prenostodione, perhaps due
to the scarcity of its isolation from natural sources, even though
its synthetic preparation has been reported twice. These
protocols each utilized a Knoevenagel condensation as a key
transformation but in quite distinct reaction conditions
(Scheme 1). Samanta et al. used methyl 2-(3-formyl-1H-indol-2-
yl)acetate 4 as a crucial intermediate and exploited the
carboxaldehyde moiety of the indole 4 to perform an L-proline-
catalyzed condensation with 5a.9 Although they reported a
prenostodione synthesis in only 4 steps, the preparation of the
key intermediate 4 was omitted. The synthesis carried out by
Samanta et al. was indicated, based on a preceding report about
the synthesis of 4,10 to form the product with an overall yield of
only as high as 28%. More recently, Badenock published a
longer formal approach wherein N-protected (indol-2-
yl)acetate 7 was strategically condensed with the protected
aldehyde 8 under rather basic conditions. The sequence
afforded prenostodione 3a in only 3.5% overall yield (9 steps).11
The potential utility of prenostodione as an advanced synthetic
intermediate to access other alkaloid family members such as
OH
O
CO2H
O
O
CO2Me
NH
N
N
H
H
HN
O
HO
Nostodione A
HO
Prenostodione
HO
3a
2
1
Scytonemin
Fig. 1 Select examples of indole alkaloids isolated from cyanobacteria.
Scytonemin (1), known since 1849,3 may be considered the
prototypical example of such a photoprotective molecule since
a. Instituto de Química, Universidad Nacional Autónoma de México, Circuito
Exterior, Ciudad Universitaria, Coyoacán, Ciudad de México, 04510, México. E-
mail: romar.torres@iquimica.unam.mx; robmar@unam.mx
www.iquimica.unam.mx
b. Departamento de Farmacia, Facultad de Química, Universidad Nacional
Autónoma de México, Circuito Escolar, Ciudad Universitaria, Coyoacán, Ciudad de
México, 04510, México.
c. Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de
México, Ciudad Universitaria, Coyoacán, Ciudad de México, 04510, México.
†Electronic Supplementary Information (ESI) available: Experimental procedures;
spectral data and X-ray crystal structure. CCDC 1999796. For ESI and crystallographic
data in CIF and or other electronic format see DOI: 10.1039/x0xx00000x
†Dedicated to the memory of Rocío Patiño (1965-2021) & Rosalia Orea (1968-2020)
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scytonemin and nostodione A, together with the lack of perhaps due to the reported lower reaction efficiency.11,15a,18
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biological studies, reinforce the need for developing a short and Taking inspiration from the synthesis of cDaOulIe: 1r0p.i1n03c9a/rDr1ieOdB0o0u8t9b7Hy
efficient route for converting 3a into a desirable target for both Xu,17a we opted first to condense 10 with 4-
synthetic and medicinal chemists.
hydroxybenzaldehyde (5a) using only catalytic amounts of
Our group has a general interest in the preparation of indole piperidine and acetic acid. To our delight, this first experiment
alkaloids, due to their likely therapeutic applications,12 and we yielded the unsaturated ester 14a as a E-single isomer in 73%
hence proposed and initiated an investigation involving the yield after a reaction time of 1 h, and in up to 91% yield by
preparation and biological evaluation of prenostodione 3a, the simply prolonging the reaction time (6 h). Finally, the
results of which are presented herein. Since the late-stage regioselective tert-butyl ester acidic hydrolysis furnished the
transformation of the carboxaldehyde group into the desired total synthesis of prenostodione 3a.19 To sum up, the synthetic
carboxylic acid was somewhat problematic in the previous target was efficiently prepared in only four steps and 44%
syntheses,9,11 our current design involved avoiding such an issue overall yield (the highest reported so far).
by installing orthogonally distinct ester groups. Based on our
CO2H
CO2tBu
CO2tBu
CO2Me
SOCl2
toluene, reflux
13, DLP
retrosynthetic strategy (Scheme 1c), we set out to obtain
prenostodione 3a by carrying out a Knoevenagel condensation
of diester 10 with p-hydroxybenzaldehyde 5a, followed by
further acid-mediated tert-butyl ester hydrolysis. And finally,
we set out to prepare intermediate 10 by performing an
esterification and C-2 alkylation of indole-3-carboxylic acid 11.
DCE, reflux
72%
then KOtBu
tBuOH, 85%
N
H
N
H
N
H
10
12
11
5a, piperidine (cat.)
AcOH (cat.), PhMe,
Dean-Stark, reflux, 91%
CO2H
CO2Me
CO2tBu
EtO(S)CS
CO2Me
CHO
a. Samanta (2013)9
CO2Me
13
CHO
CO2Me
N
N
H
CHO
H
N
L-Proline
TFA:DCM
H
CO2Me
+
(1:4), rt, 79%
DMSO, rt
76%
HO
CHO
N
H
HO
HO
OH
5a
4
3a
HO
14a
5a
6
b. Badenock (2018)11
Scheme 2 Preparation of prenostodione 3a.
CHO
CO2Me
LDA, THF
-78 °C;
N
H
CO2Me
Since our developed route to 3a was more step- and atom-
economic than the routes reported previously,9,11 we decided
to determine the feasibility of synthesizing various
prenostodione analogues by just replacing the aromatic
aldehyde in the condensation step (Table 1). Gratefully, a set of
aromatic aldehydes (5b-k) gave the desired products in good to
excellent yields (Table 1). Analysis of the results suggested that
the electronic nature of the substituent on the phenyl ring
might have a slight effect on the condensation step, as the
aldehydes with either strongly or weakly electron-withdrawing
groups, such as nitro, cyanide, trifluoromethyl, and halide
groups, afforded the expected products (14f-k) in somewhat
lower yields (Table 1, entries 5-10). As we had observed with
the condensation product 14a, all of the new alkenes were
similarly isolated as single E-isomers.
+
then NaH
reflux, 44%
N
Boc
OTBS
7
TBSO
8
9
c. This work (retrosynthetic plan)
CO2H
CO2tBu
CO2Me
CO2H
N
H
CO2Me
N
H
N
H
10
11
HO
Key feature
Orthogonal ester groups
3a
Scheme 1 Key reaction of the previously reported syntheses of prenostodione 3a and
proposed retrosynthetic plan.
Results and discussion
Table 1 Scope of the Knoevenagel condensation of 10 with 5a
Chemistry
CO2tBu
CHO
Our investigations began with the preparation of the
disubstituted indole 10, whose synthesis was achieved through
esterification13 and radical oxidative alkylation14 of the
carboxylic acid 11 in 61% yield (2 steps) (Scheme 2). Even
though other methods could have also provided the expected
indole, those take longer to implement, are less efficient, and
are aimed at dimethyl or diethyl indole diesters.15 With 10 in
hand, our efforts were focused on using it in the Knoevenagel
reaction.16 Most of the previously described procedures
regarding this transformation on similar substrates were
conducted on 3-formyl indole derivatives.9,17 Indoles bearing an
ester group at C-3 have been much less commonly used,
CO2Me
CO2tBu
CO2Me
piperidine (cat.)
N
H
+
AcOH (cat.), PhMe,
Dean-Stark, reflux
N
H
R
10
R
5
14
2 | J. Name., 2012, 00, 1-3
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Table 2 Syntheses of prenostodione analogues each resulting from tert-butyl ester
Entry
1
2
3
4
5
6
7
8
R
H
T (h)
2
2
6
6
24
24
6
6
6
Product
14b
14c
14d
14e
14f
14g
14h
14i
Yield (%)b,c
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hydrolysisa
DOI: 10.1039/D1OB00897H
92
90
89
93
60
65
74
74
74
73
Me
OMe
N(Me)2
NO2
CN
CF3
Br
Cl
CO2tBu
CO2Me
CO2H
CO2Me
N
N
H
H
TFA:CH2Cl2
(1:4), rt
R
R
14
3
Yield (%)b
9
10
14j
14k
Entry
1
2
3
4
5
6
7
8
R
H
Product
3b
3c
3d
3e
3f
3g
3h
3i
F
6
80
79
87
79
78
76
77
89
87
70
Me
OMe
N(Me)2
NO2
CN
CF3
Br
Cl
a 10 (0.17 mmol), 5 (0.2 mmol), piperidine (cat.) and HOAc (cat.) in toluene (3 mL),
reflux, Dean-Stark; b Isolated yield; c Single E-isomer was observed.
The excellent stereoselectivity of the condensation can be
rationalized based on the mechanism depicted in Scheme 3.
According to this mechanism, first 5 forms intermediate A and
10 forms enolate B (Scheme 3a), and then A condenses with B
(Scheme 3b). In principle, the nucleophilic attack of B onto the
electrophilic carbon of A can occur on either of the iminium
faces, but Si-face addition is preferred since the steric hindrance
between the reactants is less pronounced in this case (favored
pathway). The reversibility of the Re-face-addition (unfavored
pathway) ensures the regeneration of intermediates A and B
(Scheme 3b).
9
10
3j
3k
F
a 14 (0.1 mmol) in TFA:CH2Cl2 (1:4; 0.04 M), 0 °C then rt, 1.5 h; b Isolated yield.
Cytotoxic activity
We evaluated the activities of compounds 3a-k (-COOH) in
inhibiting the growth of U-251 central nervous system cancer,
PC-3 prostate cancer, K-562 leukemia, HCT-15 colon cancer,
MCF-7 breast cancer, and SKLU-1 lung cancer cells. First, we
determined the antiproliferative activity of prenostodione (3a).
It did not inhibit the proliferation of any of the six types of
cancer cells tested (Supplementary Table 3). Moreover, neither
did any of the synthesized analogs 3b-k. We hypothesized that
the hydrophilicity of the acid group (COOH) was the cause of the
lack of antiproliferative activity of prenostodione and its
analogues. To test this hypothesis, the tert-butyl ester of
prenostodione, i.e., 14a, was evaluated; but it too did not show
any anticancer property (Table 3).
a)
CO2tBu
CO2tBu
H
H
O
H
N
N
H
N
H
base
piperidine
H
HOAc
OAc
H
Ar
OMe
OMe
5
Ar
O
O
A
10
B
b)
OAc
Si-face
addition
N
OAc
Ar
N
H
N
N
H
H
Ar
OMe
N
H
H
N
H
Ar
OMe
O
H
O
CO2Me
Re-face
addition
Ar
H
H
H
N
H
We then conjectured that the absence of antiproliferative
activity of the tert-butyl ester 14a might have been due to the
presence of the phenolic moiety (-OH). To assess this
assumption, we removed the 4-hydroxy group from 14a, and
found that the resulting compound 14b (4-H) provided a level
of growth inhibition, for most of the cell lines investigated, that
exceeded the inhibitory activity of 14a. Specifically, 14b showed
IC50 values of 16.3 ± 0.5 M for U-251, 10.5 ± 2.8 M for K-562,
24.0 ± 3.0 M for HCT-15, 19.8 ± 0.7 M for MCF-7, and 18.7 ±
1.8 M for SKLU-1. Based on these results, we considered 14b
to be a lead compound and could potentially be developed into
a new drug by optimizing its beneficial effects and minimizing
its side effects—and so we speculated that an exploration of
structural modifications of 14b and an evaluation of the
anticancer activities of the resultant compounds could lead to
compounds displaying even higher activities.21 We specifically
attached various substituents to the para position of the phenyl
ring of compound 14b and measured the anticancer activities of
the resulting compounds 14c-k (Table 3). Electronic effects
were examined by introducing electron-donating groups (14c,
N
N
N
H
N
Ar
N
H
Ar
CO2Me
H
H
CO2Me
CO2Me
H
- piperidine
- piperidine
CO2tBu
CO2tBu
CO2Me
CO2Me
N
H
N
(E)
(Z)
H
Ar
Unfavoured
Favoured
Ar
Scheme 3 Mechanistic explanation of the Knoevenagel condensation of 10 with 5.
Lastly, for each compound tested, the ester hydrolysis occurred
smoothly, affording the expected carboxylic acids 3b-k in 70-
89% yields (Table 2). The alkene E-configuration was preserved
in all of the cases, and unambiguously corroborated for
analogue 3i by carrying out a single crystal X-ray diffraction
analysis of this analogue (CCDC 1999796).20
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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4-Me; 14d, 4-OMe; 14e, 4-N(CH3)2) or electron-withdrawing the biological activity, i.e., whether it increased or decreased
View Article Online
DOI: 10.1039/D1OB00897H
groups (14f, 4-NO2; 14g, 4-CN; 14h, 4-CF3). Most of these the bioactivity. Also, the bioactivity could not be explained
changes yielded significantly increased inhibitory activities, solely in terms of the distribution of electronic density across
compared to that of the lead compound 14b, in PC-3, K-562, and the phenyl group in compounds 14a-k. Interestingly, compound
SKLU-1 cell lines tested. In the PC-3 cells, compound 14d (4- 14f (4-NO2) was the most active derivative in the cells of the K-
OMe) showed a significant activity unlike the unsubstituted lead 562 and MCF-7 cancer cell lines. The nature of the nitro
compound 14b. Compound 14f was three times as active as substituent, in particular its ability to form hydrogen bonds,
compound 14b in the K-562 cells and four times as active in the appeared to increase the activity.22 The analogue 14d (4-OMe)
MCF-7 cells. The roles of the electronegativity and/or size of the also showed good activity in the PC-3 cells. The IC50 values of our
halogen group in antiproliferative activity were investigated by most active compounds (14d and 14f) were compared with
synthesizing and testing compounds 14i (4-Br), 14j (4-Cl), and those of the commercially available etoposide and cisplatin. As
14k (4-F). As shown in Table 3, the fluorine derivative 14k was shown in Table 3, when tested in cells of the leukemia K-562 cell
the most active of the halogenated compounds in the HCT-15 line, compound 14f (4-NO2) (with an IC50 = 3.62 ± 0.2 M) was
cells. Compound 14j (4-Cl) was the most active in the 1.7 times more active than cisplatin (with IC50 value of 5.73 ± 0.8
halogenated series against the PC-3 cells, and the activity of 14j M). The activities of 14f, etoposide, and cisplatin were similar
in the MCF-7 cells was similar to that in the SKLU-1 cells. These in the MCF-7 cells. Compound 14d (4-OMe) was three times
findings confirmed that substitution at the para position more active than etoposide in the cells of the prostate cancer
influenced the biological activity. Unfortunately, it was not clear PC-3 cell line (IC50 = 10.5 ± 0.5 M Vs. IC50 = 31.47 ± 2.2 M).
from these results how the type of substituent tended to alter
Table 3 IC50 values (M) of compounds 14a-14k in cell from six cancer cell lines and one noncancerous cell linea
U-251
(CNS)
ND
16.3±0.5
18.5±1.1
22.9±1.7
ND
24.9±0.8
20.5±0.5
ND
23.9±1.2
22.2±0.9
ND
2.38±0.2
4.7±0.4
PC-3
(prostate)
ND
ND
ND
10.5±0.5
ND
ND
15.1±1.3
ND
20.1±1.2
14.6±0.6
ND
K-562
(leukemia)
ND
10.5±2.8
34.5±3.8
21.6±1.7
ND
3.62±0.2
ND
53.4±3.7
19.6±1.6
20.6±1.6
ND
HCT-15
(colon)
ND
24.0±3.0
33.8±2.7
ND
ND
ND
22.0±1.3
25.2±2.7
ND
MCF-7
(breast)
ND
19.8±0.7
21.7±1.6
15.2±0.8
ND
4.47±0.5
ND
ND
19.54±0.9
14.7±0.8
ND
4.93±0.04
5.30±0.5
SKLU-1
(lung)
ND
COS-7b
(kidney)
ND
Compound
R
14a
14b
14c
14d
14e
14f
14g
14h
14i
OH
H
18.7±1.8
14.4±2.4
12.7±0.3
27.9±1.0
14.8±2.1
ND
16.9±0.3
17.3±1.7
12.3±1.1
ND
29.1±1.6
22.9±1.9
51.6±3.7
38.8±2.3
22.2±0.9
15.5±0.7
54.4±1.4
26.0±0.4
25.5±1.5
21.68±0.7
7.16±0.68
7.17±0.6
Me
OMe
N(Me)2
NO2
CN
CF3
Br
Cl
14j
14k
ND
F
16.6±0.34
4.75±0.5
5.35±0.2
etoposidec
cisplatinc
31.47±2.2
3.95±0.2
2.21±0.7
5.73±0.8
2.60±0.2
4.76±0.5
a
b
c
Values are means of the results of three experiments. COS-7 = Noncancerous monkey kidney cell. Etoposide and cisplatin were purchased from Sigma-Aldrich
Chemical Co. ND = Not determined, due to an initial screening of such compounds having exhibited a lower-than-50% inhibition at 25 M.
The ratio of the IC50 value in the noncancerous COS-7 cells to
Table 4 Selectivity index (SI)a values of active compounds 14d, 14f, etoposide, and
cisplatin
that of the corresponding human cancer cell, i.e., the selectivity
index (SI),23 was calculated for each of 14d, 14f, etoposide, and
cisplatin for each of the K-562, MCF-7, and PC-3 cancer cell lines.
As shown in Table 4, compound 14d (4-OMe) was twenty-two
times and almost three times more selective than etoposide
and cisplatin, respectively, in cells of the prostate cancer PC-3
cell line. Compound 14f (R= NO2) was two times and five times
more selective than etoposide and cisplatin, respectively, in
cells of the leukemia K-562 cell line. Also, compound 14f was
three times more selective than etoposide and cisplatin in cells
of the breast cancer MCF-7 cell line.
PC-3
(prostate)
5.03
K-562
(leukemia)
MCF-7
(breast)
Compound
R
14d
14f
14f
OMe
NO2
NO2
6.05
4.65
1.58
1.34
etoposide
cisplatin
0.23
1.87
2.69
1.19
a The selectivity index (SI) is the ratio of the IC50 value in the noncancerous COS-7
cells to that of the corresponding human cancer cell (see Table 3).
In previous work we evaluated the antituberculosis activity of
caulerpin,12b a marine alkaloid, and it showed promising
activity. Therefore, we decided to evaluate the antituberculosis
activities of prenostodione and its analogs 14a-k and 3a-k. None
4 | J. Name., 2012, 00, 1-3
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of the compounds, however, exhibited activity against the M. Permeability prediction
View Article Online
tuberculosis H37Rv strain.24
Figure 2 shows the energy profiles calcuDlaOtIe: d10f.1o0r39th/De1OtrBa0n0s8f9e7rHs
of the compounds 3a-k (orange) and 14a-k (purple) through a
dioleoyl-phosphatidylcholine (DOPC) bilayer. The high free
ADMET prediction for the prenostodione analogues
The physicochemical properties and ADMET consensus analysis energy at the bilayer center of each of the 3a-k profiles
of 14a-k (Supplementary Tables 7-9) showed that these suggested that these molecules are less permeable than those
compounds have high probabilities of exhibiting good oral that have the tert-butyl ester moiety (i.e., 14a-k). These results
bioavailability,25-27 and being unlikely to exhibit mutagenicity, were attributed to the hydrophobicity of the alkyl ester favoring
cardiotoxicity, mitochondrial toxicity, cytotoxicity, or skin the ability of each of 14a-k to permeate into the lipid acyl chain
sensitization. Nevertheless, modifications to the structure will region and, therefore, to realize an inward translocation. This
be necessary at the lead optimization stage to reduce their attribution was corroborated by the results of calculations of
potential hepatotoxicity. In addition, we found that our permeability coefficients for the molecules crossing an artificial
molecules are not pan-assay interference compounds (PAINS), black lipid membrane (BLM) (Table 5), which specifically
so the antiproliferative activities reported in this study could be showed ester compounds exhibiting higher permeability
due to a target-specific interaction.
coefficient values (-0.7 < log PBLM < 2.4) than those that were
already hydrolyzed (-4.0 < log PBLM < -0.5). Overall, these results
suggested that the low biological activity levels of the carboxylic
acids could be related to their low probabilities of being
passively transported through a biological membrane.
Figure 2 Transfer energy profiles calculated in the interval from −30 to +30 Å distance from the DOPC membrane center (dmc) for 3a-k and 14a-k.
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Bruker spectrometer. Mass spectra were recorded with JEOL SX
Table 5 Permeability coefficient values calculated for the transport of 3a-k and 14a-k
across an artificial black lipid membrane (BLM)
View Article Online
102 A spectrometers by electronic impaDctO(I:E1I0)..1R03e9a/cDt1ioOnBs00w89e7rHe
monitored by TLC and visualized by using a dual short-
wavelength/long-wavelength UV lamp. Flash column
chromatography was carried out on silica gel 60 (230–400 mesh
ASTM) from Macherey-Nagel GmbH & Co. All solvents were
distilled under a nitrogen atmosphere. Dichloromethane and
acetonitrile were distilled from calcium hydride, toluene was
distilled from sodium benzophenone ketyl. X-ray diffraction
data were obtained from Bruker Smart APEX II CCD
diffractometer equipped with graphite monochromatic MoKα
radiation.
Compound
14a
log PBLM
-0.48
2.16
2.42
0.57
0.50
1.16
-0.66
1.67
1.93
1.67
1.52
Compound
log PBLM
-3.64
-0.87
-0.48
-2.48
-2.58
-2.00
-4.02
-1.47
-1.08
-1.37
-1.59
3a
3b
3c
3d
3e
3f
3g
3h
3i
14b
14c
14d
14e
14f
14g
14h
14i
14j
14k
3j
3k
General procedure for α,β-unsaturated esters 14a-k
To a solution of indole 10 (0.17 mmol, 1.0 equiv) and the
corresponding aldehyde 5 (0.2 mmol, 1.2 equiv) in anhydrous
toluene (3 mL) were added piperidine and acid acetic (two
drops of each). The reaction flask was equipped with a Dean-
Stark apparatus and reflux condenser. The solution was refluxed
until the complete consumption of the starting material
(monitored by TLC). The solvent was concentrated under
vacuum, and the crude product was purified by column
chromatography on silica gel eluting with hexane/EtOAc to give
the desired product.
Conclusions
In summary, we have developed a novel four-step total
synthesis of the alkaloid prenostodione. Our strategy relied on
a very mild Knoevenagel condensation, and regioselective tert-
butyl ester hydrolysis. The tolerance to various functionalities
let us extend the method to prepare several prenostodione
analogues in excellent yields. The mild reaction conditions,
practical simplicity and efficiency of our synthesis make it a
highly attractive alternative to access the prenostodione
scaffold and its promising biological applications. Evaluations of
the anticancer properties of the synthesized compounds in cells
of six cancer cells lines showed excellent cytotoxic activities of
certain t-butyl ester prenostodione analogues, particularly of
14f (4-NO2) in K-562 and MCF-7 cells, and of 14d (4-OMe) in PC-
3 cells. The IC50 values of these compounds were found to
compare satisfactorily with those of the commercially available
drugs etoposide and cisplatin. Furthermore, compounds 14d
and 14f were shown to be more selective than these control
compounds in PC-3, K-562 and MCF-7 cells. Each of these two
analogues also showed a high probability of displaying good oral
bioavailability and permeability in biological membranes, a low
probability of being eliminated by P-gp, and an acceptable
toxicity that can be addressed during the lead optimization
stage. Therefore, our results suggested that the anticancer
compounds 14d and 14f might be useful as hit compounds for
the development of new anticancer agents.
tert-Butyl (E)-2-(1-(4-hydroxyphenyl)-3-methoxy-3-oxoprop-
1-en-2-yl)-1H-indole-3-carboxylate (14a). Yellow solid (60.9
1
mg, 91%), m. p. 172-174 °C. H NMR (300 MHz, CDCl3): δ 8.62
(br s, 1H), 8.20-8.17 (m, 1H), 7.79 (s, 1H), 7.25-7.16 (m, 3H), 7.04
(br s, 1H), 6.75 (d, J = 8.7 Hz, 2H), 6.51 (d, J = 8.7 Hz, 2H), 3.67 (s,
3H), 1.48 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 167.9, 164.9,
158.2, 143.5, 138.0, 135.4, 132.5, 127.1, 125.8, 123.3, 122.0,
121.8, 120.7, 116.0, 111.6, 108.5, 80.7, 52.5, 28.5. IR (KBr): ν
(cm-1) 3284, 1689, 1661. HR-MS (EI) m/z calcd for C23H23NO5
[M+]: 393.1576; found: 393.1561.
tert-Butyl (E)-2-(3-methoxy-3-oxo-1-phenylprop-1-en-2-yl)-
1H-indole-3-carboxylate (14b). Yellow solid (59.1 mg, 92%), m.
1
p. 60-62 °C. H NMR (300 MHz, CDCl3): δ 8.45 (br s, 1H), 8.25-
8.21 (m, 1H), 7.95 (s, 1H), 7.28-7.20 (m, 4H), 7.18-7.13 (m, 2H),
7.04-7.01 (m, 2H), 3.75 (s, 3H), 1.51 (s, 9H). 13C NMR (75 MHz,
CDCl3): δ 167.3, 164.4, 143.0, 137.2, 135.4, 133.8, 130.4, 130.1,
128.9, 127.2, 124.3, 123.3, 122.0, 121.9, 111.5, 109.0, 80.4,
52.6, 28.5. IR (KBr): ν (cm-1) 3299, 1690, 1665. HR-MS (EI) m/z
calcd for C23H23NO4 [M+]: 377.1627; found: 377.1640.
tert-Butyl (E)-2-(3-methoxy-3-oxo-1-(p-tolyl)prop-1-en-2-yl)-
1H-indole-3-carboxylate (14c). Yellow solid (59.8 mg, 90%), m.
p. 86-88 °C. 1H NMR (300 MHz, CDCl3): δ 8.29-8.25 (m, 2H), 7.96
(s, 1H), 7.32-7.24 (m, 3H), 7.00 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4
Hz, 2H), 3.75 (s, 3H), 2.28 (s, 3H), 1.53 (s, 9H) 13C NMR (75 MHz,
CDCl3): δ 167.3, 164.4, 143.1, 140.6, 137.4, 135.4, 131.0, 130.4,
129.6, 127.3, 123.3, 123.3, 122.0, 122.0, 111.4, 109.1, 80.4,
52.5, 28.5, 21.5. IR (KBr): ν (cm-1) 3293, 1690, 1663. HR-MS (EI)
m/z calcd for C24H25NO4 [M+]: 391.1784; found: 391.1794.
tert-Butyl (E)-2-(3-methoxy-1-(4-methoxyphenyl)-3-oxoprop-
1-en-2-yl)-1H-indole-3-carboxylate (14d). Light yellow solid
(61.8 mg, 89%), m. p. 146-148 °C. 1H NMR (300 MHz, CDCl3): δ
8.33 (br s, 1H), 8.27-8.25 (m, 1H), 7.91 (s, 1H), 7.31-7.20 (m, 3H),
6.96 (d, J = 9.0 Hz, 2H), 6.67 (d, J = 9.0 Hz, 2H), 3.73 (s, 3H), 3.72
Experimental section
General remarks
Commercially available chemicals were purchased from Merck
1
and Sigma Aldrich. H NMR and 13C NMR (300 and 75 MHz,
respectively) spectra were acquired in CDCl3 and DMSO-d6 at 25
°C on a 300 MHz Jeol Eclipse and 300 MHz Fourier Brucker
spectrometers. The chemical shifts are reported on the δ scale
in parts per million (ppm) and calibrated to residual solvents
1
(7.26 ppm in CDCl3; 2.50 ppm in DMSO-d6) for H NMR and
(77.16 ppm in CDCl3; 39.50 ppm in DMSO-d6) 13C NMR. Melting
points were measured in open capillaries using a Mel-Temp
apparatus. IR spectra were obtained using an FTIR Tensor 27
6 | J. Name., 2012, 00, 1-3
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(s, 3H), 1.51 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 167.5, 164.4, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.30-7.20V(imew,A3rtHicl)e,O7n.l1in2e
DOI: 10.1039/D1OB00897H
161.1, 142.9, 137.6, 135.4, 132.3, 127.3, 126.4, 123.3, 122.0, (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 3.73 (s, 3H), 1.51 (s,
122.0, 121.6, 114.4, 111.5, 108.9, 80.3, 55.4, 52.4, 28.5. IR (KBr): 9H). 13C NMR (75 MHz, CDCl3): δ 167.0, 164.3, 141.6, 136.8,
ν (cm-1) 3258, 1710, 1655. HR-MS (EI) m/z calcd for C24H25NO5 136.1, 135.5, 132.3, 131.5, 129.2, 127.1, 124.9, 123.6, 122.2,
[M + H+]: 408.1811; found: 408.1828.
122.0, 111.6, 109.3, 80.6, 52.7, 28.5. IR (KBr): ν (cm-1) 3292,
tert-Butyl (E)-2-(1-(4-(dimethylamino)phenyl)-3-methoxy-3- 1691, 1664. HR-MS (EI) m/z calcd for C23H22ClNO4 [M+]:
oxoprop-1-en-2-yl)-1H-indole-3-carboxylate (14e). Yellow solid 411.1237; found: 411.1244.
(66.6 mg, 93%), m. p. 112-114 °C. 1H NMR (300 MHz, CDCl3): δ tert-Butyl (E)-2-(1-(4-fluorophenyl)-3-methoxy-3-oxoprop-1-
8.30-8.27 (m, 1H), 8.24 (br s, 1H), 7.89 (s, 1H), 7.31-7.20 (m, 3H), en-2-yl)-1H-indole-3-carboxylate (14k). Yellow solid (49.1 mg,
6.89 (d, J = 9.0 Hz, 2H), 6.46 (d, J = 9.0 Hz, 2H), 3.72 (s, 3H), 2.92 73%), m. p. 168-170 °C. 1H NMR (300 MHz, CDCl3): δ 8.32 (br s,
(s, 6H), 1.50 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 164.5, 151.2, 1H), 8.25-8.22 (m, 1H), 7.92 (s, 1H), 7.32-7.22 (m, 3H), 7.05-7.00
143.8, 138.6, 135.3, 132.5, 132.5, 127.6, 123.1, 122.0, 121.9, (m, 2H), 6.89-6.83 (m, 2H), 3.75 (s, 3H), 1.52 (s, 9H). 13C NMR
118.5, 112.0, 112.0, 111.4, 80.1, 52.3, 40.2, 28.5. IR (KBr): ν (cm- (75 MHz, CDCl3): δ 167.1, 164.2, 163.5 (d, J = 250.6 Hz), 141.8,
1) 3277, 1685. HR-MS (EI) m/z calcd for C25H28N2O4 [M + H+]: 136.9, 135.4, 132.4 (d, J = 8.4 Hz), 130.0 (d, J = 3.3 Hz), 127.1,
421.2127; found: 421.2128.
124.0 (d, J = 1.7 Hz), 123.5, 122.1, 122.0, 116.1 (d, J = 21.6 Hz),
tert-Butyl (E)-2-(3-methoxy-1-(4-nitrophenyl)-3-oxoprop-1- 111.5, 109.3, 80.5, 52.6, 28.5. IR (KBr): ν (cm-1) 3292, 1690,
en-2-yl)-1H-indole-3-carboxylate (14f). Brown solid (43.2 mg, 1663. HR-MS (EI) m/z calcd for C23H22FNO4 [M+]: 395.1533;
60%), m. p. 68-70 °C. 1H NMR (300 MHz, CDCl3): δ 8.25-8.20 (m, found: 395.1538.
2H), 8.03 (d, J = 9.0 Hz, 2H), 8.00 (s, 1H), 7.32-7.28 (m, 3H), 7.21
(d, J = 9.0 Hz, 2H), 3.80 (s, 3H), 1.54 (s, 9H). 13C NMR (75 MHz,
General procedure for carboxylic acids 3a-k
CDCl3): δ 166.4, 164.1, 147.9, 140.2, 139.9, 135.8, 135.5, 130.8, To a solution of the corresponding α,β-unsaturated ester 14 (0.1
128.3, 126.8, 123.9, 123.9, 122.5, 122.2, 111.6, 109.9, 80.8, mmol) in DCM (2 mL) was added trifluoroacetic acid (0.5 mL) at
52.9, 28.5. IR (KBr): ν (cm-1) 3273, 1718, 1686, 1518. HR-MS (EI) 0 °C. The reaction mixture was stirred for 30 min at the same
m/z calcd for C23H22N2O6 [M+]: 422.1478; found: 422.1457.
temperature and then at room temperature for 60 min. The
tert-Butyl (E)-2-(1-(4-cyanophenyl)-3-methoxy-3-oxoprop-1- solvent was removed under reduced pressure and the crude
en-2-yl)-1H-indole-3-carboxylate (14g). Yellow solid (44.6 mg, product was purified by column chromatography on silica gel
65%), m. p. 96-98 °C. 1H NMR (300 MHz, CDCl3): δ 8.38 (br s, 1H), eluting with hexane/EtOAc (50:50) to give the desired product.
8.21-8.18 (m, 1H), 7.92 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.31-7.25 (E)-2-(1-(4-Hydroxyphenyl)-3-methoxy-3-oxoprop-1-en-2-yl)-
(m, 3H), 7.12 (d, J = 8.4 Hz, 2H), 3.77 (s, 3H), 1.53 (s, 9H). 13C 1H-indole-3-carboxylic acid (prenostodione, 3a). Red solid (26
1
NMR (75 MHz, CDCl3): δ 166.6, 164.2, 140.4, 138.4, 136.0, mg, 79%), m. p. 170-172 °C. H NMR (300 MHz, DMSO-d6): δ
135.6, 132.5, 130.5, 127.8, 126.9, 123.9, 122.5, 122.2, 118.4, 11.84 (br s, 2H), 10.01 (s, 1H), 8.06 (m, 1H), 7.79 (s, 1H), 7.39 (m,
113.0, 111.6, 109.8, 80.8, 52.9, 28.6. IR (KBr): ν (cm-1) 3282, 1H), 7.19 (m, 2H), 6.85 (d, J = 8.3 Hz, 2H), 6.59 (d, J = 8.3 Hz, 2H),
2227, 1690, 1663. HR-MS (EI) m/z calcd for C24H22N2O4 [M + H+]: 3.64 (s, 3H). 13C NMR (75 MHz, DMSO-d6): δ 166.7, 165.7, 159.4,
403.1657; found: 403.1663.
tert-Butyl
142.1, 139.1, 135.6, 132.1, 126.9, 124.6, 122.3, 121.1, 121.0,
(E)-2-(3-methoxy-3-oxo-1-(4-(trifluoromethyl) 120.2, 115.6, 111.9, 105.6, 51.9. IR (KBr): ν (cm-1) 3277, 2951,
phenyl)prop-1-en-2-yl)-1H-indole-3-carboxylate (14h). Yellow 1670, 1656. HR-MS (EI) m/z calcd for C19H15NO5 [M+]: 337.0950;
solid (56.2 mg, 74%), m. p. 48-50 °C. 1H NMR (300 MHz, CDCl3): found: 337.0937.
δ 8.33 (br s, 1H), 8.24-8.20 (m, 1H), 7.96 (s, 1H), 7.42 (d, J = 8.4 (E)-2-(3-Methoxy-3-oxo-1-phenylprop-1-en-2-yl)-1H-indole-3-
Hz, 2H), 7.31-7.24 (m, 3H), 7.15 (d, J = 8.4 Hz, 2H), 3.77 (s, 3H), carboxylic acid (3b). Red solid (25.8 mg, 80%), m. p. 116-118 °C.
1.52 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 166.8, 164.2, 141.1, 1H NMR (300 MHz, DMSO-d6): δ 12.00 (br s, 1H), 11.89 (s, 1H),
137.3, 136.3, 135.5, 131.4 (q, J = 32.7 Hz), 130.4, 127.0, 126.8, 8.07-8.04 (m, 1H), 7.90 (s, 1H), 7.39-7.36 (m, 1H), 7.32-7.17 (m,
125.8 (q, J = 3.7 Hz), 123.8 (q, J = 270.0 Hz), 123.8, 122.4, 122.2, 5H), 7.05-7.03 (m, 2H), 3.68 (s, 3H). 13C NMR (75 MHz, DMSO-
111.6, 109.7, 80.7, 52.8, 28.6. IR (KBr): ν (cm-1) 3292, 1693, d6): δ 166.4, 165.8, 141.8, 138.5, 135.7, 133.7, 130.0, 130.0,
1664. HR-MS (EI) m/z calcd for C24H22F3NO4 [M+]: 445.1501; 128.7, 126.8, 124.3, 122.5, 121.2, 121.1, 112.0, 106.0, 52.2. IR
found: 445.1515.
(KBr): ν (cm-1) 3280, 2951, 1695, 1652. HR-MS (EI) m/z calcd for
tert-Butyl (E)-2-(1-(4-bromophenyl)-3-methoxy-3-oxoprop-1- C19H15NO4 [M+]: 321.1001; found: 321.0989.
en-2-yl)-1H-indole-3-carboxylate (14i). Yellow solid (57.6 mg, (E)-2-(3-Methoxy-3-oxo-1-(p-tolyl)prop-1-en-2-yl)-1H-indole-
74%), m. p. 84-86 °C. 1H NMR (300 MHz, CDCl3): δ 8.25-8.21 (m, 3-carboxylic acid (3c). Yellow solid (26.5 mg, 79%), m. p. 124-
2H), 7.89 (s, 1H), 7.32-7.27 (m, 5H), 6.90 (d, J = 8.4 Hz, 2H), 3.76 126 °C. 1H NMR (300 MHz, DMSO-d6): δ 11.95 (br s, 1H), 11.85
(s, 3H), 1.53 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 167.0, 164.3, (s, 1H), 8.07-8.04 (m, 1H), 7.86 (s, 1H), 7.39-7.36 (m, 1H), 7.21-
141.6, 136.7, 135.5, 132.7, 132.2, 131.7, 127.1, 125.1, 124.5, 7.18 (m, 2H), 7.04 (d, J = 7.8 Hz, 2H), 6.91 (d, J = 7.8 Hz, 2H), 3.67
123.6, 122.2, 122.0, 111.6, 109.3, 80.6, 52.7, 28.6. IR (KBr): ν (s, 3H), 2.21 (s, 3H). 13C NMR (75 MHz, DMSO-d6): δ 166.5, 165.7,
(cm-1) 3301, 1688, 1662. HR-MS (EI) m/z calcd for C23H2279BrNO4 141.9, 140.1, 138.7, 135.7, 131.0, 130.0, 129.3, 126.9, 123.2,
[M+]: 455.0732; found: 455.0725.
122.5, 121.2, 121.1, 112.0, 105.9, 52.2, 20.9. IR (KBr): ν (cm-1)
tert-Butyl (E)-2-(1-(4-chlorophenyl)-3-methoxy-3-oxoprop-1- 3281, 2950, 1697, 1655. HR-MS (EI) m/z calcd for C20H17NO4
en-2-yl)-1H-indole-3-carboxylate (14j). Yellow solid (52 mg, [M+]: 335.1158; found: 335.1151.
74%), m. p. 238-240 °C. 1H NMR (300 MHz, CDCl3): δ 8.48 (br s,
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(E)-2-(3-Methoxy-1-(4-methoxyphenyl)-3-oxoprop-1-en-2-yl)- 2H), 7.39-7.36 (m, 1H), 7.23-7.17 (m, 2H), 6.98 (d, JV=ie8w.A4rtHiclze,O2nHlin)e,
1H-indole-3-carboxylic acid (3d). Red solid (30.6 mg, 87%), m. 3.68 (s, 3H). 13C NMR (75 MHz, DMSO-d6)D: OδI1: 1606.1.033,91/6D51O.6B,0104809.75H,
1
p. 98-100 °C. H NMR (300 MHz, DMSO-d6): δ 11.87 (br s, 2H), 138.0, 135.7, 133.1, 131.7, 131.7, 126.7, 125.1, 123.4, 122.6,
8.07-8.05 (m, 1H), 7.85 (s, 1H), 7.40-7.38 (m, 1H), 7.21-7.18 (m, 121.3, 121.1, 112.0, 106.2, 52.3. IR (KBr): ν (cm-1) 3285, 2950,
2H), 6.98 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 3.69 (s, 3H), 1700, 1655. HR-MS (EI) m/z calcd for C19H1479BrNO4 [M+]:
3.66 (s, 3H). 13C NMR (75 MHz, DMSO-d6): δ 166.6, 165.7, 160.7, 399.0106; found: 399.0103.
141.7, 138.9, 135.7, 131.9, 126.9, 126.2, 122.4, 121.3, 121.1, (E)-2-(1-(4-Chlorophenyl)-3-methoxy-3-oxoprop-1-en-2-yl)-
121.1, 114.3, 112.0, 105.7, 55.3, 52.0. IR (KBr): ν (cm-1) 3282, 1H-indole-3-carboxylic acid (3j). Red solid (31 mg, 87%), m. p.
1
2952, 1965, 1653. HR-MS (EI) m/z calcd for C20H17NO5 [M+]: 78-80 °C. H NMR (300 MHz, DMSO-d6): δ 11.87 (s, 1H), 8.06-
351.1107; found: 351.1117.
(E)-2-(1-(4-(Dimethylamino)phenyl)-3-methoxy-3-oxoprop-1-
8.03 (m, 1H), 7.89 (s, 1H), 7.45-7.36 (m, 2H), 7.32 (d, J = 8.4 Hz,
2H), 7.23-7.17 (m, 2H), 7.05 (d, J = 8.4 Hz, 2H), 3.68 (s, 3H). 13
C
en-2-yl)-1H-indole-3-carboxylic acid (3e). Brown solid (28.8 mg, NMR (75 MHz, DMSO-d6): δ 166.3, 165.6, 140.4, 138.0, 135.7,
1
79%), m. p. 230 °C. H NMR (300 MHz, DMSO-d6): δ 11.83 (s, 134.5, 132.7, 131.5, 128.8, 126.7, 125.0, 122.6, 121.3, 121.1,
1H), 8.07-8.04 (m, 1H), 7.77 (s, 1H), 7.41-7.37 (m, 1H), 7.22-7.15 112.0, 106.2, 52.3. IR (KBr): ν (cm-1) 3293, 2952, 2851, 1701,
(m, 2H), 6.82 (d, J = 8.7 Hz, 2H), 6.50 (d, J = 8.7 Hz, 2H), 3.63 (s, 1655. HR-MS (EI) m/z calcd for C19H14ClNO4 [M+]: 355.0611;
3H), 2.86 (s, 6H). 13C NMR (75 MHz, DMSO-d6): δ 166.9, 165.7, found: 355.0603.
151.3, 142.8, 139.9, 135.6, 131.9, 127.1, 122.2, 121.1, 121.0, (E)-2-(1-(4-Fluorophenyl)-3-methoxy-3-oxoprop-1-en-2-yl)-
120.8, 117.5, 111.9, 111.6, 105.4, 51.7. Dimethylamino signal 1H-indole-3-carboxylic acid (3k). Brown solid (23.9 mg, 70%),
overlaps with the solvent peaks. IR (KBr): ν (cm-1) 3280, 2918, m. p. 160-162 °C. 1H NMR (300 MHz, DMSO-d6): δ 11.88 (s, 2H),
1735, 1648. HR-MS (EI) m/z calcd for C21H20N2O4 [M+]: 364.1423; 8.07-8.04 (m, 1H), 7.90 (s, 1H), 7.40-7.37 (m, 1H), 7.21-7.18 (m,
found: 364.1435.
(E)-2-(3-Methoxy-1-(4-nitrophenyl)-3-oxoprop-1-en-2-yl)-1H-
2H), 7.10 (d, J = 7.2 Hz, 4H), 3.67 (s, 3H). 13C NMR (75 MHz,
DMSO-d6): δ 166.4, 165.7, 162.7 (d, J = 247.3 Hz), 140.7, 138.3,
indole-3-carboxylic acid (3f). Red solid (28.7 mg, 78%), m. p. 135.7, 132.3 (d, J = 8.7 Hz), 130.4 (d, J = 3.2 Hz), 126.8, 124.0,
144-146 °C. 1H NMR (300 MHz, DMSO-d6): δ 11.91 (s, 1H), 8.10- 122.6, 121.3, 121.1, 115.9 (d, J = 21.7 Hz), 112.1, 106.1, 52.3. IR
8.07 (d, J = 9.0 Hz, 2H), 8.08-8.03 (m, 1H), 8.01 (s, 1H), 7.40-7.34 (KBr): ν (cm-1) 3286, 2955, 1731, 1698. HR-MS (EI) m/z calcd for
(m, 1H), 7.31 (d, J = 9.0 Hz, 2H), 7.24-7.18 (m, 2H), 3.71 (s, 3H). C19H14FNO4 [M+]: 339.0907; found: 339.0895.
13C NMR (75 MHz, DMSO-d6): 166.0, 165.6, 147.4, 140.5, 139.4,
137.3, 135.8, 130.8, 128.0, 126.7, 123.7, 122.8, 121.4, 121.2,
112.1, 106.7, 52.5. IR (KBr): ν (cm-1) 3281, 2948, 1704, 1656,
1517. HR-MS (EI) m/z calcd for C19H14N2O6 [M+]: 366.0852;
found: 366.0848.
Conflicts of interest
There are no conflicts to declare.
(E)-2-(1-(4-Cyanophenyl)-3-methoxy-3-oxoprop-1-en-2-yl)-1H-
indole-3-carboxylic acid (3g). Red solid (26.4 mg, 76%), m. p.
150-152 °C. H NMR (300 MHz, DMSO-d6): δ 12.10 (br s, 1H),
Acknowledgements
1
We acknowledge CONACYT (grant A1-S-16584), DGAPA-UNAM
(grant IN204619) and NUATEI-IIB-UNAM for financial support.
A. R. O. thanks CONACYT for a M.Sc. fellowship (CVU 770510).
We are also grateful for the technical support provided by
Rubén Toscano, Javier Pérez, Carmen García, Ángeles Peña,
Elizabeth Huerta, Beatriz Quiroz, Isabel Chávez, Héctor Ríos,
Lucero Ríos and Rocío Patiño (IQ-UNAM).
11.90 (s, 1H), 8.06-8.03 (m, 1H), 7.95 (s, 1H), 7.72 (d, J = 8.1 Hz,
2H), 7.38-7.35 (m, 1H), 7.22-7.20 (m, 4H), 3.70 (s, 3H). 13C NMR
(75 MHz, DMSO-d6): δ 166.0, 165.6, 139.8, 138.5, 137.5, 135.7,
132.4, 130.3, 127.4, 126.6, 122.8, 121.4, 121.1, 118.4, 112.1,
111.7, 106.5, 52.4. IR (KBr): ν (cm-1) 3281, 2952, 2229, 1705,
1656. HR-MS (EI) m/z calcd for C20H14N2O4 [M+]: 346.0954;
found: 346.0966.
(E)-2-(3-Methoxy-3-oxo-1-(4-(trifluoromethyl)phenyl)prop-1-
en-2-yl)-1H-indole-3-carboxylic acid (3h). Red solid (30 mg,
77%), m. p. 102-104 °C. H NMR (300 MHz, DMSO-d6): δ 12.08
Notes and references
1
1
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(br s, 1H), 11.87 (s, 1H), 8.07-8.04 (m, 1H), 7.97 (s, 1H), 7.62 (d,
J = 8.4 Hz, 2H), 7.39-7.36 (m, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.22-
7.19 (m, 2H), 3.70 (s, 3H). 13C NMR (75 MHz, DMSO-d6): δ 166.1,
165.6, 140.0, 137.9, 137.6, 135.7, 130.3, 126.9, 126.7, 125.5 (q,
J = 3.2 Hz), 123.8 (q, J = 271.0 Hz), 122.7, 121.3, 121.1, 112.1,
106.5, 52.4. One of the aromatic quaternary carbons could not
be detected due to its low intensity. IR (KBr): ν (cm-1) 3289,
2953, 1702, 1657. HR-MS (EI) m/z calcd for C20H14F3NO4 [M+]:
389.0875; found: 389.8079.
2
3
(E)-2-(1-(4-Bromophenyl)-3-methoxy-3-oxoprop-1-en-2-yl)-
1H-indole-3-carboxylic acid (3i). Red solid (35.6 mg, 89%), m. p.
4
a) R. P. Rastogi, R. R. Sonani and D. Madamwar, Appl.
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1
158-160 °C. H NMR (300 MHz, DMSO-d6): δ 12.05 (br s, 1H),
11.87 (s,1H), 8.06-8.03 (m, 1H), 7.87 (s, 1H), 7.46 (d, J = 8.4 Hz,
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
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