Quinazoline antifolate thymidylate synthase inhibitors: Replacement of glutamic acid by aminophosphonic acids

Article abstract of DOI:10.1080/10426500307844

The synthesis of six analogues of the potent thymidylate synthase (TS) inhibitor N-[4-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinoyl)-methyl] -N-prop-2-ynylamino]benzoyl]-L-glutamic acid 2 is described in which the glutamic acid residue has been replaced

Full text of DOI:10.1080/10426500307844

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Quinazoline Antifolate Thymidylate Synthase
Inhibitors: Replacement of Glutamic Acid by
Aminophosphonic Acids
Maciej Makowski a , Krzysztof Pawełczak a , Paweł Kafarski b , Jolanta M. Dzik c , Barbara
Gołos c , Małgorzata Balinska c & Wojciech Rode c
a Institute of Chemistry , University of Opole , Opole, Poland
b Technical University of Wrocław , Wrocław, Poland
c Nencki Institute of Experimental Biology , Warszawa, Poland
Published online: 27 Oct 2010.
To cite this article: Maciej Makowski , Krzysztof Pawełczak , Paweł Kafarski , Jolanta M. Dzik , Barbara Gołos , Małgorzata
Balinska & Wojciech Rode (2003) Quinazoline Antifolate Thymidylate Synthase Inhibitors: Replacement of Glutamic
Acid by Aminophosphonic Acids, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:8, 1639-1651, DOI:
10.1080/10426500307844
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Phosphorus, Sulfur, and Silicon, 178:1639–1651, 2003
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print
DOI: 10.1080/10426500390225605
QUINAZOLINE ANTIFOLATE THYMIDYLATE
SYNTHASE INHIBITORS: REPLACEMENT OF
GLUTAMIC ACID BY AMINOPHOSPHONIC ACIDS
Maciej Makowski,a Krzysztof Pawelꢀczak,a Pawelꢀ Kafarski,b
Jolanta M. Dzik,c Barbara Golꢀos,c Malꢀgorzata Balinska,c
and Wojciech Rodec
Institute of Chemistry, University of Opole, Opole, Poland;a
Technical University of Wroclꢀaw, Wroclꢀaw, Poland;b and Nencki
Institute of Experimental Biology, Warszawa, Polandc
(Received June 3, 2002; accepted June 3, 2002)
The synthesis of six analogues of the potent thymidylate synthase
(TS) inhibitor N-[4-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinoyl)-
methyl]-N-prop-2-ynylamino]benzoyl]-L-glutamic acid
2 is descri-
bed in which the glutamic acid residue has been replaced by
DL-aminophosphonic acids. New antifolates were tested as inhibitors
of TS isolated from mouse L1210 leukemic cells as well as inhibitors
of growth mouse leukemic L5178Y cells. In general these modifications
result in compounds that are considerably less potent than 2 as TS in-
hibitors with Ki’s 0.17–1.10 µM. Very poor solubility in water limited
their proper assay of growth cells inhibition.
Keywords: Aminophosphonic acid analogues of antifolates; antifolates;
thymidylate synthase inhibitors
Discovery, development, and clinical trial of 10-propargyl-5,8-
dideazafolic acid 1, a potent inhibitor of thymidylate synthase (TS) have
stimulated and refocused antifolate cancer chemotherapy in the last
two decades.1−5 Clinically active but renal toxic drug 1 was withdrawn
from the clinic and replaced with the more soluble and non toxic 2-
methyl-2-desamino compound 2 with improved pharmacological prop-
erties (Figure 1).6−10 Antifolates containing glutamyl residue (classical
This work was supported by the State Committee for Scientific Research grant
no. 6 6254 92 03.
Address correspondence to Krzysztof Pawelꢀczak, Institute of Chemistry, University
of Opole, 48 Oleska Street, Opole 45052, Poland. E-mail: pawel@uni.opole.pl
1639

1640
M. Makowski et al.
FIGURE 1

Quinazoline Antifolate Thymidylate Synthase Inhibitors
1641
TS inhibitors like 1 and 2) require transport by the reduced folate
carrier for entry into cells and are converted intracellularly into poly-
glutamylated species. Intracellular polyglutamylation is an important
aspect of their pharmacology.11 The fact that tumor cells can acquire
resistance to classical antifolates by deletion or modification of active
transport or enzymic polyglutamylation have stimulated the search for
compounds that do not require these mechanisms to express antitu-
mor activity. Compounds 1 and 2 with well defined TS inhibitory ac-
tivity and cytotoxic potencies are still the starting point for molecular
modifications in the search for antifolates, which do not require active
transport into cells or polyglutamylation for activity. An example of
such an approach is the synthesis and evaluation of biological activ-
ity of analogues of 2 in which the glutamic acid residue was replaced
by other amino acids.11 In general these modifications resulted in com-
pounds that have equivalent TS inhibitory potency to 2. Moreover these
compounds had lower cytotoxicity if compared to 2 because of their in-
ability to undergo intracellular conversion to polyglutamylated forms.
In this article we describe the synthesis and evaluation of biological ac-
tivity of six analogues (33–38) of TS inhibitor 2 in which the glutamic
acid residue is replaced by aminophosphonic acid residues containing
lipophilic α-substituents (Figure 1).
CHEMISTRY
The general method for the synthesis of aminophosphonate analogues
of 2 is outlined in Chart 1. 4-Nitrobenzoyl chloride was coupled with
appropriate dialkyl esters of aminophosphonic acid (3–8) to give ni-
tro derivatives (9–14) which after reduction by catalytic hydrogenation
gave diesters of N-(4-aminobenzoyl)aminophosphonic acids (15–20).
Alkylation with propargyl bromide yielded the appropriate secondary
amines (21–26). Further alkylation with 2-methyl-(6-bromomethyl)-4-
quinazolone gave antifolate esters. Removal of the alkyl groups from
the blocked phosphonate esters was the limiting step of the synthe-
ses and was accomplished by standard silylation procedure. This pro-
cedure caused the isolation of final product without laborious col-
umn chromatography. The purity of all compounds was established
by elemental analysis; structures of phosphonate diesters (27–32)
1
and final products (33–38) were confirmed by H, 13C, and 31P NMR
spectroscopy.

1642
M. Makowski et al.
CHART 1

Quinazoline Antifolate Thymidylate Synthase Inhibitors
1643
TABLE I Inhibition of Thymidylate Symnthase (TS) from Mouse L1210 Cells
and In Vitro Cytotoxicity of Aminophosphonate Analogues
TS inhibition
Ki (µM)
Cell growth inhibition
I50 (mM)
Compd.
R
L1210
Mouse L5178 leukemic cells
2
33
34
35
36
37
38
0.010a
0.83
0.43
0.71
0.29
0.17
1.1
0.09b
1
1.5
1
3
CH2CH(CH3)2
CH(CH3)2
CH2CH2CH3
CH2CH3
C6H5
C(CH3)3
5
2
aRef. 9.
bin µM units.
BIOLOGICAL EVALUATION
The antifolates 33–38 listed in Table I were tested as inhibitors of TS
isolated from mouse leukemia L1210 cells. The purification and assay
method used for TS from L1210 cells was previously described.12 Mouse
leukemia L5178Y cells used for I50 assay were plated with density 105
per ml, grown for 4 h exposed to different concentration of inhibitor for
48 h. Direct cell counting was conducted with inverted light microscope
staining with trypan blue. Each experiment was conducted three times
in triplicates.
RESULTS AND DISCUSSION
Replacement of the C-terminal carboxylic moiety of the amino acid by a
phosphonic acid group is a well-established strategy for the synthesis of

1644
M. Makowski et al.
new amino acids mimetics. This approach, applied in numerous cases,
has shown that strong electrostatic binding of a phosphonate dianion
by appropriate portions of target enzymes accounts significantly for the
inhibitory action of many of the phosphonic acid analogues of amino
acids and their derivatives.13
The synthesis of antifolates containing phosphonic acid analogues
of glutamic acid has been limited so far to the compounds in which
the γ -carboxylic moiety of glutamic acid was replaced by phospho-
nate, and thus did not give the information about the binding abil-
ity of α-carboxylic part of molecule.14−18 In this article we synthesized
analogues 33–38 of compound 2 based on the premise that the bineg-
ative phosphonate anion will be bound by the positively charged α-
carboxylate binding site of the thymidylate synthase and thus act as
the inhibitor of the enzyme. This appeared, however, to be not the case
since data shown in Table I indicate 17–110 times weaker inhibition of
enzyme caused by these compounds if compared with the parent com-
pound 2. The antileukemic activity of our phosphonic acid analogues
of antifolates was negligible. This may result in part from very weak
solubility of compounds 33–38 in water, which was a limiting factor in
cell growth inhibition studies.
EXPERIMENTAL
Oxalates of dialkyl esters of aminophosphonic acids (3–8) were prepared
according to a procedure previously reported and 6-(bromomethyl)-3,4-
dihydro-2-methyl-4-quinazolone was prepared according to the known
procedure.8,12 4-Nitrobenzoyl chloride and propargyl bromide were
commercial products (Merck, 820885; Fluka, 81830). Tetrahydrofu-
ran (THF), dioxane, diethyl ether, and triethylamine were distilled
◦
˚
from sodium and stored over activated (250 C) 4 A molecular sieves.
Dimethylformamide was azeotropically distilled and similarly dried.
The hydrogenolysis catalyst was 10% Pd/C and was used at 20%
of substrate weight. Reactions were monitored and the homogene-
ity of products checked by TLC on silica gel 60 (Merck, 5553) with
the following eluents: (A) 8% CH3OH/CHCl3; (B) 20% CH3OH/CHCl3;
(C) 35% acetone/CHCl3; (D) 5% acetone/CHCl3; (E) acetone. Spots
were visualized with chlorine-tolidine reagent. Full protected com-
pounds 21–38 were purified by low pressure short column chromatog-
raphy on silica gel 60 (Merck, 7736). Melting points were determined
on a Boëtius heating block and are uncorrected. 1H, 31P, and 13C
NMR spectra were determined on Brucker (300 MHz) spectrometer.

Quinazoline Antifolate Thymidylate Synthase Inhibitors
1645
The elemental analyses were performed at the Institute of Organic
Chemistry, Biochemistry and Biotechnology of Technical University of
Wroclꢀaw.
Preparation of Dialkyl Esters
of N-(4-Nitrobenzoyl)aminophosphonic Acids (9--14)
To a stirred suspension of an appropriate oxalate of aminophosphonic
acid alkyl ester 3–8 (1 mmol) in dioxane (4 ml), N-methyl-morpholine
(0.33 ml, 3 mmol) was added. After 15 min, stirring at room temper-
ature, 4-nitrobenzoyl chloride (0.186 g, 1 mmol) was added and stir-
ring was continued for 1.5 h. Salts were filtered off and the filtrate
evaporated to a dense oil that was dissolved in ethyl acetate (50 ml).
The organic layer was washed with 0.2N HCl, saturated NaHCO3 and
brine, dried (MgSO4), and concentrated to one-half volume. A white
crystalline solid was obtained from AcOEt–hexane. Yields and melting
points of products are given in Table II.
Preparation of Dialkyl Esters
of N-(4-Aminobenzoyl)aminophosphonic Acids (15--20)
A
solution of an appropriate dialkyl ester of N-(4-nitro-
benzoyl)aminophosphonic acid (9–14) (1 mmol) in EtOH (10 ml)
containing Pd/C in suspension was stirred under nitrogen for 30 min,
whereupon TLC (system A) showed the absence of starting material.
The catalyst was removed by filtration and the filtrate evaporated to
dryness. The white crystalline solids after evaporation were crystal-
lized from the solvent mixture MeOH–AcOEt–pentane. Yields and
melting points of products are given in Table II.
Preparation of Dialkyl Esters
of N-[4-(Prop-2-ynylamino)benzoyl)aminophosphonic
Acids (21--26)
A
mixture of appropriate dialkyl ester of N-(4-amino-
benzoyl)aminophosphonic acid (15–20) (1 mmol), CaCO3 (1.5 mmol),
and propargyl bromide (1.5 mmol) in DMAA (0.5 ml) was stirred
in the absence of light at room temperature for 24 h. The mixture
was diluted with MeOH (1 ml), filtered, and the solvent removed
in vacuo to give a brown oil. The oil was dissolved in 2% pyridine in
CHCl3 (1 ml) and purified on a column (3 cm i.d. × 7 cm L) of silica
gel (22 g) using CHCl3 and solutions 1–4% of pyridine in CHCl3 as

1646
M. Makowski et al.
TABLE II Preparation of Anifolate Syntons (9–26)
Analysis (%) Calcd (Found)
Scale
(mmol)
Yield
(%)
Compd.
m.p. (◦C)
Formula
C
H
N
9
10
10
10
10
10
10
5
80
87
76
89
78
73
93
97
98
98
91
94
41
40
47
38
53
37
160–162 C14H21N2O6P
127–128 C15H23N2O6P
48.84
(48.52
50.28
(50.38
47.28
(47.42
45.58
(45.64
55.10
(55.37
48.84
(48.95
53.50
(53.18
54.87
(54.71
52.00
(51.82
50.35
55.32
59.66
(59.54
53.50
(53.65
57.95
(58.12
59.01
(59.34
56.80
(56.67
55.55
(55.67
62.99
(63.15
57.95
(58.17
6.15
6.23
6.47
6.18
5.80
5.57
5.42
5.12
5.39
5.34
6.15
6.05
7.38
7.42
7.67
7.82
7.05
7.08
6.69
6.56
6.40
6.34
7.38
7.12
7.15
7.01
7.43
7.12
6.85
6.92
6.53
6.41
6.29
6.18
7.15
7.02
8.14
8.31)
7.82
7.75)
8.48
8.18)
8.86
8.57)
7.14
7.18)
8.14
8.11)
8.91
8.97)
8.53
8.65
9.33
9.37)
9.79
9.54
7.33
7.23)
8.91
8.97)
7.95
7.83)
7.65
7.82)
8.28
8.32
8.64
8.65)
7.00
7.08
7.95
7.19)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
12–122
C13H19N2O6P
166–167 C12H17N2O6P
144–147
166–168
195–198
184–185
C
C
C
C
18H21N2O6P
14H21N2O6P
14H23N2O4P
15H25N2O4P
5
5
158–161 C13H2N2O4P
5
184–187
181–184
181–184
167–169
C
C
C
C
12H19N2O4P
18H23N2O4P
14H23N2O4P
17H25N2O4P
5
5
4
5
119–121 C18H27N2O4P
4
153–156
146–149
147–148
145–147
C
C
C
C
16H23N2O4P
15H21N2O4P
21H23N2O4P
17H25N2O4P
1
5
5
eluents. Product containing fractions were combined and evaporated
in vacuo to give an oil. The oil was dissolved in MeOH (1 ml) and
AcOEt (5 ml), and petroleum ether was added to turbidity. Yields,
melting points, and analytical data of these products are given in
Table II.

1647

1648
M. Makowski et al.
TABLE IV 1H and 13C NMR Data for the Main Chain of Representative
Antifolate Ester
C or H
δ
1H, ppm (m, J in Hz)a
13C, ppm (J in Hz)b
1
2
3
4
5
6
1.152 and 1.335 (t, J = 7.1 Hz, 3H, each)
2.485 (s, 3H)
16.56 and 16.59 (5.5 Hz)
22.35
40.44
50.73 (154.6 Hz)
54.83
63.88 (7.2 Hz)
4.120 (d, J = 2.2 Hz, 2H)
5.91 (d-d, JHNH = 9.6 Hz, JPH = 21.5 Hz, 1H)
4.710 (s, 2H)
3.791 and 3.819 (q-q, J = JPH = 8.6 Hz, 0.5H each)
3.995 and 4.005 (q-q, J = JPH = 8.6 Hz, 0.5H each)
4.184 and 4.207 (q-q, J = JPH = 7.5 Hz, 1H)
2.256 (t, J = 2.2 Hz, 1H)
7
8
73.30
79.07
9
6.863 (d, J = 8.9 Hz, 2H)
7.933 (d, J = 8.9 Hz, 2H)
7.642 (d, J = 8.4 Hz, 1H)
7.691 (d, J = 8.4 Hz, 0.5H each)
8.225 and 8.229 (s, 0.5 each)
113.38
129.01
128.5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
133.77
124.85
123.73
149.36
121.13
135.70
151.30
154.10
163.78
167.11 (7.9 Hz)
8.146 and 8.157 (d, JHNH = 9.6 Hz, 0.5H each)
10.886 (s, 1H)
a300 MHz, CDCl3.
b75.47 MHz in CDCl3.

Quinazoline Antifolate Thymidylate Synthase Inhibitors
1649
TABLE V 1H Data for the Side Chain of the Various Antifolate Esters
Compd. Side chain R
δ
1H, ppm (m, J in Hz)a
27
28
29
i-butyl
0.93 and 0.95 (d, J = 6.4 Hz, 3H each); 1.70 (m, 3H, γ CH, β CH2);
4.89 (dd-t, J = 6.4 Hz, JNH = 9.8, JPH = 12.3 Hz, 1H, αCHα)
1.10 (d, J = 6.4 Hz, 3H each); 2.29 (m, J = 6.4 Hz, 1H, β CH);
4.74 (d-d, J = 6.4 Hz, JPH = 20.2 Hz, JNH = 10.2 Hz, 1H, αCH)
0.92 (t, J = 7.3 Hz, 3H); 1.42 (q-q, J = 7.3 Hz, JPH = 14.1 Hz,
1H each, β CH2); 1.75–1.9 (m, 2H, γ CH2); 4.84 (d-t-t,
J = 5.6 Hz, JNH = 9.6 Hz, JPH = 19.5 Hz, 1H, αCH)
1.00 (t, J = 7.3 Hz, 3H, γ CH3); 1.75–1.8 and 1.8–2.05 (m, 1H
each); 4.71 (q-t, J = 6.1 Hz, JNH = 9.8 Hz, JPH = 21.9 Hz,
1H, αCH)
i-propyl
n-propyl
30
ethyl
31
32
phenyl
5.91 (dd, JNH = 9.6, JPH = 21.5 Hz, 1H, αCH) 7.25–7.35
(m, 3H, phenyl); 7.59 (d, J = 6.3, 2H, phenyl)
t-butyl
1.11 (s, 9H, β C(CH3)3); 4.64 (dd, JNH = 10.5 Hz, JPH = 18.7 Hz,
1H, αCH)
a300 MHz, CDCl3.
Preparation of Dialkyl Esters
of N-[4-[N-[3,4-Dihydro-2-methyl-4-oxoquinazolin-
6-yl)methyl]-N-prop-2-ynylamino]benzoyl]-
aminophosphonic Acids (27--32)
A
mixture of appropriate dialkyl ester of N-[4-(prop-2-
ynylamino)benzoyl)-aminophosphonic acid (21–26) (1 mmol), 6-
(bromomethyl)-3,4-dihydro-2-methyl-4-oxoquinazoline (1.5 mmol), and
CaCO3 (2 mmol) in N,N-dimethylacetamide (DMA) (3 ml) was stirred
in 50◦C for 6 h in the dark under argon atmosphere. The mixture was
diluted with MeOH (7 ml) and AcOEt (150 ml), and filtered. The filtrate
was washed with brine (4 × 15 ml), water (4 × 15 ml), and then dried
(MgSO4) and evaporated in vacuo to give an oil. The oil was dissolved

1650
M. Makowski et al.
in 4% MeOH in CHCl3 (4 ml) and purified on a column (4 cm i.d. ×
6 cm L) of silica gel (40 g) using CHCl3 and solutions 0.5–3.5% of MeOH
in CHCl3 as the eluents. Product containing fractions were combined
and evaporated in vacuo to give an oil. The products were crystallized
from the mixture of AcOEt–MeOH (5:1) and petroleum ether. Yields,
melting points, analytical, and 31P NMR data of products 27–33 are
given in Table III; 1H and 13C NMR data are given in Tables III and IV.
Preparation of N-[4-[N-[3,4-Dihydro-2-methyl-
4-oxoquinazolin-6-yl)methyl]-N-prop-2-
ynylamino]benzoyl]aminophosphonic Acids (33--38)
To a solution of an appropriate dialkyl ester of N-[4-[N-[3,4-
dihydro-2-methyl-4-oxoquinazolin-6-yl)methyl]-N-prop-2-ynylamino]
benzoyl]amino-phosphonic acid (27–32) (0.5 mmol) in CHCl3 (10 ml)
iodotrimethylsilane (0.27 ml, 2 mmol) was added at 0◦C, and the
mixture was stirred for 10 min under argon. The cooling bath was
TABLE VI 1H NMR Data for the Main Chain of the
Representative Antifolate Free Acid
Atom H No.
δ
1H, ppm, (m, J in Hz)a
1
2
2.2–2.4 (m, usually overlapped with the side chain signals)
2.43 (s)
3
4.02 (s)
4
5
4.04 (d-d, J = 6.7 Hz, JPH = 17.3 Hz)
4.38 (s)
6
7
8
9
6.87 (d, J = 8.8 Hz)
7.25 (d, J = 8.4 Hz)
7.39 (d, J = 8.4 Hz)
7.85 (d, J = 8.8 Hz)
7.93 (s)
10
a300 MHz, D2O + NaOD.

Quinazoline Antifolate Thymidylate Synthase Inhibitors
1651
then removed and solvent was evaporated in vacuo. The residue was
dissolved in EtOH (96%, 25 ml) and stirred at 40◦C for 24 h in dark.
The solvent was removed in vacuo to give an oil, which was treated
with 1N NaOH (2 ml) and mixed for 4 h at room temperature. The
mixture was acidified to pH 3.0 with 4N HCl; the precipitate was
filtered, washed with water (4 × 5 ml), and dried. Yields, melting
points, and analytical data of these products are given in Table III; 1H
and 31P NMR data are given in Tables V and VI.
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