Synthesis and Fluorescence Properties of new Monastrol Analogs Conjugated Fluorescent Coumarin Scaffolds

Article abstract of DOI:10.1007/s10895-015-1695-x

A mild and efficient method has been used for the synthesis of ethyl 4-(3-hydroxphenyl)-6-methyl-2-thioxo-1,3-dihydroprimidine-5-carboxylate (monastrol) (2), via Biginelli reaction. Alkylation of 2 with the fluorescent coumarin 3 afforded the new thioethe

Full text of DOI:10.1007/s10895-015-1695-x

J Fluoresc
DOI 10.1007/s10895-015-1695-x
SHORT COMMUNICATION
Synthesis and Fluorescence Properties of new Monastrol Analogs
Conjugated Fluorescent Coumarin Scaffolds
Najim A. Al-Masoudi1,2 & Niran J. Al-Salihi1 & Yossra A. Marich1 & Timo Markus3
Received: 3 July 2015 /Accepted: 14 October 2015
#
Springer Science+Business Media New York 2015
Abstract A mild and efficient method has been used for the
synthesis of ethyl 4-(3-hydroxphenyl)-6-methyl-2-thioxo-1,3-
dihydroprimidine-5-carboxylate (monastrol) (2), via Biginelli
reaction. Alkylation of 2 with the fluorescent coumarin 3
afforded the new thioether analog 4. Similarly, ethyl 4-(6,8-
dichloro-2-oxo-2 H-chromen-3-yl)-6-methyl-2-thioxo-1,2,3,
4-tetrahydro-pyrimidine-5-carboxylate (6) was prepared. The
synthesized compounds are fluorescent active and show
wavelength of maximum absorption (λmax) in UV or visible
region in MeOH at room temperature.
movement [1]. Therefore, microtubule dynamics is an impor-
tant target for the developing anticancer drugs [2] but differ in
their mode of action from other drugs because they target the
mitiotic spindle and not the DNA. Avariety of such drugs that
bind to tubulin and thus inhibit spindle assembly are currently
under investigation in cancer therapy, however, they have
been classified on the basis of their mode of action
and binding site [3–5]. Among these drug is monastrol
(ethyl 4-(3-hydroxyphenyl)-6-methyl-2-sulfanylidene-3,4-
dihydro-1 H-pyrimidine-5-carboxylate) (2) [6–9]. Cou-
marin core moieties have wide biological application,
in particular for the imaging of living cells [10, 11],
since exhibited spectral range and high emission quan-
tum yields [12]. In this communication, two new monastrol
analogs have been prepared with study of their fluorescence
properties.
.
.
Keywords Biginelli reaction Coumarins MPA supported
.
.
on Y zeolite Monastrol Fluorescence properties
Introduction
A common strategy for cancer therapy is the development of
drugs that interrupt the cell cycle during the stage of mitosis.
Compounds that perturb microtubule shortening
(depolymerization) or lengthening (polymerization) cause ar-
rest of the cell cycle in mitosis due to perturbation of the
normal microtubule dynamics necessary for chromosome
Experimental
Physical Measurements: See ref. [13]
Ethyl 4-(3-hydroxphenyl)
-6-methyl-2-thioxo-1,3-dihydroprimidine-5-carboxylate
(Monastrol) (2)
Method A. A mixture of 1 (122 mg, 1.0 mmol), ethyl
acetoacetate (130 mg, 1.0 mmol), and thiourea (190 mg,
2.5 mmol) in MeCN (15 ml) was mixed with HPA supported
on Y zeolite (8 wt% NaY + 0.5 mM HPA) and refluxed for
7 h. After cooling, the heteropoly acid (HPA) supported on
HY filtered off and washed with hot water and ethanol to
remove thiourea from the surface of the catalyst. Then, the
catalyst dried and was maintained for new runs. The filtrate
was evaporated to dryness and the residue was recrystallized
* Najim A. Al-Masoudi
najim.al-masoudi@gmx.de
1
Department of Chemistry, College of Science, University of Basrah,
Basrah 61001, Iraq
2
Present address: Am Tannenhof 8, 78464 Constance, Germany
3
Department of Chemistry, University of Konstanz, P.O. Box 5560,
78457 Constance, Germany

J Fluoresc
from EtOH to afford 2 (254 mg, 87 %), m.p. 181–185 °C (Lit.
[6, 7] 184–186 °C), Rf = 0.71. 1H NMR (DMSO-d6): δ 10.29
(s, 1 H, NH), 9.60 (s, 1 H, NH), 9.44 (s, 1 H, OH), 7.10 (t,
J = 7.8 Hz, H-5), 6.65 (d, 1 H, J2’,4′ = 2.4 Hz, Harom.-2′), 6.64
(m, 2 H, Harom.-4 + Harom.-6), 5.09 (d, 1 H, JNH,4 = 5.5 Hz,
H-4), 4.02 (q, 2 H, J = 7.8 Hz, CH2CH3), 2.28 (s, 3 H, C6-Me),
1.12 (t, 3 H, J = 7.8 Hz, CH2CH3). 13C NMR (DMSO-d6): δ
174.6 (C = S), 165.7 (CO2Et), 157.9 (C-6), 145.3 (C3’-
OH + Carom.-1′), 130.0 (Carom.-5′), 117.7 (Carom.-2′ +
Carom.-6′), 133.6 Carom.-4′), 101.2 (C-5), 60.1 (CH2CH3),
54.5 (C-4), 17.7, 17.6 (C6-Me), 14.5 (CH2CH3). EI-MS:
m/z (%) = 292 [M]+. Anal. Calcd. for C14H16N2O3S
(292.35): C, 57.52; H, 5.52; N, 9.58. Found: C, 57.32;
H, 5.39; N, 9.32 %.
Method B. A mixture of 1 (244 mg, 2.0 mmol), ethyl
acetoacetate (300 mg, 2.30 mmol), and thiourea (380 mg,
5.0 mmol) in EtOH (15 ml) in the presence conc. Hydrochlo-
ric acid (1 ml) was heated under reflux for 3 h. After cooling,
the mixture was poured onto ice (20 g). The precipitate was
filtered and dried and recrystallized from EtOH to give 2
(292 mg, 50 %), The NMR spectra, m.p. and mixed m.p. were
almost similar for those of 2 prepared in method A.
Ethyl 4-(6,8-dichloro-2-oxo-2 H-chromen-3-yl)
-6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-
5-carboxylate (6)
Method A. This compound was prepared following the same
procedure of preparation 2 (method B) using aldehyde 5
(243 mg, 1.0 mmol), ethyl acetoacetate (130 mg, 1.0 mmol),
and thiourea (190 mg, 2.5 mmol), and HPA supported on Y
zeolite (8 wt% NaY + 0.5 mM HPA) in MeCN (15 ml). The
mixture was heated under reflux for 9 h to give, after working
up, 6 (343 mg, 83 %); m.p. 256–257 °C, Rf = 0.81. 1H NMR
(DMSO-d6): δ 10.36 (s, 1 H, NH-1), 9.91 (d, 1 H, JNH,
4 = 5.0 Hz, NH-3), 8.37 (s, 1 H, Hcoum.-4’), 9.97 (d, 1 H, J5’,
7′ = 2.3 Hz, Hcoum.-7′), 8.18 (d, 1 H, J5’,7′ = 2.3 Hz, Hcoum.-5′),
4.08, 3.98 (2xq, 2 H, J = 7.5 Hz, CH2CH3 [R + S]), 2.28 (s,
3 H, C6-Me), 1.17, 1.08 (2xt, 3 H, J = 7.5 Hz, CH2CH3 [R +
S]). 13C NMR (DMSO-d6): δ 174.6 (C = S), 166.5 (CO2Et),
163.5 (Ccoum.-2′), 144.4 (Ccoum.-8a’), 136.2 (Ccoum.-4′), 130.1
(Ccoum.-8′), 129.8 (Ccoum.-6′ + Ccoum.-7′), 126.4 (C-4a’ +
Ccoum.-3′), 122.3 (Ccoum.-5′), 104.6 (C-5), 60.1 (CH2CH3),
53.1 (C-4), 19.8 (C6-Me), 14.2 (CH2CH3). EI-MS: m/z
(%) = 413 [M]+. Anal. Calcd. for C17H14Cl2N2O4S
(413.28): C, 49.41, H, 3.41; N, 6.78. Found: C, 49.20; H,
3.33; N, 6.52 %.
Ethyl 4-(3-hydroxphenyl)
-2-(((7-methoxy-2-oxo-2 H-chromen-4-yl)methyl)thio)
-6-methyl-1,4-dihydropyrimidine-5-carboxylate (4)
Method B. A mixture of ethyl acetoacetate (42 mg,
0.32 mmol), 6,8-dichloro-2-oxo-2 H-chromene-3-
carbaldehyde (5) (100 mg, 0.29 mmol) and thiourea (55 mg,
0.73 mmol) in EtOH (10 ml) in the presence conc. Hydrochlo-
ric acid (0.5 ml) was heated under reflux for 3 h. After cooling,
the mixture was poured onto ice (10 g). The precipitate was
filtered and dried and recrystallized from EtOH to give 6
(50 mg, 42 %). The NMR spectra, m.p. and mixed m.p. were
identical for those of 6 prepared in method A.
A mixture of 2 (100 mg, 0.34 mmol) and 4-bromomethyl-7-
methoxycoumarin (3) (97 mg, 0.36 mmol) in DMF (10 ml)
containing K2CO3 (50 mg, 0.36 mmol) was heated 100 °C for
5 h. After cooling, the solution was evaporated to dryness and
the residue was partitioned between CHCl3 (20 ml) and water
(3 × 20 ml). The combined organic extracts were dried
(Na2SO4), filtered and evaporated to dryness. The residue
was poured onto an SiO2 column (10 g) and eluted, in gradi-
ent, with MeOH (0–5 %) and CHCl3 as eluent to give 4
(60 mg, 35 %), m.p. 94–97 °C, Rf = 0.84. 1H NMR
(DMSO-d6): δ 9.88 (d, 1 H, JNH,4 = 4.5 Hz, NH), 7.93–
7.84 (m, 8 H, Harom. + OH), 6.69 (s, 1 H, Hcoum.-3′),
5.18 (d, 1 H, JNH,4 = 4.5 Hz, Hpyrimid.-4), 4.06 (q, 2 H,
J = 7.2 Hz, CH2CH3), 2.23 (s, 3 H, C6-Me), 1.16 (t,
3 H, J = 7.2 Hz, CH2CH3). - 13C NMR (DMSO-d6): δ
= 166.7 (CO2Et), 160.3 (Cpyrimid.-2 + Ccoum.-2′), 160.2
(Ccoum.-7′), 156.9 (C3’-OH), 155.7 (C-4 + Ccoum.-4′),
153.8 (Ccoum.-8a’), 139.4 (Carom.-1), 132.4 (Carom.-5),
128.3 (Ccoum.-5′), 116.9 (Carom.-6), 115.5 (Ccoum.-4a’),
114.3 (Carom.-2), 112.8 (Ccoum.-3′ + Carom.-4), 112.0
(Ccoum.-6′), 107.9 (Ccoum.-8), 102.0 (Carom.-6), 59.9 (CH2-
CH3), 59.6 (OMe), 56.5 (C-4), 34.8 (CH2S), 22.4 (C6-Me),
14.6 (CH2CH3). EI-MS: m/z (%) = 480 [M]+. Anal. Calcd. for
C25H24N2O6S (480.53): C, 62.49; H, 5.03; N, 5.83. Found: C,
62.28; H, 4.89; N 5.59 %.
Results and Discussion
Chemistry
Our attention was focused on the synthesis of a new fluores-
cent coumarin conjugated monastrol via alkylation of thio
group of the later scaffold, aiming to study their application
as a tracer for detection of hypermetabolic circulating tumor
cells (CTC) by fluorescence imaging. Thus, 2 has been pre-
pared (50 %), via Biginelli reaction [14] in a one-pot three-
component cyclocondensation reaction of 3-hydroxy-
benzaldehyde 1, ethyl acetoacetate and thiourea in the pres-
ence of catalytic amount of HCl. The literatures reported var-
ious Lewis acids as a catalyst in an attempt to optimize the
yield percentage due to the formation of monastrol in R and S
isomers. However, we have optimized the yield of 2 (87 %) by
using molybdophosphoric acid (MPA) supported on Y zeolite
[15] as an efficient and reusable catalyst in boiling MeCN.

J Fluoresc
OH
Scheme 1 Reagents and
condition: (i) method A: HCI,
Et0H, reflux, 3 h; (ii) method B:
molybdophosphoric acid (MPA)
supported on Y zeolite, MeCN,
reflux 7 h; (iii) 3, DMF, K2CO3,
100 °C, 5h
OH
S
i.(methodA.yield:50%),
ii.(methodB.yield:87%)
O
O
+
+
H
CO2Et
Me
H2N
NH2
Me
OEt
HN
CHO
S
N
1
OH
H
Br
2
H
4
CO2Et
MeO
8'
6'
HN
MeO
O
O
3
5'
S
N
6 Me
2
4a'
4'
iii
8a'
4
O
3'
2'
O
Alkylation of 2 with the commercially available coumarin
fluorescent, 4-(bromomethyl)-7-methoxy-2 H-chromon-2-
one (3) in DMF as a solvent and K2CO3 as a catalyst at
100 °C to give, after chromatographic purification, 4 (35 %)
(Scheme 1).
Alternatively, 6 was obtained in 83 % yield, using MPA in boil-
ing MeCN (Scheme 2).
The structure of 6 was assigned from the 1H and 13C NMR
spectra, where the singlets at δ 10.36 and 8.37 ppm were
assigned to NH-1 and H-4’ of the coumarin moiety. The dou-
blets at δ 9.91 and 8.81 ppm (JNH,4 = 5.0 Hz, J5’,7′ = 2.3 Hz)
were attributed to NH-3, and H-5′ of the coumarin, whereas
the doublet and singlet at δ 9.97 and 2.28 ppm were assigned
to H-7 of coumarin and methyl protons at C-6 of pyrimidine
ring, respectively. The methylene and methyl protons of
CO2Et group were appeared as two doublets and triplets (as
R + S isomers) at δ 4.08, 3.98 ppm and δ 1.17, 1.08 ppm
(J = 7.5 Hz), respectively. In the 13C NMR spectrum of 6,
the resonance at δ 174.6 ppm was attributed to C = S
(Cpyrimid.-2), meanwhile the signals at δ 163.5, 136.2,
126.4 ppm were assigned to carbon atoms 2’, 4’, 4’a and 3’
of coumarin scaffold. The carbon atoms 5’-8a’ of coumarin
were appeared at δ 122.3, 129.8, 130.1 and 144.4 ppm, re-
spectively, in addition to resonance of carbonyl carbon atom
(CO2Et) at δ 166.5 ppm. C-5 and C-4 of pyrimidine ring
together with methylene and methyl carbon atoms of ester
group were oriented at δ 104.6, 60.1, 53.1 and 14.2 ppm,
respectively. The structures of 4 and 6 were further identified
from the HSQC [16] and HMBC [17] NMR experiments.
In the 1H NMR spectrum of 4, NH-3 and H-4 appeared as
doublets at δ 9.88 and 5.18 ppm (JNH,4 = 4.5 Hz), respectively,
whereas the aromatic protons and OH resonated as a multiplet
at the region δ 7.93–7.84 ppm. In the 13C NMR spec-
trum of 6, the lower field signals at δ 166.7 ppm were
assigned to C-6 and CO2Et of the pyrimidine ring,
while the resonance at δ 160.3 ppm was attributed to
C-S (Cpyrimidin.-2) together with C-2 of coumarin ring.
The resonances at δ 160.2 and 155.7 ppm were
assigned to Ccoum.-7’ and Cpyrimid.-4 together with C−4’
of coumarin, respectively, meanwhile carbon atoms 4a’,
5’, 6’ and 8’ of coumarin appeared at δ 115.5, 128.3,
112.0 and 107.9 ppm, respectively. Carbon atom of the
same moiety 3’ appeared together with Carom.-4 at δ
112.8 ppm, while CH2S and C-4 of pyrimidine resonat-
ed at δ 34.8 and 56.5 ppm, respectively. The difference in the
chemical shifts value (~ 14 ppm) between Cpyrimidin.-2 (C-S)
of 4 and Cpyrimid.-2 (C = S) of 2, is indicative for the alkylation
of 2 by the fluorescent coumarin 3.
By following the same procedure of preparation of 2, via
Biginelli reaction, 6 was obtained in 42 % yield via a one-pot
three-component cyclocondensation reaction of 6,8-
dichlorocoumarin 3-carboaldehyde (5), ethyl acetoacetate and
thiourea in the presence of catalytic amount of hydrochloric acid.
Fluorescence and Photophysical Properties
Derivatization procedures in fluorescence enhancement are
especially attractive because they introduce an additional
Scheme 2 Reagents and
condition: (i) method A: HCI,
Et0H, reflux, 3h, 42 % yield; (ii)
method B: molybdophosphoric
acid (MPA) supported on Y
zeolite, MeCN, reflux, 9 h, 83 %
yield

J Fluoresc
Fig. 1 UV-visible and
fluorescence spectra of
compounds 4 in MeOH and
EtOH
dimension of selectivity than can simplify analyses in a pre-
dictable and reproducible manner. The importance of 3 as an
active fluorescent lable in biological system, especially for
fatty acids [18–21] as well as alkylating agent prompted
us for measurement the fluorescence property of
comarinyl-monatrol 4, with the aim to develop a new
tracer for detection of hypermetabolic circulating tumor
cells (CTC) by fluorescence imaging. An effective fluo-
rescent agent for biological application has to present a
good fluorescent intensity, high quantum yield and high
photostability.
The absorption and emission spectra of 4 (Fig. 1) and 6
were measured in MeOH and EtOH. Table 1 illustrated the
absorption (λex), emission (λem) and quantum yields (ΦF) of
these analogs, using Rhodamin 6G as standard. Compounds 4
and 6 exhibited λem = 398 and 339 nm, with quantum yields
(ΦF) = 0.17 and 0.09, respectively, and remarkable stoke’s
effects (76 and 28, respectively) in MeOH. Unexpectedly, 4
showed a low quantum yield although 3 possesses a spectral
property of (λex 322 nm; λem = 395 nm, stoke’s effect 73) [21]
on derivatization. It is well known that the electron donating
groups substituted on coumarin will increase the intermolec-
ular electron transfer and thus enhance the fluorescence of
coumarin derivatives, especially at position 7 [22]. Although
4 having coumarin moiety with methoxy group at C-7, but
exhibited a low quantum yield. Such data may due to two
factors: distortion of molecule in its own plane or twisted
out of plane on intramolecular charge transfer caused by sol-
vent, whereas the other factor may due to collosional
quenching occurs when the excited state fluorophore
(coumarin-methylthio moiety) is deactivated upon joining
with other molecule (monastrol) via the thioether linkage in
solution [23].
Regarding compound 6, the presence of two electron with
drawing groups (3,5-dichloro residues) at coumarin moiety
might decrease the conjugation therefore would reduced the
fluorescence property of such molecules instead of its optimi-
zation. The other reason of low quantum yield of 6 may due to
distortion of the planarity of the molecule as in compound 4,
as well as the decrease in π−conjugation because of the satu-
rated carbon atom (C-4) of monastrol. Furthermore, the emis-
sion spectrum of 4 has been measured in EtOH which re-
vealed almost a similar pattern of emission as in MeOH
(Fig. 1). The fluorescence of compounds 4 and 6 in CH2Cl2
showed a red chromic shift (λem = 386 and 322 nm, respec-
tively), therefore, it is obvious that λem of both compounds are
shifted to longer wavelengths with increasing solvent polarity.
Such result indicated that solvent polarity had obvious effect
on the emission spectrum [24, 25].
The quantum yield (ΦF) has been calculated according to
the equation reported by C. Vielsack, h.D. Thesis, University
of Konstanz, 1999.
Table 1 Absorption and emission data of some new monastrol analogs
a
Compd.
Mass [μg]
Molar Mass [μg/μmol]
λ
em[nm]a
λ
em[nm]b
ΦF
λex[nm]a
λex[nm]a
4
176
271
–
480.45
413.28
269.09
398
339
395
386
322
–
0.17
0.09
–
278
224
322
322
311
–
6
3c
a in MeOH; b in CH2Cl2; c after derivatization [21]; Volume: 25 ml; Ref.-Subst. Rh6G in EtOH (ΦF: 0.95) at RT; n2 D (MeOH): 1.77; n2 D (EtOH): 1.86/
Equipment and software: Perkin Elmer LS 50, Cary UV/vis 50; SpekWin 1.71.3, FL WinLab.

J Fluoresc
Acknowledgments We thank Basrah University for a scholarship to
Miss Y.A. Marich. Miss A. Friemel of Chemistry Department, Konstanz
University, Germany is highly acknowledged for the 2D-NMR
experiments.
12. Ivana K, Andrea J, Pavol K (2006) Synthesis of coumarin or ferro-
cene labeled nucleosides via Staudinger ligation. Beilstein J Org
Chem 2:23–26
13. Al-Masoudi NA, Maricha YA, Al-Salihi NJ, Saeed B (2014)
Synthesis and modeling study of some potential pyrimidine deriv-
atives as HIV inhibitors. Z Naturforsch 69b:913–923
14. Biginelli P (1893) Derivati aldeiduredici degli eteri acetil-e dossal-
acetico. Gaza Chim Ital 23:360–416
15. Moosavifar M (2012) An appropriate one-pot synthesis of
dihydropyrimidinones catalyzed by heteropoly acid supported on
zeolite: An efficient and reusable catalyst for the Biginelli reaction.
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