Synthesis of novel perillyl-dihydropyrimidinone hybrids designed for antiproliferative activity

Article abstract of DOI:10.1039/C8MD00270C

A series of fifteen novel dihydropyrimidinone hybrid compounds were synthesized in good yields via a multicomponent reaction combined with the Huisgen reaction. The antiproliferative activity was investigated against nine tumor cell lines, and four hybrid

Full text of DOI:10.1039/C8MD00270C

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and D. Russowsky, Med. Chem. Commun., 2018, DOI: 10.1039/C8MD00270C.
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Synthesis of novel Perillyl-Dihydropyrimidinone Hybrids designed
for antiproliferative activity
Vinicius Vendrusculo,a Vanessa P. de Souza,a Luiz Antônio M. Fontoura,b,c Marcelo G. M. D’Oca,d
Thais P. Banzato,e,f Paula A. Monteiro,e,f Ronaldo A. Pilli,g João Ernesto de Carvalho,e,f* and Dennis
Russowskya*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A series of fifteen novel dihydropyrimidinone hybrid compounds were synthesized via multicomponent reaction combined
with Huisgen reaction in good yields. The antiproliferative activity was investigated against nine tumor cell lines and four
hybrid compounds (TGI < 10ꢀM) showed promising antiproliferative activity against OVCAR-3 (ovarian), UACC-62
(melaoma) and U251 (glioma) tumor cell lines. Several hybrid compounds assayed have high TGI values ( TGI 147.92-
507.82) for the human keratinocytes cell line (HaCat),which reveals selectivity to cancer cells.
goal is to find molecules that can act on various targets or
molecular receptors, and this process is called "one-compound-
multiple-targets strategy".5 Molecules that are able to on more
Introduction
Multifunctional Drugs and Hybrid Compounds
than one molecular targets are called "multifunctional compounds"
(MFC) and have brought promising results in terms of improving the
therapeutic potential with synergistic effects and minimizing side
effects. It is also possible to highlight the lower risk of drug-drug
interaction in relation to drug cocktails.6
The modern pharmaceutical industry has faced unprecedented
challenges regarding the development of new drugs. Although the
amount of funds spent in scientific research has doubled since
1991, the approval of new drugs decreased around 50% over the
same period. While most diseases involve multiple pathogenic
factors, the decline in new drug development can be attributed in
part to the "one drug and one target paradigm," which defines the
development of a specific drug to each target.1 Additionally, many
of traditional treatments for multifactorial diseases, using a single
drug, have proven to be inefficient because of the inability of the
drug to act at different and specific sites inside the body.2
Alternatively, the use of drug cocktails represents a breakthrough.
However, several drawbacks associated with undesired side effects
and low patient compliance, prevent their use as standard
protocol.3
To have access to such compounds, it is necessary to use
strategies able to join two structures with different activities in a
single chemical entity. The MFCs are classified as hybrid drugs when
two or more drugs with different activities are linked through a
stable or metabolizable connection (linker). In this case, the
chemical structures of the original molecules remain essentially the
same. On the other hand, the MCFs are designed as chimeric drugs
when the new chemical entity is formed by the fusion of two or
more pharmacophores from different molecules, which hold only
parts of the original parent structures (Figure 1).7
To circumvent this problem, a new conception for drugs has
been postulated, in which the objective is to create a "single
chemical entity" with multiple associated biological activities, as
exemplified by
a
pioneer work in the treatment of
neurodegenerative disorders.4 Searching for these structures, the
Figure 1. Picture definition of Hybrid Drugs and Chimera Drugs
Although both types of MFCs (hybrids and chimeras) have their
advantages and disadvantages, the central idea of the association of
two pharmacophores is to increase the potency of both and/or
reduce their dosage.8 Recent reports in the literature have proven
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O
O
the success of hybridization of several drugs, improving the
characteristics of each original compound. For example: tacrine was
the first drug to combat the Alzheimer Disease (AD) by the
inhibition of acetylcholinesterase enzyme (AChE). However, poor
selectivity and hepatoxicity were observed as injurious collateral
effects due to oxidative stress.9 The hybridization of tacrine with
the antioxidant compounds such as ferulic or caffeic acids led to a
new hybrid compounds with an increase of antioxidant properties
and a high selectivity on the inhibition of AChE. Additionally, the
hybrid compounds have been found to inhibit AChE-induced
αβ aggregation inhibitory activity.10
This strategy was also successfully applied in the field of
anticancer agents.11 A synergistic effect can be achieved when the
two pattern molecules have similar effects. The biologically active
β-lactams and chalcones, used to form hybrid compounds via
formation of 1,2,3-triazole linker, showed antiproliferative activity
against A-549 (lung), THP-1 (leukemia) and Caco-2 tumor cell lines,
at low concentrations (Figure 2).12
OH
OH
O
O
O
NH
EtO
NH
EtO
NH
N
H
N
H
S
S
N
S
H
Monastrol
Dimthylenastron
Piperastrol
Figure 3. Antiproliferative Ddihydropyrimidinones
Monastrol,16 dimethylenastron17 and piperastrol18 are three
notorious members of these extensive class of bioactive
heterocycles and their antiproliferative activity against cancer cell
lines have been established (Figure 3). Their antiproliferative
activities were attributed to its ability to inhibit the enzyme Eg5
Kinesin, responsible for the mobility of organelles during the mitotic
cycle of cell division. Inhibition of this enzyme blocks the formation
of the bipolar spindle and causes disruption in the cell cycle.19
Armed with this background, we choose the dihidropyrimidinone
scaffold as constitutive half-part of the new hybrid compounds to
be synthesized. On the other hand, the other part of the hybrid
molecule was chosen based on the antiproliferative activities
exhibited by perillyl alcohol.20 Perillyl alcohol is a natural occurring
monocyclic terpene, found in the essential oils extracted from
lavender, lemongrass, and peppermint, among others. Its
antitumoral properties have been extensively studied in the last
decades as active compound against various cancer cell lines, such
as pancreatic,21 liver,22 melanoma,23 colon,24 leukemia25 and
remarkable activity against gliomas.26 Furthermore, perillyl alcohol
has been used clinically as nasal spray applications to minimize the
injurious effects of recurrent malignant glioma.27 However, there
are few reports of synthesis and applications of hybrid compounds
based on perillyl moiety (Figure 4).28
Tacrine
O
β-Lactam
OH
OR
MeO
O
H
H
O
R
N
N
( )n
N
N
O
N
Chlacone
N
R= H - from Caffeic acid
R= Me - Froms Ferulic acid
Triazole
Linker
Ph
Hybrid β-Lactam-Chalcone
(Antiproliferative)
Hybrid Tacrine-Ferulic Acid
(Antioxidant)
Dihydropyrimidinone
Moiety
NO2
Dihydropyrimidinone
Moiety
OH
H
H
tBu
N
N
O
N
Pyrrol-3-Carboxylic
Acid Derivative
O
EtO
NH
O
OMe
Ph
N
Me
N
O
EtO
Me
NH
H
N
Semicarbazone
Deivative
Linker
N
O
H
O
Me
CO2H
Hybrid Dihydropyrimidinone-Semicarbazone
(DNA damaging agent)
Hybrid Dihydropyrimidinone-Pyrrol-3-Carboxylate
(Antimalarial)
O
HO
OH
Br
O
N
O
N3
N
H
Figure 2. Biologically active hybrid compounds
O
HO
Perillyl Alcohol-3-Bromopyruvate
Antiproliferative activity
against A549 and PC3 cells
Amino-modified Perillyl Alcohol
Antiproliferative activity against
A549, A375-S2 and HT-1080 cells
Perillyl alcohol-Glicoside
Glyceraldehyde 3-phosphate
dehydrogenase(GAPDH) inhibitor
The dihidropyrimidinones were also investigated as
a
N
O
O
component of new hybrid compounds. The hybrid
dihydropyrimidinone-pyrrol-3-carboxylate is promising
O
O
Me
N
N
H
O
N
a
O
N
Perillyl Alcohol-Temozolomide
Antiproliferative activity against
recurrent resistant Glioblastoma
Perillyl Alcohom-Retinoic Acid
Potential apoptosis agent
antimalarial compound due to high inhibitory activity on the Hsp70
molecular chaperones of Plasmodium falciparum (malaria). The
chaperones are a family of proteins that prevent a wrong folding of
a protein, helping to maintain its functional structure. Additionally,
it induces the protein destruction if the correct conformation
cannot be achieved.13 Another example is the hybrid
dihydropyrimidinone-semicarbazone, which was found to be a
highly selective human DNA ligase 1 inhibitor (hLig1). This property
resulted in an antiproliferative activity against tumour cells being a
promising prototype as hybrid anticancer compound (see Figure
2).14
Figure 4. Hybrid compounds from Pperillyl Aalcohol
Thus, the present study reports the synthesis and the cytotoxic
activities of a series of novel hybrid compounds derived from
dihydropyrimidinones and (S)-perillyl alcohol against
a set of
tumour cell lines. The hybridization process was performed using
the Huisgen reaction to create a stable 1,2,3-triazolyl linker (Figure
5).29
Dihidropyrimidinones, Perillyl Alcohol and Antiproliferative
Activities
The dihydropyrimidinones (DHPMs) are recognized as effective
bioactive agents with a large scope of pharmacological activities,
including anticancer properties.15
Figure 5. Strategy to hybridize DHPMs and Pperillyl alcohol via
1,2,3-Ttriazolyl linker
2 | J. Name., 2012, 00, 1-3
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with propargyloxy dihydropyrimidinones 4a-o, the perillyl azide 7
was required. It was not possible to prepare the azido compound
from the perillyl alcohol mesylate. Therefore, the perillyl alcohol (5)
was converted into perillyl chloride (6), via Appel’s reaction28a,33 and
then it was transformed into the corresponding perillyl azide (7).
The overall yield for these two steps was 85%.
Results and Discussion
Synthesis of Propargyl Dihydropyrimidinones
The synthesis of dihydropyrimidonones 4a-o was accomplished
via the multicomponent Biginelli reaction through
a
cyclocondensation of ethyl acetoacetate 1a, acetylacetone 1b or
dimedone 1c, as the 1,3-dicarbonyl compounds, urea (2), and a
series of propargyloxy benzaldehydes 3a-e, under Bronsted or Lewis
acids catalysis30 (Scheme 1, Table 1). The aldehydes were easily
prepared, in good yields, by O-alkylation reactions from the
corresponding hydroxy-substituted benzaldehydes and propargyl
bromide.31
With the propargyloxy-dihydropyrimidinones 4a-o and the
perillyl azide (7) in hands, we proceeded to the synthesis of the
hybrids perillyl-dihydropyrimidinone 8a-o through the copper-
catalyzed Huisgen reaction. (Scheme 2). The results for the
synthesis of hybrids perillyl-DHPM are shown in the Table 2, below
Scheme 2. Synthesis of Perillyl Azide and the Cu(I) catalyzed
Huisgen reaction
Scheme 1. Synthesis of Propargyloxy Dihydropyrimidinones
The hybrids perillyl-dihydropyrimidinones 8a-o were purified
through column chromatography on silica gel. The yields were
calculated after the isolation of the pure products. All compounds
were fully characterized by conventional spectroscopic methods
including HRMS for the novel compounds and the data were
compatible with the proposed structures (Table 2).
Table 1. Synthesis of propargyloxy-Dihydropyrimidinones
DHPM
1
3
Y-%
90
75
83
86
75
69
67
67
62
64
67
74
70
72
81
R1
R2
R3
R4
R5
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
3a
3b
3c
3d
3e
3a
3b
3c
3d
3e
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
4f
EtO
Me
H
H
OPga
EtO
EtO
EtO
EtO
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
OPga
H
OPga
H
H
H
OPga
OMe
H
OMe
OPga
OPga
H
Table 2. Synthesis of hybrids perillyl-dihydropyrimidinones
H
H
4g
4h
4i
H
OPga
OPga
H
H
H
OPga
OMe
H
OMe
OPga
OPga
H
4j
H
Perillyl-DHPM Hybrids
4k
4l
-CH2C(CH3)2CH2-
-CH2C(CH3)2CH2-
-CH2C(CH3)2CH2-
-CH2C(CH3)2CH2-
-CH2C(CH3)2CH2-
H
Entry
Y-%
90
79
85
73
71
72
71
68
67
76
84
68
80
71
79
R1
R2
R3
R4
R5
H
OPga
1
8a
8b
8c
8d
8e
8f
EtO
Me
H
H
Xc*
4m
4n
4o
OPga
H
H
2
EtO
EtO
EtO
EtO
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Xc*
H
Xc*
H
H
H
OPga
OMe
OMe
OPga
3
H
H
4
Xc*
OMe
H
OMe
Xc*
Xc*
H
a
5
H
OPg= OCH2CCH
6
H
7
8g
8h
8i
H
Xc*
H
The propargyloxy dihydropyrimidinones were purified through
8
Xc*
H
H
column chromatography on silica gel (4a-j) or simple crystallization
(4k-o). All compounds were fully characterized by conventional
spectroscopic methods including HRMS for the novel compounds.
The data were in accordance with the proposed structures. The
9
Xc*
OMe
H
OMe
Xc*
Xc*
H
10
11
12
13
14
15
8j
H
8k
8l
-CH2C(CH3)2CH2-
-CH2C(CH3)2CH2-
-CH2C(CH3)2CH2-
-CH2C(CH3)2CH2-
-CH2C(CH3)2CH2-
H
1
H
Xc*
H
main H NMR spectroscopic evidences of the DHPM formation are
the broad singlets at 9.20 ppm and 7.70 ppm, respectively, assigned
to N-H groups. The singlet around 5.10 ppm assigned to the benzylic
hydrogen also corroborates the formation of the DHPM ring.
8m
8n
8o
Xc*
H
H
Xc*
OMe
OMe
Xc*
H
Synthesis of Hybrids Perillyl-Dihydropyrimidinones
The appearance of a low field singlet (7.40-8.20 ppm) assigned
The chosen strategy to hybridize molecules was the
regioselective copper(I) catalyzed [3+2] cycloaddition of alkynes and
azide compounds.32 Thus, to perform the molecular hybridization
to the triazolic hydrogen along with characteristic signals of DHPM
1
and terpene ring in the H NMR spectra, corroborate the obtention
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of the desired compounds. All spectroscopic data were compatible indicative of the mechanism of action by its comparison with known
with the proposed structures.
chemotherapeutics.
Next, the fifteen synthesized new hybrid molecules were
The antiproliferative activities of hybrid compounds 8a-o were
screened for their antiproliferative activities against nine different evaluated against the human cancer cell lines: UACC-62
tumor cell lines, using the Total Growth Inhibition (TGI) as a (melanoma), U251 (glioma), MCF7 (breast), NCI/ADR-RES
parameter of the antiproliferative activity.
(multidrug resistant breast), 786-0 (kidney), NCI-H460 (lung), PC-3
(prostate), OVCAR-3 (ovarian), HT29 (colon). The TGI values for
HaCaT (normal human keratinocytes) were evaluated to
determinate the action against the non-tumoral cells. Doxorubicin
(DOX) was employed as the positive control (Table 3).
In vitro antiproliferative activity of hybrid compounds
In vitro studies of cytotoxicity are widely used in the initial drug
screening for anticancer drug development.34 Furthermore, these
studies are important to identify whether the tested substance
interferes with either cell metabolism or cell survival, and it can be
Table 3. In vitro antiproliferative activity (TGI)a of hybrid compounds 8a-o.
Hybrid UACC-62 U251 MCF7 NCI/ADR-RES 786-0 NCI-H460 PC-3 OVCAR-3 HT29
43.14 >100 97.08 >100 92.21
HaCaT
8a
8b
8c
19.18
22.92
>100
37.75
26.73
20.50
31.56
34.23
>100
3.83
12.43
12.19
>100
98.09
11.34
19.99
30.52
30.21
>100
77.91
6.61
6.90
18.45
81.19
13.45
53.76
32.65
13.33
34.31
>100
48.03
29.34
>100
11.81
>100
94.99
0.04
77.13 165.69
42.52
>100
39.67
>100
>100
>100
>100
78.17
>100
83.14
>100
>100
>100
51.61
38.72
>100
>100
0.46
>100
>100
>100
54.39
49.27
49.76
62.01
>100
85.69
23.98
21.87
21.68
79.92
>100
15.69
73.42 507.82
>100
>100
82.50
28.97
42.96
68.70
>100
53.26
>100
30.97
44.95
44.81
91.94
0.99
>100
>100
>100
>100
>100
>100
84.90
80.17
>100
>100
>100
>100
>100
0.78
>100
>100
87.34
23.26
44.08
80.31
>100
88.09
53.16
>100
26.67
>100
>100
0,02
>100
>100
>100
62.63
294.37
79.75
75.76
44.47
8d
8e
8f
8g
8h
8i
86.22 115.66
79.55 29.51
95.99 486.19
94.95 147.92
8j
8k
8l
29.94
20.92
26.47
62.01
86.16
1.66
>100
48.99
28.95
>100
>100
0.88
436.18
36.44
78.72
451.02
71.34
1.47
25.97
26.98
8.28
8m
8n
8o
Dox
44.04
0.09
a The concentration that elicits total growth inhibition (TGI in ꢀM) was determined from a non-linear regression analysis using ORIGIN 8.0® (OriginLab Corpo
ration). The experiments were conducted in triplicate. Dox: doxorubicin, positive control.
The TGI (concentration that produces total growth inhibition, or the UACC-62 cell line. Hybrids 8k and 8n displayed TGI values of
cytostatic effect) was determined through a non-linear regression
analysis. The values presented in Table 2 were obtained from the
tumor cells lines mentioned above. After careful analysis, we were
able to identify four compounds with TGI values less than 10 ꢀM.
6.62 ꢀM and 8.28 ꢀM, respectively, both for glioblastoma
multiform (U256) tumor cell line (Figure 6).
Additionally, a series of seven hybrids compounds revealed TGI
range values between 10-20 ꢀM, being considered promising
Compound 8a exhibited TGI value of 6.90 ꢀM for the OVCAR-3 compounds: 8a (UACC-62 and U251), 8b (U251 and OVCAR-3), 8d
(OVCAR-3), 8e (U251), 8f (U251), 8g (OVCAR-3) and 8m (OVCAR-3).
tumor cell line, while the hybrid 8j showed TGI value of 3.83 ꢀM for
4 | J. Name., 2012, 00, 1-3
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Interesting to note, these compounds were mainly selective to 9). Thus, the presence of the perillyl group in the hybrid structures
three tumour cell lines. For UACC-62, hybrid compounds 8a and 8j may have brought about an increase in the antiproliferative
were the most active, while compounds 8a, 8b, 8e, 8f, 8k, 8n were potencies of oxo-derivative 8b as well as other perillyl-
more active to U251. For OVCAR cell line, compounds 8a, 8b, 8d, 8g dihydropyrimidinone hybrids described herein.
and 8m showed the best activities. Thus, U251 and OVCAR-3 were
the tumour cell lines that showed greater sensitivity for most
compounds.
Figure 6. The most potent perillyl-dihydropyrimidinone hybrids.
Figure 8. Profile of oxo-monastrol against different tumor cell lines
Compounds 8b, 8i, 8k and 8n showed high TGI values for HaCaT.
Noteworthy are compounds 8b, 8k and 8n with antiproliferative
activity against tumor cell line U251 and TGI value for HaCaT of
507.82 ꢀM, 436.18 ꢀM and 451.02 ꢀM, respectively. The ratio of
HaCaT/U251 values to compounds 8b, 8k and 8n is 41.66, 65.98 and
54.47, respectively, and makes evident the high selectivity of these
compounds relative to U251 tumor cell line.
Previous comparative studies of monastrol and oxo-monastrol
regarding the antiproliferative activities,18 indicated that thio-
derivatives were always cytotoxic while the oxo-analogues were
cytostatic. One of the main conclusions from this initial study was
the influence of sulfur atom in monastrol on the potency of
antiproliferative activity. Comparison between monastrol and oxo-
Figure 9. Profile of hybrid 8b against different tumor cell lines
monastrol showed significant difference in growth inhibition
profiles. For example, monastrol was more potent than oxo-
The antiproliferative activity of these DHPM hybrids against
monastrol at concentrations of 25 ꢀM (Figure 7 and 8, respectively).
glioblastomas were not entirely surprise. Early studies conducted by
our research group, showed the DHPMs were active against human
U138-MG and Rat-C6 tumour cell lines.35 In other study, it was
demonstrated the DHPM was able to inhibit the Ecto-
5’Nucleotidase/CD73,36 an ecto-enzyme responsible for hydrolysing
the nucleoside monophosphates such as AMP to adenosine.37 More
recently, hybrids of monastrol-fatty acids exhibited antiproliferative
activity against glioblastomas,38 as well as the Hantzsch
dihydropyridine-fatty acids hybrids showed similar properties.39
Experimental Section
Chemistry
General procedure for synthesis of Propargyloxy Benzaldehydes
Figure 7. Profile of oxo-monastrol against different tumor cell lines
3a-e.
Although the activity of thio-dihydropyrimidinones hybrids were
not evaluated in the present study, the results obtained for perillyl-
dihydropyrimidinone 8b (an oxo-derivative) showed growth
inhibition profile similar to those of Monostrol (thio-derivative)
rather than to oxo-monastrol, at the concentration of 25 ꢀM (Figure
A mixture of hydroxy aldehydes (5.0 mmol), propargyl bromide (10
mmol), potassium carbonate (10 mmol) and acetone (50 mL) was
stirred under reflux for 1-4 h period, monitored by TLC. After, the
crude mixture was filtered, and the solvent was retired under
vacuum to yield the propargyloxy benzaldehydes 3a-e with
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satisfactory level of purity. The characterization of compound 3a-e 3123, 2978, 2116, 1707, 1655, 1224, 1100, 790, 645; HRMS calc. for
were confirmed by comparison with the reported data. The [C17H18N2O4+Na]: 337.1159; Found: 337.1152.
compounds 3a-e were used in the next step without further Ethyl
6-methyl-2-oxo-4-[3-(prop-2-yn-1-yloxy)phenyl]-1,2,3,4-
purification.
tetrahydropyrimidine-5-carboxylate (4b): Yield 90%; white solid;
4-(prop-2-yn-1-yloxy)benzaldehyde (3a):40 Yield 95%; yellow solid;
1
m.p. 156ºC; H NMR (400 MHz, DMSO-d6):
δ 9.21 (br s, 1H); 7.75
m.p. 71oC; 1H NMR (400 MHz, CDCl3):
8.8 Hz); 7.09 (d, 2H, J= 8.6 Hz); 4.78 (d, 2H, J= 2.5 Hz); 2.58 (t, 1H, J= 3.3 Hz); 4,75 (d, 2H, J= 2.3 Hz); 4,00 (q, 2H, J= 7.3 Hz); 3.55 (t, 1H, J=
2.5Hz); 2,24 (s, 3H); 1.11 (t, 3H, J= 7.0 Hz); 13C NMR (100 MHz,
DMSO-d6): 165.8; 157.7; 152.7; 149.0; 146.8; 130.0; 119.5; 113.8;
113.4; 99.6; 79.6; 78.6; 59.8; 55.8; 54.1; 18.2; 14.6; IR (νmax cm-1):
δ 9.90 (s, 1H); 7.86 (d, 2H, J= (br s, 1H); 7.26 (t, 1H, J= 7.8 Hz); 6.90-6.81 (m, 3H); 5.11 (d, 1H, J=
2.4 Hz); 13C NMR (75 MHz, CDCl3):
115.1; 77.5; 76.4; 55.9; IR (νmax cm-1): 3413, 3214, 2834, 2744, 2115,
δ 190.8; 162.3; 131.9; 130.5;
δ
1686, 1606, 1256, 1160, 1003, 827.
3-(prop-2-yn-1-yloxy)benzaldehyde (3b) 40
:
Yield 85%; colorless 3279, 3247, 3118, 2977, 2928, 2117, 1717, 1699, 1643, 1225, 1097,
777; HRMS calc. for [C17H18N2O4+Na]: 337.1159; Found: 337.1158.
Ethyl 6-methyl-2-oxo-4-[2-(prop-2-yn-1-yloxy)phenyl]-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (4c): Yield 83%; Pale green
1
liquid; H NMR (400 MHz, CDCl3):
7.23 (ddd, 1H, J= 7.8; 2.8 and 1.5 Hz); 4.76 (d, 2H, J= 2.5 Hz); 2.56 (t,
1H, J= 2.5 Hz); 13C NMR (100 MHz, CDCl3):
191.7; 157.9; 137.6;
δ 9.98 (s, 1H); 7.53-7.46 (m, 3H);
δ
1
130.0; 123.9; 121.9; 113.4; 77.8; 76.1; 55.8; IR (νmax cm-1): 3284,
solid; m.p. 155ºC; H NMR (300 MHz, DMSO-d6):
δ 9.14 (br s, 1H);
7.21-7.27 (m, 2H); 7.06-7.10 (m, 2H); 6,92 (t, 1H, J= 7.0 Hz); 5.49 (d,
1H, J= 2.2 Hz); 4.85 (dd, 1H, J= 2.3; 16.1 Hz); 4.78 (dd, 1H, J= 16,1
and 2.6 Hz); 3.99-3.84 (m, 2H); 3.58 (t, 1H, J= 2.3 Hz); 2.28 (s, 3H);
1.03 (t, 3H, J= 7.0 Hz); 13C NMR (75 MHz, DMSO-d6):
δ 165.3; 154.6;
152.1; 149.0; 132.3; 128.5; 127.4; 121.0; 112.6; 97.6; 79.5; 78.2;
59.0; 55.8; 48.8; 17.8; 14.1; IR (νmax cm-1): 3252, 3115, 2981, 2928,
2123, 1707, 1668, 1637, 1488, 1228, 1088, 759; HRMS calc. for
[C17H18N2O4+Na]: 337.1159; Found: 337.1156.
2836, 2740, 2123, 1701, 1588, 1266, 1246, 1038, 791, 681.
2-(prop-2-yn-1-yloxy)benzaldehyde (3c) 40
:
Yield 95%; Yellow solid;
10.50 (s, 1H); 7.87 (dd, 1H,
J= 7.6 and 2.0 Hz); 7.60-7.56 (m, 1H); 7.14-7.08 (m, 2H); 4.85 (d, 2H,
J= 2.3 Hz); 2.57 (t, 1H, J= 2,3 Hz); 13C NMR (100 MHz, CDCl3):
m.p. 66oC; 1H NMR (400 MHz, CDCl3):
δ
δ
189.4; 160.0; 135.6; 128.4; 125.4; 121.6; 113.1; 77.6; 76.4; 56.3; IR
(νmax cm-1): 3266, 2879, 2119, 1686, 1599, 1478, 1458, 1227,758.
4-methoxy-3-(prop-2-yn-1-yloxy)benzaldehyde (3d) 41
:
Yield 97%;
Yellow solid; m.p. 71oC; 1H NMR (400 MHz, CDCl3):
δ
9.86 (s, 1H);
Ethyl 4-[4-methoxy-3-(prop-2-yn-1-yloxy)phenyl]-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4d): Yield 75%; Yellow
7.55-7.51 (m, 2H); 7.01 (d, 1H, J= 8.1 Hz); 4,82 (d, 2H, J= 2.3 Hz);
3.96 (s, 3H); 2.55 (t, 1H, J= 2,5 Hz); 13C NMR (100 MHz, CDCl3):
1
solid; m.p. 149ºC; H NMR (400 MHz, DMSO-d6):
δ 8.40 (br s, 1H);
δ
7.04 (d, 1H, J= 1.8 Hz); 6.92 (dd, 1H, J= 8.3 and 1.8 Hz); 6.81 (d, 1H
J= 8.3 Hz); 5.97 (br s, 1H); 5.36 (d, 1H, J= 2.5 Hz); 4.73 (d, 2H, J= 2.0
Hz); 4.09 (q, 2H, J= 7.3 Hz); 3.84 (s, 3H); 2.49 (t, 1H, J= 2.4 Hz); 2.34
190.6; 154.8; 147.2; 129.8; 127.2; 111.9; 110.8; 77.6; 76.4; 56.5;
56.1; IR (νmax cm-1): 3225, 2936, 2836, 2122, 1669, 1588, 1508,
1438, 1257, 1126, 1015, 714, 634.
(s, 3H); 1.18 (t, 3H, J= 7.0 Hz); 13C NMR (100 MHz, DMSO-d6):
δ
3-methoxy-4-(prop-2-yn-1-yloxy)benzaldehyde (3e) 40
Yellow solid; m.p. 88oC; 1H NMR (400 MHz, CDCl3):
:
Yield 96%;
165.7; 153.6; 149.4; 146.8; 146.3; 136.3; 120.2; 113.3; 111.7; 101.4;
78.5; 76.0; 60.0; 57.0; 55.9; 55.1; 18.6; 14.2; IR (νmax cm-1): 3268,
3237, 2976, 2122, 1701, 1642, 1511, 1219, 1089, 1018, 798; HRMS
calc. for [C18H20N2O5+Na]: 367.1264; Found: 367.1259.
δ
9.86 (s, 1H);
7.45 (dd, 1H, J= 2.0 and 8.1 Hz); 7.43 (d, 1H, J= 1.8 Hz); 7.14 (d, 1H,
J= 8.3 Hz); 4.85 (d, 2H, J= 2.4 Hz); 3.93 (s, 3H); 2.56 (t, 1H, J= 2.4 Hz);
13C NMR (75 MHz, CDCl3):
112.5; 109.4; 77.4; 76.6; 56.5; 55.9; IR (νmax cm-1): 3245, 3006, 2845,
δ 190.8; 152.0; 150.0; 130.8; 126.1;
Ethyl 4-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4e): Yield 86%; Yellow
2121, 1685, 1584, 1504, 1263, 1132, 1001, 800, 740.
1
solid; m.p. 119ºC; H NMR (400 MHz, DMSO-d6):
δ 9.17 (br s, 1H);
General procedure for synthesis of Propargyloxy DHPMs 4a-j
The aldehyde (2.0 mmol), urea (2.4 mmol), 1,3-dicarbonyl
compound (2.0 mmol), CeCl3.7H2O (20 mol%) and ethanol (2 mL)
were stirred under reflux conditions for 3h-6h period, monitored by
TLC. After, the solvent was evaporated under vacuum and the crude
mixture was purified by chromatography in column of silica gel
using a hexane-ethyl acetate as eluent to isolate the desired DHPMs
4a-j in pure form. The characterization of compound 4a was
confirmed by comparison with the reported data.
7.70 (br s, 1H); 6.96 (d, 1H, J= 8.3Hz); 6.87 (d, 1H, J= 1.8Hz); 6.71
(dd, 1H, J= 8.3 and 1.8 Hz); 5.10 (d, 1H, J= 3.0 Hz); 4.73 (d, 2H, J= 2.0
Hz); 4.00 (q, 2H, J= 7.0 Hz); 3.73 (s, 3H); 3.53 (t, 1H, J= 3.5 Hz); 2.24
(s, 3H); 1.11 (t, 3H, J= 7.0 Hz); 13C NMR (100 MHz, DMSO-d6):
δ
165.4; 152.3; 149.0; 148.3; 145.7; 138.6; 117.7; 114.2; 110.8; 99.3;
79.4; 78.2; 59.2; 56.1; 55.5; 53.5; 17.8; 14.2; IR (νmax cm-1): 3236,
3102, 2937, 2122, 1695, 1654, 1510, 1220, 1096, 786, 642; HRMS
calc. for [C18H20N2O5+Na]: 367.1264; Found: 367.1269.
5-acetyl-6-methyl-4-(4-(prop-2-yn-1-yloxy)phenyl)-3,4-dihydropyri
midin-2(1H)-one (4f): Yield 67%; Yellow solid; m.p. 187ºC; 1H NMR
Ethyl
6-methyl-2-oxo-4-[4-(prop-2-yn-1-yloxy)phenyl]-1,2,3,4-
Yield 75%; White solid;
9.18 (br s, 1H); 7.69
tetrahydropyrimidine-5-carboxylate (4a) 42
:
1
(400 MHz, DMSO-d6):
δ 9.14 (br s, 1H); 7.75 (br s, 1H); 7.17 (d, 2H,
m.p. 153ºC; H NMR (400 MHz, DMSO-d6):
δ
J= 8.6 Hz); 6.93 (d, 2H, J= 8.6 Hz); 5,20 (d, 1H, J= 3.3 Hz); 4.76 (d, 2H,
J= 2.3 Hz); 3.53 (t, 1H, J= 2.5 Hz); 2.28 (s, 3H); 2.09 (s, 3H); 13C NMR
(br s, 1H); 7.15 (d, 2H, J= 8.8 Hz); 6.92 (d, 2H, J= 8.8 Hz); 5.08 (d, 1H,
J= 3.3 Hz); 4.76 (d, 2H, J= 2.3 Hz); 3.98 (q, 2H, J= 7.0 Hz); 3.55 (t, 1H,
J= 2.3 Hz); 2.24 (s, 3H); 1.10 (t, 3H, J= 7.0 Hz); 13C NMR (75 MHz,
(100 MHz, DMSO-d6):
δ 194.4; 156.4; 152.1; 147.9; 137.2; 127.6;
114.8; 109.7; 79.3; 78.2; 55.4; 53.3; 30.2; 18.9; IR (νmax cm-1): 3297,
DMSO-d6):
δ 165.8; 156.8; 152.6; 148.6; 138.3; 127.8; 115.1; 99.9;
79.8; 78.6; 59.7; 55.8; 53.8; 18.2; 14.6; IR (νmax cm-1): 3276, 3247,
6 | J. Name., 2012, 00, 1-3
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1
2940, 2117, 1674, 1613, 1238, 1029; HRMS calc. for
[C16H16N2O3+Na]: 307.1053; Found: 307.1047.
m.p. 223ºC; H NMR (400 MHz, DMSO-d6):
δ 9,42 (br s, 1H); 7.69
(br s, 1H); 7.15 (d, 2H, J= 8,8 Hz); 6.91 (d, 2H, J= 8.8 Hz); 5.10 (d, 1H,
J= 2.8 Hz); 4.75 (d, 2H, J= 2.5 Hz); 3.52 (t, 1H, J= 2.3 Hz); 2.40 (d, 1H,
J= 17.4 Hz); 2.28 (d, 1H, J= 17.1 Hz); 2.18 (d, 1H, J= 16.1 Hz); 2.03 (d,
5-acetyl-6-methyl-4-(3-(prop-2-yn-1-yloxy)phenyl)-3,4-dihydropyri
midin-2(1H)-one (4g): Yield 69%; Pale yellow solid; m.p. 190ºC; 1H
NMR (400 MHz, DMSO-d6): δ
9.17 (br s, 1H); 7.80 (br s, 1H); 7.26 (t, 1H, J= 16.1 Hz); 1.01 (s, 3H); 0.90 (s, 3H); 13C NMR (75 MHz, DMSO-
1H, J= 7.8 Hz); 6.90-6.84 (m, 3H); 5.24 (d, 1H, J= 3.3 Hz); 4.75 (d, 2H,
J= 2.0 Hz); 3.54 (t, 1H, J= 2.3 Hz); 2.29 (s, 3H); 2.12 (s, 3H); 13C NMR
d6):
δ 193.4; 156.7; 152.7; 152.3; 130.1; 127.8; 115.0; 108.0; 79.8;
78.6; 55.8; 51.9; 50.3; 39.6; 32.8; 29.2; 27.4; IR (νmax cm-1): 3303,
(75 MHz, DMSO-d6):
δ 194.3; 157.3; 152.2; 148.3; 145.8; 129.6;
3241, 3069, 2965, 2872, 2129, 1693, 1625, 1502, 1373, 1250, 1023,
119.3; 113.6; 112.9; 109.4; 79.2; 78.3; 55.4; 53.6; 30.3; 18.9; IR (νmax 826; HRMS calc. for [C19H20N2O3+Na]: 347.1366; Found: 347.1362.
cm-1): 3278, 3254, 2959, 2129, 1709, 1680, 1606, 1379, 1225, 1029, 7,7-dimethyl-4-(3-(prop-2-yn-1-yloxy)phenyl)-4,6,7,8-tetrahydro-
760; HRMS calc. for [C16H16N2O3+Na]: 307.1053; Found: 307.1048.
quinazoline-2,5(1H,3H)-dione (4l): Yield 67%; Pale yellow solid; m.p.
1
5-acetyl-6-methyl-4-(2-(prop-2-yn-1-yloxy)phenyl)-3,4-dihydropyri
203ºC; H NMR (400 MHz, DMSO-d6):
δ 9.45 (br s, 1H); 7.74 (br s,
1
midin-2(1H)-one (4h): Yield 67%; Yellow solid; m.p. 182ºC; H NMR
1H); 7.24 (t, 1H, J= 7.9 Hz); 6.88-6.81 (m, 3H); 5.12 (d, 1H, J= 2.8 Hz);
(400 MHz, DMSO-d6): δ 9.16 (br s, 1H); 7.34 (br s, 1H); 7.27 (td, 1H, 4.73 (d, 2H, J= 2.5 Hz); 3.53 (t, 1H, J= 2.3 Hz); 2.40 (d, 1H, J= 17.1
J= 7.5 and 1.5 Hz); 7.11 (d, 1H, J= 7.8 Hz); 7.07 (dd, 1H, J= 7.6 and Hz); 2.28 (d, 1H, J= 17.1 Hz); 2.19 (d, 1H, J= 16.1 Hz); 2.05 (d, 1H, J=
16.4 Hz); 1,02 (s, 3H); 0.91 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
δ
1.5 Hz) 6.94 (t, 1H, J= 7.3 Hz); 5.56 (d, 1H, J= 3.3 Hz); 4.89 (dd, 2H, J=
16.1 and 2.3 Hz); 4.84 (dd, 2H, J= 16.1 and 2.3 Hz); 3.59 (t, 1H, J= 2.3
Hz); 2.29 (s, 3H); 2.03 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
194.4; 154.3; 152.1; 148.2; 131.7; 128.8; 127.1; 121.3; 112.8; 107.8;
79.4; 78.3; 55.8; 48.7; 29.7; 18.7; IR (νmax cm-1): 3297, 2948, 2117, for [C19H20N2O3+Na]: 347.1366; Found: 347.1367.
193.4; 157.7; 153.1; 152.4; 146.6; 129.9; 119.6; 113.9; 113.2; 107.6;
79.7; 78.7; 55.8; 52.2; 50.3; 39.6; 32.8; 29.2; 27.4; IR (νmax cm-1):
3272, 2952, 2123, 1680, 1607, 1373, 1232, 1035, 760; HRMS calc.
δ
1674, 1613, 1225, 1029; HRMS calc. for [C16H16N2O3+Na]: 307.1053; 7,7-dimethyl-4-(2-(prop-2-yn-1-yloxy)phenyl)-4,6,7,8-tetrahydro-
Found: 307.1049.
quinazoline-2,5(1H,3H)-dione (4m): Yield 70%; Pale yellow solid;
1
5-acetyl-4-(4-methoxy-3-(prop-2-yn-1-yloxy)phenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one (4i): Yield 64%; Yellow solid; m.p.
m.p. 218ºC; H NMR (400 MHz, DMSO-d6):
δ 9.38 (br s, 1H); 7.25-
7.20 (m, 2H); 7.07 (m, 2H); 6.90 (t, 1H, J= 7.3 Hz); 5.39 (d, 1H, J= 1.8
143ºC; H NMR (400 MHz, DMSO-d6):
δ 9.13 (br s, 1H); 7.73 (br s, Hz); 4.80 (d, 1H, J= 15.9 Hz); 4.76 (d, 1H, J= 15.9 Hz); 3.56 (s, 1H);
1
1H); 6.97 (d, 1H, J= 1.8 Hz); 6.93 (d, 1H, J= 8.3 Hz); 6.81 (dd, 1H, J= 2.40 (d, 1H, J= 17.1 Hz); 2.33 (d, 1H, J= 17.4 Hz); 2.16 (d, 1H, J= 16.1
8.3 and 1.8 Hz); 5.19 (d, 1H, J= 3.3 Hz); 4.69 (d, 2H, J= 2.3 Hz); 3.73 Hz); 2,01 (d, 1H, J= 16.1 Hz); 1.03 (s, 3H); 0.98 (s, 3H); 13C NMR
(s, 1H); 3.51 (t, 1H, J= 2.3 Hz); 2.28 (s, 3H); 2.08 (s, 3H); 13C NMR
(100 MHz, DMSO-d6):
δ 192.6; 155.0; 153.1; 151.7; 132.0; 128.5;
(100 MHz, DMSO-d6):
δ 194.4; 152.1; 148.7; 148.0; 146.3; 136.5; 128.2; 120.8; 112.8; 105.4; 79.5; 78.2; 55.9; 48.9; 48.5; 39.5; 32.2;
28.7; 27.3; IR (νmax cm-1): 3416, 3290, 3210, 3100, 2960, 2125, 1705,
119.7; 113.5; 112.2; 109.3; 79.2; 78.4; 56.3; 55.6; 53.2; 30.1; 18.8;
IR (νmax cm-1): 3303, 3272, 3117, 2941, 2125, 1691, 1618, 1505, 1613, 1385, 1237, 746; HRMS calc. for [C19H20N2O3+Na]: 347.1366;
1226, 1133, 1019; HRMS calc. for [C17H18N2O4+Na]: 337.1159; Found: 347.1362.
Found: 337.1167.
7,7-dimethyl-4-(4-methoxy-3-(prop-2-yn-1-yloxy)phenyl)-4,6,7,8-
tetrahydroquinazoline-2,5(1H,3H)-dione (4n) Yield 81%; White
solid; m.p. 236ºC; H NMR (400 MHz, DMSO-d6): 9.44 (br s, 1H);
5-acetyl-4-(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)-6-methyl-3,4-
:
1
dihydropyrimidin-2(1H)-one (4j): Yield 62%; Yellow solid; m.p.
δ
1
183ºC; H NMR (400 MHz, DMSO-d6):
δ 9.15 (br s, 1H); 7.76 (br s, 7.71 (br s, 1H); 6.95 (d, 1H, J= 1.8 Hz); 6.92 (d, 1H, J= 8.3 Hz); 6.80
1H); 6.96 (d, 1H, J= 8.3 Hz); 6.93 (d, 1H, J= 2.0 Hz); 6,70 (dd, 1H, J= (dd, 1H, J= 8.3 e 1.8 Hz); 5.10 (d, 1H, J= 2.8 Hz); 4.68 (d, 2H, J= 2.3
8.3 and 2.0 Hz); 5.21 (d, 1H, J= 3.5 Hz); 4.74 (d, 2H, J= 2.5 Hz); 3.74 Hz); 3.73 (s, 3H); 3.53 (t, 1H, J= 2.4 Hz); 2.41 (d, 1H, J= 17.1 Hz); 2.28
(s, 3H); 3.51 (t, 1H, J= 2.4 Hz); 2.29 (s, 3H); 2.10 (s, 3H); 13C MNR (75 (d, 1H, J= 17.4 Hz); 2.20 (d, 1H, J= 16.1 Hz); 2.05 (d, 1H, J= 15.9 Hz);
MHz, DMSO-d6):
114.2; 111.1; 109.3; 79.4; 78.2; 56.1; 55.5; 53.5; 30.2; 18.8; IR (νmax
cm-1): 3380, 3266, 2947, 2114, 1672, 1590, 1232, 1139, 1015; HRMS 78.3; 56.4; 55.6; 51.4; 49.9; 39.2; 32.3; 28.8; 27.0; IR (νmax cm-1):
δ
194.5; 152.1; 149.2; 148.0; 145.8; 137.8; 117.8; 1.02 (s, 3H); 0.94 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
δ 192.9;
152.3; 151.9; 148.6; 146.3; 137.0; 119.6; 113.2; 111.9; 107.4; 79.2;
calc. for [C17H18N2O4+Na]: 337.1159; Found: 337.1153.
3256, 2974, 2153, 1676, 1603, 1376, 1231, 1138, 1014, 776, 694,
General Procedure for synthesis of Propargyloxy DHPMs 4k-o
642; HRMS calc. for [C20H22N2O4+Na]: 377.1472; Found: 377.1471.
The aldehyde (3a-e, 2.0 mmol), urea (2.4 mmol), HCl (3 drops) and 7,7-dimethyl-4-(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)-4,6,7,8-te
ethanol (2 mL) were stirred under reflux for 1 h period. Next, trahydroquinazoline-2,5(1H,3H)-dione (4o): Yield 72%; Pale green
1
dimedone (2.0 mmol) was added in 5 portions, during a total time
of 2.5 h, maintaining the reaction mixture at 60 oC under stirring.
The end of the reaction was monitored by TLC and the solvent was
retired under vacuum. The crude product was purified through
recrystallization from hot ethanol to give the DHPMs in the pure
form.
solid; m.p. 215ºC; H NMR (300 MHz, DMSO-d6):
δ 9.45 (br s, 1H);
7.73 (br s, 1H); 6.95 (d, 1H, J= 8.3 Hz); 6.86 (d, 1H, J= 1.8 Hz); 6.71
(dd, 1H, J= 8.3 and 1.8 Hz); 5.11 (d, 1H, J= 3.0 Hz); 4.73 (d, 2H, J= 2.5
Hz); 3.71 (s, 3H); 3.53 (t, 1H, J= 2.3 Hz); 2.41 (d, 1H, J= 17.1 Hz); 2.28
(d, 1H, J= 17.4 Hz); 2.20 (d, 1H, J= 16.1 Hz); 2.05 (d, 1H, J= 16.1 Hz);
1.02 (s, 3H); 0.94 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
δ 193.0;
7,7-dimethyl-4-(4-(prop-2-yn-1-yloxy)phenyl)-4,6,7,8-tetrahydro-
quinazoline-2,5(1H,3H)-dione (4k): Yield 74%; Pale yellow solid;
152.5; 151.9; 149.0; 145.6; 138.2; 117.8; 114.0; 110.7; 107.3; 79.4;
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78.2; 56.1; 55.4; 51.5; 49.9; 39.2; 32.3; 28,8; 26,9; IR (νmax cm-1):
3324, 3272, 2962, 2122, 1676, 1614, 1366, 1222, 1125, 1007, 758;
HRMS calc. for [C20H22N2O4+Na]: 377.1472; Found: 377.1469.
Procedure for synthesis of Perillyl Azide (7)
1H, J= 7.8 Hz); 6.88 (d, 1H, J= 7.8 Hz); 6.10 (br s, 1H); 5.76 (br s, 1H);
5.36 (s, 1H); 5.17 (s, 2H); 4.84 (s, 2H); 4.73 (s, 1H); 4.69 (s, 1H); 4.06
(q, 2H, J= 7.3 Hz); 2.33 (s, 3H); 2.21-2.11 (m, 2H); 2.04-1.93 (m, 4H);
1.72 (s, 3H); 1.49-1.41 (m, 1H); 1.15 (t, 3H, J= 7.3 Hz); 13C NMR (75
To
a
mixture of (s)-perillyl chloride (5.0 mmol) and MHz, CDCl3): δ 165.6; 158.5; 153.4; 149.0; 146.7; 145.3; 144.1;
dimethylformamide (1.5 mL) was added sodium azide (15.0 mmol) 131.8; 129.7; 127.3; 122.5; 119.4; 113.8; 113.4; 109.0; 100.9; 62.1;
59.9; 56.4; 55.4; 40.4; 30.4; 27.0; 26.3; 20.7; 18.6; 14.1; IR (νmax cm-
and the reaction was stirred for 12h at room temperature. The end
1): 3232, 3101, 2818, 1695, 1634, 1596, 1446, 1224, 1084, 773;
of the reaction was monitored by TLC and water (5.0 mL) was
added in one portion. The aqueous phase (H2O/DMF) was washed
with hexane (3 x 15.0 mL). The organic phase was separated and
washed with NaCl saturated solution, dried over anhydrous
magnesium sulfate. After simple filtration, the filtrate was removed
over vacuum* to yield the crude perillyl azide (7) in 90%. The perillyl
azide was used in a next step without further purification. *This
process should be carefully controlled to avoid the loss of mass.
HRMS calc. for [C27H33N5O4+H]: 492.2605; Found: 492.2609.
5-etoxycarbonyl-6-methyl-4-(2-((1-perillyl-methyl)-1H-1,2,3-tria-
zol-4-yl)-methoxyphenyl)-3,4-dihidropirimidin-2-(1H)-one
Yield 85%; White solid; m.p. 182ºC; 1H NMR (400 MHz, CDCl3):
(8c)
:
δ
8.34 (br s, 1H); 7.62 (s, 1H); 7.22 (td, 1H, J= 7.8 and 1.8 Hz); 7.06
(dd, 1H, J= 7.6 and 1.8 Hz); 7.01 (d, 1H, J= 7.8 Hz); 6.90 (t, 1H, J= 7.6
Hz); 5.99 (br s, 1H); 5.74 (br s, 2H); 5.28 (s, 2H); 4.87 (d, 1H, J= 16.1
Hz); 4.83 (d, 1H, J= 16.1Hz); 4.73 (s, 1H); 4.69 (s, 1H); 4.04 (q, 2H, J=
7.0 Hz); 2.39 (s, 3H); 2.21-2.10 (m, 2H); 1.98-1.79 (m, 4H); 1.72 (s,
3H); 1.50-1.40 (m, 1H); 1.09 (t, 3H, J= 7.0 Hz); 13C NMR (100 MHz,
(S)-1-(azidomethyl)-4-(prop-1-en-2-yl)cyclohex-1-ene (7)
:
Yield
1
90%; Colorless liquid; H NMR (400 MHz, CDCl3):
δ 5.76 (br s, 1H);
4.76-4.73 (m, 2H); 3.70 (d, 1H, J= 13.4 Hz); 3.65 (d, 1H, J= 13.1 Hz);
2.19-2.10 (m, 4H); 2.05-1.96 (m, 1H); 1.90-1.86 (m, 1H); 1.75 (s, 3H);
CDCl3):
δ 165.8; 155.5; 153.7; 149.0; 148.2; 143.9; 131.8; 130.4;
1.55-1.49 (m, 1H); 13C NMR (100 MHz, CDCl3):
126.4; 108.9; 57.4; 40.7; 30.4; 27.3; 27.0; 20.7; IR (νmax cm-1): 3085,
δ 149.3; 134.1;
129.0; 127.3; 127.0; 122.5; 121.2; 112.2; 109.0; 98.2; 62.3; 59.8;
56.5; 50.1; 40.4; 30.4; 27.0; 26.3; 20.7; 18.5; 14.1; IR (νmax cm-1):
3397, 3113, 2980, 1724, 1694, 1639, 1592, 1446, 1221, 1080, 753;
HRMS calc. for [C27H33N5O4+H]: 492.2605; Found: 492.2605.
2923, 2096, 1645, 1439, 1242, 891.
General procedure for synthesis of Hybrids Perillyl-DHPM 8a-o
The DHPM (4a-o) (0.5 mmol), perillyl azide (7, 0.6 mmol),
dichloromethane (5.0 mL) and water (5.0 mL) were mixed in flask
and then, copper sulfate pentahydrate (10.0 mol%) and sodium
ascorbate (10.0 mol%) were added in this order. The reaction was
kept under stirring at room temperature for 24h. The end of the
reaction was monitored by TLC. Next, EDTA 0.1M (10.0 mL) was
added and mixture was stirred for 15 min. The aqueous phase was
washed with dichloromethane (3 x 10 mL). The organic phase
separated and was washed with NaCl saturated solution. After
separation, the organic layer was dried over anhydrous magnesium
sulfate and filtered. The filtrate was removed under vacuum and
the crude solid was purified by chromatography in column of silica
gel using hexane-ethyl acetate as eluent to give a Perillyl-DHPM
hybrid in pure form.
5-etoxycarbonyl-6-methyl-4-(4-methoxy-3-((1-perillyl-methyl)-1H-
1,2,3-triazol-4-yl)-methoxyphenyl)-3,4-dihidropirimidin-2-(1H)-one
(8d): Yield 71%; yellow solid; m.p. 182ºC; 1H NMR (400 MHz,
DMSO-d6): δ 9.17 (br s, 1H); 8.10 (s, 1H); 7.70 (br s, 1H); 7.01 (d, 1H,
J= 1.8 Hz); 6.91 (d, 1H, J= 8.6 Hz); 6.76 (dd, 1H, J= 8.3 and 1.8 Hz);
5.66 (br s, 1H); 5.10 (d, 1H, J= 3.0 Hz); 5.07 (d, 1H, J= 11.8 Hz); 5.04
(d, 1H, J= 11.8 Hz); 4.91 (s, 2H); 4.69 (s, 2H); 3.99 (q, 2H, J= 7.3 Hz);
3.71 (s, 3H); 2.25 (s, 3H); 2.14-2.04 (m, 2H); 1.94-1.86 (m, 3H); 1.75-
1.72 (m, 1H); 1.69 (s, 3H); 1.39-1.33 (m, 1H); 1.10 (t, 3H, J= 7.0 Hz);
13C NMR (100 MHz, DMSO-d6):
δ 165.4; 152.3; 148.9; 148.5; 148.3;
147.1; 142.6; 137.3; 132.5; 125.5; 124.7; 118.8; 112.6; 112.0; 109.1;
99.3; 61.9; 59.2; 55.5; 55.1; 53.4; 40.0; 29.9; 26.8; 26.0; 20.6; 17.8;
14.2; IR (νmax cm-1): 3260, 3115, 2929, 1692, 1511, 1454, 1256,
1225, 1084, 1001, 754; HRMS calc. for [C28H35N5O5+Na]: 544.2530;
Found: 544.2527.
5-etoxycarbonyl-6-methyl-4-(4-((1-perillyl-methyl)-1H-1,2,3-tria-
zol-4-yl)-methoxyphenyl)-3,4-dihidropirimidin-2-(1H)-one
Yield 79%; White solid; m.p. 80ºC; 1H NMR (300 MHz, CDCl3):
(8a)
:
5-etoxycarbonyl-6-methyl-4-(3-methoxy-4-((1-perillyl-methyl)-1H-
1,2,3-triazol-4-yl)-methoxyphenyl)-3,4-dihidropirimidin-2-(1H)-one
(8e): Yield 73%; yellow solid; m.p. 78ºC; 1H NMR (400 MHz, DMSO-
δ
8.50
(br s, 1H); 7.58 (s, 1H); 7,23 (d, 2H, J= 8.8 Hz); 6.91 (d, 2H, J= 8.8 Hz);
6.02 (br s, 1H); 5.76 (br s, 1H); 5.34 (d, 1H, J= 2.4 Hz); 5.17 (s, 2H);
4.85 (s, 2H); 4.78 – 4.65 (m, 2H), 4.08 (m, 2H); 2.32 (s, 3H); 2.17-
2.10 (m, 2H); 1,94-1,80 (m, 4H); 1.72 (s, 3H); 1.52-1.41 (m, 1H); 1.16
d6): δ 9.16 (br s, 1H); 8.13 (s, 1H); 7.68 (br s, 1H); 7.07 (d, 1H, J= 8.3
Hz); 6.87 (d, 1H, J= 2.0 Hz); 6.73 (dd, 1H, J= 8.3 and 2.0 Hz); 5.67 (br
s, 1H); 5.12 (d, 1H, J= 3.3 Hz); 5.08 (s, 2H); 4.91 (s, 2H); 4.71 (s, 2H);
4.01 (q, 2H, J= 7.0 Hz); 3.72 (s, 3H); 2.25 (s, 3H); 2.17-2.05 (m, 2H);
1.93-1.89 (m, 3H); 1.77-1.73 (m, 1H); 1.70 (s, 3H); 1.42-1.32 (m, 1H);
(t, 3H, J= 7.0 Hz); 13C NMR (100 MHz, CDCl3):
δ 165.7; 157.9; 153.5;
149.0; 146.2; 144.2; 136.7; 131.8; 127.8; 127.4; 122.4; 114.8; 109.0;
101.4; 62.1; 59.9; 56.5; 55.0; 40.4; 30.4; 27.0; 26.3; 20.7; 18.5; 14.1;
IR (νmax cm-1): 3230, 3102, 2936, 1693, 1638, 1600, 1427, 1227,
1082, 777; HRMS calc. for [C27H33N5O4+H]: 492.2605; Found:
492.2607.
1.12 (t, 3H, J= 7.0 Hz); 13C NMR (75 MHz, DMSO-d6):
δ 165.4; 152.2;
148.9; 148.8; 148.2; 146.6; 142.7; 138.0; 132.5; 125.4; 124.6; 117.8;
113.7; 110.7; 109.0; 99.3; 61.8; 59.2; 55.4; 55.0; 53.5; 40.0; 29.8;
26.7; 26.0; 20.6; 17.7; 14.1; IR (νmax cm-1): 3232, 3105, 2929, 1698,
1640, 1515, 1449, 1220, 1082, 774; HRMS calc. for [C28H35N5O5+Na]:
544.2530; Found: 544.2533.
5-etoxycarbonyl-6-methyl-4-(3-((1-perillyl-methyl)-1H-1,2,3-tria-
zol-4-yl)-methoxyphenyl)-3,4-dihidropirimidin-2-(1H)-one
Yield 90%; White solid; m.p. 74ºC; 1H NMR (400 MHz, CDCl3):
(8b):
δ
8.41
5-acetyl-6-methyl-4-(4-((1-perillyl-methyl)-1H-1,2,3-triazol-4-yl)-
(br s, 1H); 7.59 (s, 1H); 7.21 (t, 1H, J= 7.8 Hz); 6.95 (s, 1H); 6.91 (d,
methoxyphenyl)-3,4-dihidropirimidin-2-(1H)-one (8f): Yield 71%;
8 | J. Name., 2012, 00, 1-3
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1
3.73 (s, 1H); 2.30 (s, 3H); 2.14-2.05 (m, 5H); 1.95-1.89 (m, 3H); 1.76-
(br s, 1H); 8.14 (s, 1H); 7.76 (br s, 1H); 7.17 (d, 2H, J= 8.6 Hz); 6.98 1.70 (m, 4H); 1.42-1.32 (m, 1H); 13C NMR (75 MHz, DMSO-d6):
pale green solid; m.p. 92ºC; H NMR (400 MHz, DMSO-d6):
δ 9.14
δ
(d, 2H, J= 8.8 Hz); 5.65 (br s, 1H); 5.21 (d, 1H, J= 3.3 Hz); 5.11 (s, 2H); 194.4; 152.1; 149.0; 148.9; 148.0; 146.8; 142.8; 137.2; 132.5; 125.4;
4.90 (s, 2H); 4.69 (s, 2H); 2.28 (s, 3H); 2.14-2.03 (m, 5H); 1.94-1.84 124.6; 118.0; 113.7; 111.0; 109.2; 109.0; 61.8; 55.4; 55.0; 53.6;
(m, 3H); 1.75-1.72 (m, 1H); 1.69 (s, 3H); 1.41-1.31 (m, 1H); 13C NMR
40.0; 30.1; 29.8; 26.7; 26.0; 20.6; 18.8; IR (νmax cm-1): 3232, 3134,
(75 MHz, DMSO-d6):
δ 194.3; 157.3; 152.0; 148.9; 147.8; 142.7; 2929, 1701, 1600, 1514, 1417, 1226, 1131, 754; HRMS calc. for
136.7; 132.5; 127.6; 125.4; 124.5; 114.6; 109.6; 109.0; 61.1; 55.0; [C27H33N5O4+Na]: 514.2425; Found: 514.2431.
53.3; 40.0; 30.2; 29.8; 26.7; 25.9; 20.5; 18.8; IR (νmax cm-1): 3242,
3112, 2922, 1699, 1609, 1509, 1429, 1227, 1168, 1006, 781; HRMS
calc. for [C26H31N5O3+Na]: 484.2319; Found: 484.2317.
7,7-dimethyl-4-(4-((1-perillyl-methyl)-1H-1,2,3-triazol-4-yl)-metho-
xyphenyl)-4,6,7,8-tetrahydroquinazoline-2,5(1H,3H)-dione (8k)
Yield 68%; white solid; m.p. 223ºC; 1H NMR (400 MHz, DMSO-d6):
:
δ
5-acetyl-6-methyl-4-(3-((1-perillyl-methyl)-1H-1,2,3-triazol-4-yl)-
9.42 (br s, 1H); 8.13 (s, 1H); 7.70 (br s, 1H); 7.15 (d, 2H, J= 8.6 Hz);
methoxyphenyl)-3,4-dihidropirimidin-2-(1H)-one (8g): Yield 72%; 6.96 (d, 2H, J= 8.6 Hz); 5.65 (s, 1H); 5.09 (br s, 3H); 4.89 (s, 2H); 4.69
(s, 2H); 2.40 (d, 1H, J= 17.4 Hz); 2.27 (d, 1H, J= 17.1 Hz); 2.20-2.00
white solid; m.p. 145ºC; 1H NMR (400 MHz, DMSO-d6):
δ 9.17 (br s,
(m, 4H); 1.94-1.88 (m, 3H); 1.76-1.69 (m, 4H); 1.39-1.33 (m, 1H);
J= 8.1 and 2.3 Hz); 6.87-6.84 (m, 2H); 5,66 (br s, 1H); 5.24 (d, 1H, J= 1.01 (s, 3H); 0.90 (s, 3H); 13C NMR (75 MHz, DMSO-d6):
192.8;
3.5 Hz); 5.11 (s, 2H); 4.90 (s, 2H); 4.69 (s, 2H); 2.29 (s, 3H); 2.14-2.04 157.1; 152.1; 151.9; 148.9; 142.7; 137.3; 132.5; 127.3; 125.4; 124.5;
(m, 5H); 1.95-1.88 (m, 3H); 1.76-1.69 (m, 4H); 1.41-1.31 (m, 1H); 13
114.4; 109.1; 107.6; 61.1; 55.0; 51.3; 49.8; 40.0; 32.3 (x2); 29.8;
NMR (75 MHz, DMSO-d6):
194.2; 158.1; 152.1; 148.9; 148.2; 28.8; 26.9; 26.7; 26.0; 20.6; IR (νmax cm-1): 3310, 3099, 2938, 1681,
1H); 8.14 (s, 1H); 7.81 (br s, 1H); 7.25 (t, 1H, J= 7.8 Hz); 6.96 (dd, 1H,
δ
C
δ
145.8; 142.6; 132.4; 129.6; 125.4; 124.6; 118.9; 113.4; 113.0; 109.4; 1641, 1606, 1453, 1372, 1244, 1044, 818, 778, 557; HRMS calc. for
109.0; 61.0; 55.0; 53.6; 40.0; 30.2; 29.8; 26.7; 26.0; 20.5; 18.9; IR [C29H35N5O3+H]: 502.2813; Found: 502.2813.
(νmax cm-1): 3270, 3110, 2928, 1690, 1599, 1446, 1240, 1013, 806,
776; HRMS calc. for [C26H31N5O3+Na]: 484.2319; Found: 484.2310.
5-acetyl-6-methyl-4-(2-((1-perillyl-methyl)-1H-1,2,3-triazol-4-yl)-
7
,7-dimethyl-4-(3-((1-perillyl-methyl)-1H-1,2,3-triazol-4-yl)-metho-
xyphenyl)-4,6,7,8-tetrahydroquinazoline-2,5(1H,3H)-dione (8l)
Yield 84%; white solid; m.p. 192ºC; NMR 1H (400 MHz, DMSO-d6):
:
δ
methoxyphenyl)-3,4-dihidropirimidin-2-(1H)-one (8h): Yield 68%; 9.45 (br s, 1H); 8.14 (s, 1H); 7.75 (br s, 1H); 7.23 (t, 1H, J= 8.1 Hz);
white solid; m.p. 139ºC; 1H NMR (400 MHz, DMSO-d6):
δ 9.13 (br s,
6.93 (dd, 2H, J= 8.1 and 2.0 Hz); 6.85-6.82 (m, 2H); 5.66 (s, 1H); 5.14
(d, 1H, J= 2.8 Hz); 5.09 (s, 2H); 4.90 (s, 2H); 4.70 (s, 2H); 2.40 (d, 1H,
J= 17.1 Hz); 2.30 (d, 1H, J= 17.4 Hz); 2.20-2.04 (m, 4H); 1.95-1.85 (m,
3H); 1.76-1.72 (m, 1H); 1.69 (s, 3H); 1.41-1.31 (m, 1H); 1.01 (s, 3H);
1H); 8.17 (s, 1H); 7.27-7.25 (m, 2H); 7.20 (dd, 1H, J= 8.3 and 1.1 Hz);
7.07 (dd, 1H, J= 7.6 e 1.8 Hz); 6.92 (td, 1H, J= 7.3 e 1.0 Hz); 5.66 (br
s, 1H); 5.60 (d, 1H, J= 3.3 Hz); 5.29 (d, 1H, J= 12.6 Hz); 5.24 (d, 1H, J=
12.6 Hz); 4.91 (s, 2H); 4.69 (s, 2H); 2.28 (s, 3H); 2.13-2.03 (m, 2H); 0.90 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
1.96-1.87 (m, 6H); 1.74-1.68 (m, 4H); 1.40-1.30 (m, 1H); 13C NMR 151.9; 148.9; 146.1; 142.6; 132.5; 129.4; 125.4; 124.6; 118.7; 113.2;
112.8; 109.0; 107.2; 61.0; 55.0; 51.7; 49.8; 40.0; 32.3 (x2); 29.8;
δ 192.9; 158.0; 152.5;
(100 MHz, DMSO-d6):
δ 194.5; 154.8; 152.1; 148.9; 148.2; 143.1;
132.5; 131.7; 128.8; 127.0; 125.4; 124.3; 121.0; 113.0; 109.0; 107.7; 28.6; 27.0; 26.7; 26.0; 20.6; IR (νmax cm-1): 3251, 2911, 1692, 1610,
61.8; 55.1; 48.6; 40.0; 29.8; 29.6; 26.7; 25.9; 20.5; 18.6; IR (νmax cm-
1378, 1234, 1009, 764; HRMS calc. for [C29H35N5O3+H]: 502.2813;
1): 3413, 3207, 3080, 2934, 1685, 1636, 1597, 1430, 1232, 764, 583;
Found: 502.2816.
7,7-dimethyl-4-(2-((1-perillyl-methyl)-1H-1,2,3-triazol-4-yl)-metho-
xyphenyl)-4,6,7,8-tetrahydroquinazoline-2,5(1H,3H)-dione (8m)
Yield 80%; white solid; m.p. 198ºC; 1H NMR (400 MHz, DMSO-d6):
δ
HRMS calc. for [C26H31N5O3+Na]: 484.2319; Found: 484,2320.
:
5-acetyl-6-methyl-4-(4-methoxy-3-((1-perillyl-methyl)-1H-1,2,3-tri-
azol-4-yl)-methoxyphenyl)-3,4-dihidropirimidin-2-(1H)-one
(8i)
:
1
Yield 76%; yellow solid; m.p. 154ºC; H NMR (400 MHz, DMSO-d6): 9.34 (br s, 1H); 8.14 (s, 1H); 7.22-7.14 (m, 3H); 7.04 (dd, 1H, J= 7.6 e
1.5 Hz); 6.88 (t, 1H, J= 7.3 Hz); 5.67 (br s, 1H); 5.48 (d, 1H, J= 2.3 Hz);
5.24 (d, 1H, J= 12.3 Hz); 5.20 (d, 1H, J= 12.6 Hz); 4.91 (s, 2H); 4.69 (s,
2H); 2.38 (d, 1H, J= 17.4 Hz); 2.32 (d, 1H, J= 17.1 Hz); 2.16-1.84 (m,
7H); 1.74-1.68 (m, 4H); 1.41-1.30 (m, 1H); 1.02 (s, 3H); 0.98 (s, 3H);
δ
9.14 (br s, 1H); 8.09 (s, 1H); 7.75 (br s, 1H); 7.04 (d, 1H, J= 1.6 Hz);
6.90 (d, 2H, J= 8.3 Hz); 6.76 (dd, 1H, J= 8.3 and 1.6 Hz); 5.66 (br s,
1H); 5.20 (d, 1H, J= 3.0 Hz); 5.08 (s, 2H); 4.90 (s, 2H); 4.69 (s, 2H);
3.71 (s, 1H); 2.29 (s, 3H); 2.13-2.04 (m, 5H); 1.94-1.88 (m, 3H); 1.75-
13C NMR (100 MHz, DMSO-d6):
δ 192.6; 155.3; 153.0; 151.7; 148.9;
1.69 (m, 4H); 1.41-1.31 (m, 1H); 13C NMR (100 MHz, DMSO-d6):
δ
143.3; 132.4; 132.0; 128.5; 127.5; 125.4; 124.2; 120.7; 113.0; 109.0;
105.6; 62.0; 55.1; 49.9; 47.5; 40.0; 39.2; 32.3; 29.8; 28.5; 27.4; 26.7;
25.9; 20.6; IR (νmax cm-1): 3355, 3225, 2913, 1695, 1645, 1459, 1371,
1240, 1054, 796, 747, 558; HRMS calc. for [C29H35N5O3+Na]:
524.2632; Found: 524.2626.
194.5; 152.2; 149.0; 148.5; 148.1; 147.2; 142.6; 136.6; 132.5; 125.5;
124.8; 119.0; 112.8; 112.1; 109.3; 109.1; 61.8; 55.6; 55.1; 53.6;
40.0; 30.2; 29.9; 26.8; 26.0; 20.6; 18.9; IR (νmax cm-1): 3232, 3125,
2929, 1695, 1598, 1510, 1422, 1223, 1128, 757; HRMS calc. for
[C27H33N5O4+Na]: 514.2425; Found: 514.2422.
7,7-dimethyl-4-(4-methoxy-3-((1-perillyl-methyl)-1H-1,2,3-triazol-
4-yl)-methoxyphenyl)-4,6,7,8-tetrahydroquinazoline-2,5(1H,3H)-
5-acetyl-6-methyl-4-(3-methoxy-4-((1-perillyl-methyl)-1H-1,2,3-tri-
azol-4-yl)-methoxyphenyl)-3,4-dihidropirimidin-2-(1H)-one
(8j)
Yield 67%; pale green solid; m.p. 93ºC; H NMR (400 MHz, DMSO-
d6): 9.15 (br s, 1H); 8.13 (s, 1H); 7.77 (br s, 1H); 7.07 (d, 1H, J= 8.3
:
1
1
dione (8n): Yield 79%; white solid; m.p. 200ºC; H NMR (400 MHz,
DMSO-d6): δ 9.41 (br s, 1H); 8.11 (s, 1H); 7.70 (br s, 1H); 7.00 (d, 1H,
δ
J= 1.8 Hz); 6.90 (d, 1H, J= 8.3 Hz); 6.76 (dd, 1H, J= 8.3 and 1.8 Hz);
Hz); 6.93 (d, 2H, J= 2.0 Hz); 6.71 (dd, 1H, J= 8.3 and 2.0 Hz); 5.67 (br
5.67 (br s, 1H); 5.11 (d, 1H, J= 2.8 Hz); 5.06 (d, 1H, J= 11.8 Hz); 5.01
s, 1H); 5.23 (d, 1H, J= 3.3 Hz); 5.09 (s, 2H); 4.91 (s, 2H); 4.70 (s, 2H);
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(d, 1H, J= 14.9 Hz); 4.90 (s, 2H); 4.70 (s, 2H); 3.70 (s, 3H); 2.40 (d,
1H, J= 17.4 Hz); 2.32 (d, 1H, J= 17.1 Hz); 2.21-2.04 (m, 4H); 1.94-1.90
(m, 3H); 1.76-1.69 (m, 4H); 1.42-1.31 (m, 1H); 1.02 (s, 3H); 0.94 (s,
The synthesis of novel perillyl-dihidropyrimidinone hybrid
molecules was accomplished through the multicomponent
Biginelli reaction combined the Huisgen triazole ring formation
reaction in reasonable to good yields. A series of four
compounds showed promising antitumoral activity against
UACC-62, U251 and OVCAR-3, with TGI values lower than 10
3H); 13C NMR (75 MHz, DMSO-d6):
δ 193.0; 152.4; 151.9; 148.9;
148.3; 147.0; 142.5; 137.0; 132.5; 125.5; 124.7; 118.8; 112.5; 111.9;
109.0; 107.3; 61.8; 55.5; 55.0; 51.4; 49.9; 40.0; 39.1; 32.3; 29.8;
28.6; 27.1; 26.7; 26.0; 20.6; IR (νmax cm-1): 3265, 3138, 2933, 1692,
1642, 161, 1442, 1374, 1246, 1129, 1002, 770; HRMS calc. for
[C30H37N5O4+H]: 554.2738; Found: 554.2735.
ꢀ
M (8a
antiproliferative activity against UACC-62, U251 and OVCAR-3,
with TGI values between 10-20 M (8a 8b 8d 8e 8f 8g 8m).
, 8j, 8k, 8n) while a series of seven compounds showed
ꢀ
,
,
,
,
,
,
Additionally, four compounds showed high TGI value for non-
7,7-dimethyl-4-(3-methoxy-4-((1-perillyl-methyl)-1H-1,2,3-triazol-
4-yl)-methoxyphenyl)-4,6,7,8-tetrahydroquinazoline-2,5(1H,3H)-
tumoral cell line HaCaT with high TGI values between 436.18-
507.82
ꢀM. These preliminary results are promising and
1
dione (8o): Yield 71%; peach solid; m.p. 188ºC; H NMR (400 MHz,
indicate the need for subsequent studies to determine the
mechanism of action, which are under current investigation in
our laboratory.
DMSO-d6): δ 9.44 (br s, 1H); 8.12 (s, 1H); 7.73 (br s, 1H); 7.05 (d, 1H,
J= 8.3 Hz); 6.85 (d, 1H, J= 1.8 Hz); 6.71 (dd, 1H, J= 8.3 e 1.8 Hz); 5.66
(br s, 1H); 5.10-5.06 (m, 3H); 4.90 (s, 2H); 4.69 (s, 2H); 3.68 (s, 3H);
2.42 (d, 1H, J= 17.1 Hz); 2.27 (d, 1H, J= 17.4 Hz); 2.21 (d, 1H, J= 16.1
Hz); 2.14-2.03 (m, 3H); 1.94-1.88 (m, 3H); 1.75-1.69 (m, 4H); 1.41-
1.30 (m, 1H); 1.02 (s, 3H); 0.93 (s, 3H); 13C NMR (100 MHz, DMSO-
Conflicts of interest
There are no conflicts to declare.
d6):
δ 193.0; 152.4; 152.0; 148.9; 148.8; 146.6; 142.8; 137.7; 132.5;
125.4; 124.6; 117.9; 113.4; 110.5; 109.1; 107.4; 61.7; 55.4; 55.0;
51.4; 49.9; 40.0; 32.3 (x2); 29.8; 28.9; 26.8; 26.7; 26.0; 20.6; IR (νmax
cm-1): 3229, 3102, 2936, 1678, 1630, 1517, 1449, 1373, 1246, 1138,
1020, 603; HRMS calc. for [C30H37N5O4+H]: 554.2738; Found:
554.2737.
Acknowledgements
The authors would like to acknowledge Fundação de Amparo à
Pesquisa do Estado do Rio Grande do Sul (FAPERGS) and
Conselho Nacional de Desenvolvimento Científico
e
Tecnológico (CNPq) for Grant Universal Proc. 455791/2014-7.
D.R. acknowledge CNPq-Produtividade Proc. 302952/2014-4.
V.V. acknowledge Coordenação de Aperfeiçoamento de
Pessoal de Nível Superior (CAPES) for fellowship.
Biological Assays
In vitro antiproliferative assay
The antiproliferative activity of EERP was evaluated in vitro against
nine different human cancer cell lines (U251 (glioma), UACC-62
(melanoma), MCF-7 (breast), NCI-ADR/RES (multidrug-resistant
ovary carcinoma), OVCAR-3 (ovary), 786-0 (renal), NCI-H460 (non-
small cell lung cancer), PC-3 (prostate), and HT-29 (colon), kindly
provided by Frederick Cancer Research Development Center,
National Cancer Institute, Frederick, MA, USA. The antiproliferative
activity of EERP was also evaluated in vitro against spontaneously
transformed keratinocytes from histologically normal skin (HaCaT
cells) provided by Dr. Ricardo Della Coletta (University of
Campinas). Doxorubicin was employed as the positive control.
Cells in 96-well plates (100 µL cells/well) were exposed to EERP
at 0.25, 2.5, 25 and 250 µg/mL in DMSO/RPMI at 37°C, 5% of CO2 in
air for 48 h. Doxorubicin was used as standard (0.025, 0.25, 2.5 and
25 µg/mL). Final DMSO concentration (0.2%) did not affect cell
viability. Before (T0 plate) and after (T1 plates) sample addition,
cells were fixed with 50% trichloroacetic acid and cell proliferation
was determined by spectrophotometric quantification (540 nm) of
cellular protein content using sulforhodamine B assay. The TGI
(concentration that produces total growth inhibition or cytostatic
effect) were determined through non-linear regression analysis
using the concentration-response curve for each cell line in ORIGIN
8.0® (OriginLab Corporation).
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