Синтез та протиракова активність 2,5-діарил-оксазоло[5,4-d]піримідин-7-амінів та відповідних амідів
A series of novel oxazolo[5,4-d]pyrimidine derivatives were synthesized and evaluated for anticancer activity against NCI 60 cancer cell lines. This work is a continuation of our investigation of the anticancer activity of a number of isomeric oxazolopyrimidines, and the study of the dependence of s...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2025
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Ukrainica Bioorganica Acta| _version_ | 1871193535090262016 |
|---|---|
| author | Pilyo, Stepan G. Kachaeva, Maryna V. Popilnichenko, Serhii V. Brovarets, Volodymyr S. |
| author_facet | Pilyo, Stepan G. Kachaeva, Maryna V. Popilnichenko, Serhii V. Brovarets, Volodymyr S. |
| author_institution_txt_mv | [
{
"author": "Stepan G. Pilyo",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Maryna V. Kachaeva",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine "
},
{
"author": "Serhii V. Popilnichenko",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine "
},
{
"author": "Volodymyr S. Brovarets",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine "
}
] |
| author_sort | Pilyo, Stepan G. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:56Z |
| description | A series of novel oxazolo[5,4-d]pyrimidine derivatives were synthesized and evaluated for anticancer activity against NCI 60 cancer cell lines. This work is a continuation of our investigation of the anticancer activity of a number of isomeric oxazolopyrimidines, and the study of the dependence of structure on anticancer effect. Previously described oxazolo[4,5-d]pyrimidines containing N-unsubstituted amino groups of piperazine or diazepane exhibited high cytotoxicity, with submicromolar IC₅₀ values against breast (MDA-MB-231), ovarian (OVCAR-3), and colon (HCT-116) cancer cell lines in NCI screening. Synthesized 2,5-diaryl-oxazolo[5,4-d]pyrimidin-7-amines did not demonstrate significant anticancer effects, unlike the previously described isomeric oxazolo[4,5-d]pyrimidines. Inhibition activity was observed for 7-amino-2-phenyl-5-(4-methylphenyl)oxazolo[5,4-d]pyrimidine (D-765554), particularly against the MCF7 (79.6%), UO-31 (78.4%), and OVCAR-5 (88.1%) cell lines, but anticancer potential among the tested oxazolo[5,4-d]pyrimidine derivatives was not noticeable. The results of anticancer activity in the oxazolopyrimidine series, obtained in this work and published previously, may be useful for studying the bioactivity of oxazolopyrimidines in the future |
| doi_str_mv | 10.15407/bioorganica2025.02.060 |
| first_indexed | 2026-02-08T07:59:47Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
UDC 547.73/.9:577.1
DOI: https://doi.org/10.15407/bioorganica2025.02.060
60
Ukrainica Bioorganica Acta
www.bi oorgan ica . com.u a
RESEARCH ARTICLE
Synthesis and anticancer activity of 2,5-diaryl-oxazolo[5,4-d]pyrimidin-7-
yl amines and corresponding amides
Stepan G. Pilyo, Maryna V. Kachaeva*, Serhii V. Popilnichenko, Volodymyr S. Brovarets
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
Abstract: A series of novel oxazolo[5,4-d]pyrimidine derivatives were synthesized and evaluated for anticancer activity against NCI 60
cancer cell lines. This work is a continuation of our investigation of the anticancer activity of a number of isomeric oxazol opyrimidines,
and the study of the dependence of the anticancer effect on the structure. Previously described oxazolo[4,5-d]pyrimidines containing
N-unsubstituted amino groups of piperazine or diazepane exhibited high cytotoxicity, with submicromolar IC₅₀ values against breast
(MDA-MB-231), ovarian (OVCAR-3), and colon (HCT-116) cancer cell lines in NCI screening. Synthesized 2,5-diaryloxazolo[5,4-
d]pyrimidin-7-amines did not demonstrate significant anticancer effects, unlike the previously described isomeric oxazolo[4,5-
d]pyrimidines. Inhibition activity was observed for 7-amino-2-phenyl-5-(4-methylphenyl)oxazolo[5,4-d]pyrimidine (D-765554),
particularly against the MCF7 (79.6%), UO-31 (78.4%), and OVCAR-5 (88.1%) cell lines, but anticancer potential among the tested
oxazolo[5,4-d]pyrimidine derivatives was not noticeable. The results of anticancer activity in the oxazolopyrimidine series, obtained in this
work and published previously, may be useful for studying the bioactivity of oxazolopyrimidines in the future.
Keywords: oxazolo[5,4-d]pyrimidin-7-amine; amides; anticancer activity.
Introduction
Bicyclic aromatic fused heterocycles are well-known
pharmacophores in the development of new drugs with
anticancer properties. Oxazolopyrimidines are receptor
modulators, in particular P2Y1 with an in vitro Ki value of
24 nM [1], adenosine A2 receptor antagonist with an IC50
value below 100 nM [2], selective adenosine A2A receptor
antagonists [3], and an in vitro transient receptor potential
antagonist of human vanilloid receptor 1 protein with an
IC50 value of 136 nM [4]. Such antagonists may have
significant benefits in the treatment of various blood
clotting disorders, pain, insomnia, depression, drug
addiction and Parkinson's disease [2], itching, arthritis,
cough, asthma or inflammatory bowel diseases [4].
It is known that oxazolopyrimidines are inhibitors of
adenosine kinase (ADK) with an IC50 value of 10 nM.
Received:
Revised:
Accepted:
Published online:
10.08.2025
25.09.2025
06.10.2025
30.12.2025
Corresponding author. Tel.: +38-(044) 573-26-78;
e-mail: kachaeva@bpci.kiev.ua (M.V. Kachaeva)
ORCID: 0000-0003-1517-4807
Inhibition of ADK is an attractive therapeutic approach for
conditions such as neurodegeneration, seizures, ischemia,
pain, and inflammation [5].
Oxazolo[4,5-d]pyrimidines with various substituents at
the 7-position of the ring (Scheme 1), such as N-alkyl-
substituted (A), N-sulfonyl-substituted (B, C) and N-unsub-
stituted piperazine or 1,4-diazepane moiety were evaluated
for their antitumor activity against the NCI-60 cell lines [6].
Compounds containing a piperazine or diazepane
substituent at the N-position showed lower anticancer
activity compared to NH-unsubstituted piperazine/1,4-
diazepane group [7]. Nevertheless, 7-sulfonyldiazepan- and
7-sulfonylpiperazine-substituted oxazolo[4,5-d]pyrimidines
demonstrated cytotoxic activity and a high level of
selectivity to CNS SNB-75 and non-small lung cancer
NCI-H460 cell line. The compounds met drug-like criteria
according to ADMET analysis. Molecular docking
investigations of synthesized compounds demonstrated
complex formation with carbonic anhydrase XII as a
potential mechanism [6].
Oxazolo[4,5-d]pyrimidines with N-unsubstitited pipera-
zine/diazepane displayed high anticancer activity regarding
almost all or most all cancer cell lines at submicromolar
concentrations [7].
© Pilyo S.G. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.
S.G. Pilyo, M.V. Kachaeva et al.
61
Ar, Ar1 = Ph, 4-MeC6H4; R1 = Me, Ph, 4-MeC6H4.
N
N
O
N Ar1
N
Ar
N
S
R1O
O
N
N
O
N Ar1
N
Ar
N
S
O
R1
O
N
N
O
N Ar1
N
Ar
N
Me
A B C
N
NN
O
N
N
H
N
NN
O
N
NH
N
NN
O
N
H
N
Me
D E F
Figure 1. Oxazolo[4,5-d]pyrimidines A-E and oxazolo[5,4-d]pyrimidine F.
N
O
CN
Ar1 SO2Cl
+ Ar2
HN
H2N
2Et3N N
O
Ar1
N
N
NH2
Ar2
1-4
Ar1 = Ph (1, 2), 4-MeC6H4 (3, 4);
Ar2 = 4-MeC6H4 (1), 4-EtC6H4 (3), 4-MeOC6H4 (2, 4)
. HCl
I
N
O N
N
NH2
Me
N
O N
N
NH2
OMe
N
O N
N
NH2
Et
Me
N
O N
N
NH2
OMe
Me
1 2 3
4
Scheme 1. Synthesis of 7-amino-1,3-oxazolo[5,4-d]pyrimidines 1-4.activity as compared to C(8)-unsubstituted analog 11.
In work [8], the activity of three isomeric oxazolopyri-
midines was studied on four hamster kidney cell lines with
and without different ADK isoform profiles. The ability of
all new synthesized oxazolopyrimidines and their
precursors to inhibit cell proliferation of ovarian (OVCAR-
3), colon (HCT-116) and breast (MDA-MB-231) cancer
cells was analyzed after 96 h treatment.
Oxazolo[4,5-d]pyrimidines D and E exhibited slightly
higher antiproliferative activity (IC50: 0.24 ± 0.05 μM for D
and 0.21 ± 0.03 μM for E) than doxorubicin (IC50 = 0.36 ±
0.03 μM) on MDA-MB-231 and have relatively good
results on OVCAR-3 (IC50: 1.8 ± 0.3 μM and 1.7 ± 0.2 μM)
and HCT-116 (IC50: 3.9 ± 0.3 μM and 0.24 ± 0.03 μM).
Isomeric oxazolo[5,4-d]pyrimidine F inhibited the growth
of OVCAR-3, HCT-116, and MDA-MB-231 at micromolar
concentrations (IC50: 5.3 ± 0.3 μM, 3.9 ± 0.4 μM and 1.4 ±
0.3 μM, respectively) [9].
Analyzing the results of the anticancer activity of
different isomeric oxazolopyrimidines, it can be concluded
that the presence of NH-group in the unsubstituted
piperazine/diazepane plays an important role, and could be
useful for developing new anticancer agents.
The fused heterocyclic scaffold oxazolo[5,4-
d]pyrimidine has emerged as a promising anticancer
pharmacophore: several derivatives have shown strong
inhibition of VEGFR2 kinase and suppression of VEGF-
induced proliferation of human endothelial (HUVEC) cells,
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
62
with IC₅₀ values reaching 0.29 μM for the most active
compound in a series of 2,5,7-trisubstituted analogues [10].
Structure-activity relationship (SAR) analysis demonstrated
that p-methyl or p-fluoro substitution on the 7-anilino ring
and replacement of the 2-phenyl fragment with a methyl-
piperazine moiety significantly improved both potency and
selectivity [10]. In addition to anti-angiogenic activity,
some oxazolo[5,4-d]pyrimidines exhibit proapoptotic
effects in tumor cell lines displayed GI₅₀ values of 55 nM
(T-47D) and 14 nM (MDA-MB-435) and induced caspase-
mediated apoptosis [10]. Related studies have also
described anti-angiogenic oxazolo[5,4-d]pyrimidines such
as CPU-12, which inhibits VEGF signaling and tumor
neovascularization [11].
Despite these advances, most research remains limited to
in vitro evaluations, with insufficient data on in vivo
efficacy, pharmacokinetics, and toxicity [12].
Consequently, the oxazolo[5,4-d]pyrimidine scaffold
represents a valuable platform for anticancer drug design,
but further comprehensive studies are required to optimize
ADMET properties, confirm in vivo antitumor efficacy, and
clarify molecular mechanisms.
Results and Discussion
Chemistry
The reaction of 2-aryl-4-cyano-1,3-oxazole-5-sulfonyl
chlorides I with amidines leads to the formation of 7-
amino-1,3-oxazolo[5,4-d]pyrimidines 1-4. The reaction
proceeds under mild conditions at 20-25 ºC in
tetrahydrofuran in the presence of triethylamine to form
compounds 1-4 in 44-60% yields (Scheme 1) [13]. The IR
spectra of compounds 1-4 contain stretching vibration
bands of the NH₂ group at ν 3208-3213 and 3326-3322
cm⁻¹, as well as absorption bands related to the 7-amino-
1,3-oxazolo[5,4-d]pyrimidine ring [14]. The ¹H NMR
spectra, in addition to the signals of the protons of the
aromatic rings and the groups bound to them, contain a
broadened singlet of the NH₂ group at δ 7.73-7.78 ppm.
For the synthesis of substances 5-9, a method [15] based
on the recyclization of trimer III, obtained by cyclo-
condensation of benzoyl bromide II with 3 equivalents of
silver cyanide was used (Scheme 3). Thus, the interaction of
7-benzoylimino-2,5-diphenyloxazolo[5,4-d][1,3]oxazine III
with sodium methoxide and subsequent treatment of the
crude product with acetic acid leads to the formation of 2,5-
diphenyloxazolo[5,4-d]pyrimidin-7(6Н)-one IV. Boiling
the latter in phosphorus oxychloride in the presence of
N,N-dimethylaniline leads to the desired 7-chloro-
substituted 2,5-diphenyloxazolo[5,4-d]pyrimidine V, which
contains a mobile chlorine atom capable of being
substituted by amines, and further reacts with amines to
give isomeric oxazolo[5,4-d]pyrimidines 5-9. The structure
of compounds 5-9 has been reliably confirmed be spectral
and elemental analysis.
Biological evaluation
Among nine synthesized oxazolo[5,4-d]pyrimidines five
derivatives 1-4, 8 (NSC D-818708, D-765550, D-765551,
D-765554, and D-765555) were selected for evaluation of
antiproliferative activity within the NCI Developmental
Therapeutics Program [16] in the one-dose assay at
1·10 ⁻⁵ M concentration (Table 1).
Among the tested compounds, 1 and 8 (D-765554 and
D-818708) exhibited the lowest growth percentages,
indicating comparatively higher inhibition potential. For
compound 1 (D-765554), the most sensitive cell lines were
UO-31 (78.4 %), MCF7 (79.6 %), and CAKI-1 (89.6 %),
corresponding to the renal and breast cancer panels, with a
mean growth of 102.38 %. Compound 8 (D-818708) also
reduced cell growth notably in SNB-75 (85.8 %), MCF7
(91.5 %), and A498 (94.2 %), yielding an average growth of
101.83 %.
The remaining compounds 2-4 (D-765555, D-765550,
and D-765551) displayed higher mean growth values
(104.67%, 105.84%, and 105.95%, respectively), sugges-
ting limited inhibition at the tested concentration.
Nevertheless, certain individual cell lines such as NCI-
H522 (90.7%) for compound 4 (D-765551) and T-47D
(89.2%) for compound 2 (D-765555) showed partial
sensitivity.
Overall, all five oxazolo[5,4-d]pyrimidine derivatives
demonstrated moderate to low cytostatic activity across the
60-cell-line panel at 10 µM. Inhibition activity were
observed for compounds 1 and 8 (D-765554 and
D-818708).
Conclusions
On average, all five oxazolo[5,4-d]pyrimidines
demonstrated moderate cytotoxic activity in the NCI One
Dose assay, with mean cell growth percentages ranging
from approximately 102% to 106%, indicating
predominantly weak inhibition of cancer cell proliferation,
unlike the previously described isomeric oxazolo[4,5-
d]pyrimidines. The most pronounced activity was observed
for compound D-765554, particularly against the MCF7
(79.6%), UO-31 (78.4%), and OVCAR-5 (88.1%) cell lines,
suggesting its relatively higher anticancer potential among
the tested oxazolo[5,4-d]pyrimidine derivatives. The results
of anticancer activity in the oxazolopyrimidine series,
obtained in this work and published previously, may be
useful for studying the bioactivity of this class of
compounds in the future.
Experimental section
Synthesis
All reagents and solvents used in synthetic procedures
were purchased from Aldrich and used as received. The
reactions were followed by TLC (Silica gel, aluminum
sheets 60 F254, Merck). Melting points were recorded on a
Fisher-Johns apparatus. 1H and 13C NMR spectra were
S.G. Pilyo, M.V. Kachaeva et al.
63
Scheme 2. Synthesis of 7-amino-1,3-oxazolo[5,4-d]pyrimidines 5-9.
Table 1. Anticancer activity results for compounds 1-4, 8.
Comp
No
NSC (ID) a Panel / Cell Line (3 lowest Growth % b) Range c Mean
Growth d
1 D-765554 Leukemia (HL-60 91.7 b, HCT-15 92.2, CAKI-1 89.6); NSCLC (H522 89.7, H322M 90.2,
A549 97.6); Colon (HCT-15 92.2, KM12 97.3, HCT-116 104.1); CNS (SF-539 94.8, ACHN
93.0, UO-31 78.4); Melanoma (MALME-3M 97.6, SK-MEL-2 99.1, SK-MEL-5 101.4);
Ovarian (OVCAR-5 88.1, IGROV1 102.4, OVCAR-8 104.2); Renal (UO-31 78.4, CAKI-1
89.6, ACHN 93.0); Breast (MCF7 79.6, T-47D 92.6, BT-549 104.6)
41.83 102.38
2 D-765555 Leukemia (CCRF-CEM 99.8, HL-60 103.2, MOLT-4 101.3); NSCLC (NCI-H226 92.9,
NCI-H522 92.9, A549 96.0); Colon (HCT-15 103.0, HT-29 103.1, COLO 205 108.9); CNS
(SF-268 96.4, CAKI-1 95.5, UO-31 99.0); Melanoma (MALME-3M 102.5, SK-MEL-2
104.5, SK-MEL-5 101.7); Ovarian (OVCAR-5 98.4, OVCAR-8 104.6, SK-OV-3 110.8);
Renal (786-0 97.4, CAKI-1 95.5, UO-31 99.0); Breast (T-47D 89.2, MCF7 94.0, MDA-MB-
468 94.2)
48.21 105.95
3 D-765550 Leukemia (K-562 99.2, HL-60 99.7, RPMI-8226 99.7); NSCLC (H522 91.8, H226 100.2,
H23 110.4); Colon (HCT-15 96.2, HCT-116 99.0, HT-29 100.8); CNS (SF-295 94.4, SNB-
19 101.5, SF-268 101.3); Melanoma (MALME-3M 95.9, SK-MEL-2 101.1, MDA-MB-435
102.6); Ovarian (OVCAR-5 89.5, SK-OV-3 91.1, NCI/ADR-RES 115.3); Renal (786-0
93.9, CAKI-1 95.2, UO-31 94.5); Breast (BT-549 98.1, T-47D 101.3, MDA-MB-468 100.7)
36.38 104.67
4 D-765551 Leukemia (K-562 98.9, HL-60 99.7, H322M 99.1); NSCLC (NCI-H522 90.7, NCI-H226
96.7, NCI-H322M 99.1); Colon (HT-29 98.0, COLO 205 99.0, HCT-15 101.7); CNS (SF-
539 97.3, UO-31 93.6, SF-295 100.1); Melanoma (SK-MEL-28 97.4, MALME-3M 104.1,
LOX IMVI 104.4); Ovarian (OVCAR-5 98.9, SK-OV-3 100.6, OVCAR-8 108.4); Renal
(UO-31 93.6, CAKI-1 100.1, RXF-393 102.8); Breast (MCF7 89.0, T-47D 92.3, BT-549
106.5)
32.44 105.84
3 AgCN
Et2O,
30-35oC
Ar1 Br
O
3
N
ON
O
Ar1
N
Ph
O
Ph 1) MeONa,
2) MeCOOH,
20-25oC
MeOH, 20-25oC
N
NHN
O
Ar1
O
Ph
POCl3 , Me2NPh,
N
NN
O
Ar1
Cl
Ph
R1R2NH
Et3N,
100-105oC
N
NN
O
Ar1
5-9
NR1R2
Ph
II
V
III IV
N
O N
N
HN N
N
O N
N
HN
N
OMe
N
O N
N
N
O NH2
N
O N
N
N
N
Et
N
O N
N
N
N
N
5
6
7
8
9
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
64
Table 1. (Contd.)
Comp
No
NSC (ID) a Panel / Cell Line (3 lowest Growth % b) Range c Mean
Growth d
8 D-818708 Leukemia (CCRF-CEM 101.5, K-562 97.4, SR 99.3); NSCLC (NCI-H322M 93.5, UO-31
93.7, A498 94.2); Colon (HCT-116 98.8, SW-620 108.2, COLO 205 108.5); CNS (SNB-75
85.8, SF-539 96.9, SNB-19 97.7); Melanoma (M14 98.1, SK-MEL-5 99.9, MDA-MB-435
103.0); Ovarian (OVCAR-5 98.8, IGROV1 101.8, OVCAR-8 102.8); Renal (UO-31 93.7,
RXF-393 97.2, CAKI-1 97.2); Breast (MCF7 91.5, BT-549 100.9, PC-3 99.6)
28.91 101.83
a NSC (ID) stands for National Service Center (Identification Number) - it’s a unique compound identifier assigned by the U.S. National Cancer Institute
(NCI) under its Developmental Therapeutics Program (DTP). b Growth % (Growth Percent) represents the percentage of cell growth or survival in treated
cancer cell lines relative to untreated control cells after drug exposure (typically 48-72 h). c Range – a measure of how differently each of the 60 cell lines
responded to the compound, showing its selectivity profile in the NCI one-dose screen. d Mean Growth (%) represents the average percentage of cell growth
across all 60 cancer cell lines after treatment with the compound at a single concentration (typically 10⁻⁵ M).
recorded on a Varian Mercury spectrometer (300 or 400
MHz for 1H NMR) or Bruker Avance DRX 500
spectrometer (500 MHz and 126 MHz, respectively for 1H
and 13C NMR spectra) in DMSO-d6 or CDCl3, taking its
residual solvent signal as a standard. Multiplicities were
described using the following abbreviations: s = singlet, br
s = broad singlet, d = doublet, t = triplet, and m = multiplet.
LC-MS analysis was performed on an Agilent 1200 Series
system equipped with a diode array and a G6130A mass-
spectrometer (atmospheric pressure electrospray
ionization). Combustion elemental analysis was performed
in the V.P. Kukhar Institute of Bioorganic Chemistry and
Petrochemistry analytical laboratory; their results were
found to be in good agreement (±0.4%) with the calculated
values. The carbon and hydrogen contents were determined
using the Pregl gravimetric method, nitrogen – using
Duma's gasometrical micromethod.
1,3-Oxazolo[5,4-d]pyrimidines (1-4).
A mixture of 0.01 mol of one of the compound I, 0.01
mol of the corresponding amidine hydrochloride and 0.02
mol of triethylamine in 50 ml of dry tetrahydrofuran was
stirred on a magnetic stirrer at 20-25 °C for 48 hours. The
precipitate was filtered off, the solvent was removed in
vacuo, the residue was treated with water, the precipitate
that had formed was filtered off and the compounds (1-4)
were purified by recrystallization from acetonitrile.
7-Amino-2-phenyl-5-(4-methylphenyl)oxazolo[5,4-d]pyri-
midine (1).
Yield: 150 mg, 70%; mp 262-264 ºС. 1H NMR (500
MHz, DMSO-d6) δ 8.26 (d, J 8.0 Hz, 2H, ArH), 8.15-8.14
(m, 2H, ArH), 7.78 (br s, 2H, NH2), 7.62-7.61 (m, 3H,
ArH), 7.30 (d, J 8.0 Hz, 2H, ArH), 2.37 (s, 3H, Me); 13C
NMR (125 MHz, DMSO-d6) δ 165.1, 159.8, 159.7, 149.4,
141.3, 135.9, 132.0, 129.7, 129.5, 129.4, 129.3, 129.2,
129.1, 129.0, 127.9, 127.8, 113.2, 21.1; IR (KBr) ν 3326,
3212 (NH2); 1635, 1590, 1393, 1313, 1278, 1129, 1048;
LC-MS m/z Сalcd. for C18H14N4O (M+H)+ 302.34. Found
303,0. Anal. calcd. for C18H14N4O, %: C 71.51; H 4.67;
N 18.53. Found, %: C 71.48; H 4.67; N 18.59.
7-Amino-2-phenyl-5-(4-methoxyphenyl)oxazolo[5,4-d]pyri-
midine (2).
Yield: 179 mg, 72%; mp 244-245 ºС. 1H NMR (500
MHz, DMSO-d6) δ 8.32 (d, J 8.5 Hz, 2H, ArH), 8.16-8.15
(m, 2H, ArH), 7.77 (br s, 2H, NH2), 7.63-7.62 (m, 3H,
ArH), 7.05 (d, J 8.5 Hz, 2H, ArH), 3.85 (s, 3H, MeO); 13C
NMR (125 MHz, DMSO-d6) δ 165.1, 163.0, 159.8, 159.7,
149.4, 132.0, 131.5, 130.6, 130.5, 129.4, 129.2, 129.1,
127.9, 127.8, 114.6, 113.8, 113.2, 56.0; IR (KBr) ν 3326,
3213 (NH2); 1634, 1607, 1395, 1304, 1253, 1131, 1048;.
LC-MS m/z Сalcd. for C18H14N4O2 (M+H)+ 318,34. Found
319,3. Anal. calcd. for C18H14N4O2, %: C 67.92; H 4.43;
N 17.60. Found, %: C 67.89; H 4.42; N 17.68.
7-Amino-2-(4-methylphenyl)-5-(4-ethylphenyl)oxazolo[5,4-
d]pyrimidine (3).
Yield: 180 mg, 78%; mp 266-267 ºС 1H NMR (400
MHz, DMSO-d6) δ 8.26 (d, J 8.0 Hz, 2H, ArH), 8.03 (d, J
8.0 Hz, 2H, ArH), 7.73 (br s, 2H, NH2), 7.42 (d, J 8.0 Hz,
2H, ArH), 7.33 (d, J 8.0 Hz, 2H, ArH), 2.67 (q, J 8.0 Hz,
2H, CH2), 2.41 (s, 3H, CH3), 1.22 (t, J 8.0 Hz, 3H, CH3);
13C NMR (125 MHz, DMSO-d6) δ 165.1, 159.8, 159.7,
149.4, 147.1, 141.8, 138.8, 132.9, 132.1, 129.5, 129.0,
128.3, 128.2, 128.0, 127.6, 127.5, 113.2, 28.2, 21.1, 13.2;
IR (KBr) ν 3322, 3208 (NH2); 1635, 1596, 1395, 1311,
1275, 1135, 1051. LC-MS m/z Сalcd. for C20H18N4O
(M+H)+ 330,39. Found 331,3. Anal. calcd. for C20H18N4O,
%: C 72.71; H 5.49; N 16.96. Found, %: C 72.74; H 5.53;
N 16.89.
7-Amino-2-(4-methylphenyl)-5-(4-methoxyphenyl)oxazo-
lo[5,4-d]pyrimidine (4).
Yield: 180 mg, 78%; mp 301-303 ºС. 1H NMR (400
MHz, DMSO-d6) δ 8.26 (d, J 8.0 Hz, 2H, ArH), 8.03 (d, J
8.0 Hz, 2H, ArH), 7.73 (br s, 2H, NH2), 7.42 (d, J 8.0 Hz,
2H, ArH), 7.33 (d, J 8.0 Hz, 2H, ArH), 2.67 (q, J 8.0 Hz,
2H, CH2), 2.41 (s, 3H, CH3), 1.22 (t, J 8.0 Hz, 3H, CH3);
13C NMR (125 MHz, DMSO-d6) δ 165.1, 159.8, 159.7,
149.4, 147.1, 141.8, 138.8, 132.9, 132.1, 129.5, 129.0,
128.3, 128.2, 128.0, 127.6, 127.5, 113.2, 28.2, 21.1, 13.2;
IR (KBr) ν 3323, 3209 (NH2); 1635, 1608, 1396, 1306,
1256, 1134, 1050. LC-MS m/z Сalcd. for C19H16N4O2
(M+H)+ 330,39. Found 331,3. Anal. calcd. For C19H16N4O2,
%: C 68.66; H 4.85; N 16.86. Found, %: C 68.62; H 4.80;
N 16.91.
1,3-Oxazolo[5,4-d]pyrimidines (5-9).
S.G. Pilyo, M.V. Kachaeva et al.
65
A mixture of 0.01 mol of one of the compound V, 0.01
mol of the corresponding amine and 0.01 mol of
triethylamine in 50 ml of dry dioxane was heated at 100-
105 °C for 8 hours and left for 12 h at 20-25 °C. The preci-
pitate was filtered off, the solvent was removed in vacuo,
the residue was treated with water, the precipitate that had
formed was filtered off and the compounds (5-9) were
purified by recrystallization from acetonitrile.
2,5-Diphenyl-N-(pyridin-3-ylmethyl)[1,3]oxazolo[5,4-d]py-
rimidin-7-amine (5).
Yield: 176 mg, 73%; mp 191-193 ºС. 1H NMR (300
MHz, DMSO-d6) δ 8.89 (br s, 1H, NH), 8.75 (s, 1H,
CHpyridine), 8.45-8.35 (m, 3H, ArH), 8.18-8.11 (m, 2H,
ArH), 7.83 (d, J 8.0 Hz, 1H, CHpyridine), 7.62-7.58 (m, 3H,
ArH), 7.50-7.46 (m, 3H, ArH), 7.16-7.14 (m, 1H, ArH),
4.87-4.85 (m, 2H, CH2); 13C NMR (125 MHz, DMSO-d6) δ
161.1, 159.4, 158.5, 148.2, 147.9, 147.5, 136.7, 135.6,
133.6, 132.0, 130.8, 129.3, 129.1, 129.0, 128.9, 129.1,
128.8, 128.0, 127.9, 127.8, 125.2, 115.0, 41.9.; IR (KBr) ν
3015, 1708, 1387, 1211, 1045, 810, 731, 715. LC-MS m/z
Сalcd. for C23H17N5O (M+H)+ 379,42. Found 380,0. Anal.
calcd. For C23H17N5O, %: C, 72.81; H, 4.52; N, 18.46.
Found, %: C, 72.75; H, 4.51; N, 18.67.
N-[2-(4-methoxyphenyl)-2-(piperidin-1-yl)ethyl]-2,5-diphe-
nyl[1,3]oxazolo[5,4-d]pyrimidin-7-amine (6).
Yield: 190 mg, 76%; mp 186-188 ºС. 1H NMR (400
MHz, DMSO-d6) δ 8.41-8.40 (m, 2H, ArH), 8.23-8.20 (m,
2H, ArH), 8.00 (br s, 1H, NH), 7.65-7.63 (m, 3H, ArH),
7.50-7.48 (m, 3H, ArH), 7.25 (d, J 8.0 Hz, 2H, ArH), 6.85
(d, J 8.0 Hz, 2H, ArH), 4.27-4.25 (m, 1H, CH), 4. 08-4.05
(m, 2H, CH2), 3.75 (s, 3H, CH3), 2.25-2.22 (m, 2H, CH2),
1.40-1.38 (m, 4H, 2CH2), 1.20-1.18 (m, 2H, CH2); 13C
NMR (125 MHz, DMSO-d6) δ 160.8, 159.9, 159.6, 158.4,
147.5, 136.7, 132.4, 132.0, 130.8, 130.3, 129.9, 129.6,
129.5, 129.3, 129.1, 129.0, 127.9, 127.8, 127.7, 127.4,
115.1, 114.8, 114.4, 70.5, 56.0, 52.9, 52.8, 46.4, 24.8, 24.6,
23.4; IR (KBr) ν 3013, 1709, 1380, 1216, 1040, 815, 737,
710. LC-MS m/z Сalcd. for C31H31N5O2 (M+H)+ 505,62.
Found 506,2. Anal. calcd. For C31H31N5O2, %: C, 73.64; H,
6.18; N, 13.85. Found, %: C, 73.61; H, 6.23; N, 13.89.
1-(2,5-Diphenyloxazolo[5,4-d]pyrimidin-7-yl)piperidine-4-
carboxamide (7).
Yield: 240 mg, 75%; mp 230-232 ºС. 1H NMR (300
MHz, DMSO-d6) δ 8.36-8.34 (m, 2H, ArH), 8.15-8.11 (m,
2H, ArH), 7.63-7.45 (m, 6H, ArH), 7.22, 6.70 (2s, 2H,
С(O)NH2), 5.33 (br s, 2H, CH2), 3.30 (br s, 2H, CH2), 2.53-
2.50 (m, 1H, CH), 1.93-1.91 (m, 2H, CH2), 1.72-1.70 (m,
2H, CH2); 13C NMR (125 MHz, DMSO-d6) δ 180.2, 162.9,
160.6, 155.5, 147.8, 136.7, 132.0, 130.8, 129.3, 129.6,
129.1, 129.1, 129.0, 128.8, 128.0, 127.8, 127.6, 115.6, 47.4,
47.2, 37.9, 26.8, 26.4; IR (KBr) ν 3011, 1703, 1385, 1212,
1044, 819, 733, 715. LC-MS m/z Сalcd. for C23H21N5O2
(M+H)+ 399,45. Found 400,2. Anal. calcd. For C23H21N5O2,
%: C, 69.16; H, 5.30; N, 17.53. Found, %: C, 69.11; H,
5.37; N, 17.64.
7-(4-Ethylpiperazin-1-yl)-2,5-diphenyloxazolo[5,4-d]pyri-
midine (8).
Yield: 220 mg, 71%; mp 184-186 ºС. 1H NMR (400
MHz, CDCl3) δ 8.45 (d, 2H, J = 8.0 Hz, ArH),-8.22 (d, 2H,
J 8.0 Hz, ArH), 7.53-7.44 (m, 6H, ArH), 4.41 (br s, 2H,
CH2), 2.67-2.63 (m, 4H, 2CH2), 2.54-2.49 (m, 2H, CH2),
1.17 (t, 3H, J 8.0 Hz, CH3); 13C NMR (125 MHz, DMSO-
d6) δ 162.9, 160.6, 155.5, 147.8, 136.7, 132.0, 130.8, 129.3,
129.1, 129.1, 129.0, 128.9, 128.8, 128.0, 127.8, 127.6,
115.6, 51.7, 51.7, 50.0, 47.7, 47.6, 12.3; IR (KBr) ν 3013,
1705, 1382, 1211, 1041, 813, 732, 712. LC-MS m/z Сalcd.
for C23H23N5O (M+H)+ 385,47. Found 386,5. Anal. calcd.
For C23H23N5O, %: C, 71.67; H, 6.01; N, 18.17. Found, %:
C, 71.60; H, 6.07; N, 18.23.
2,5-diphenyl-7-{4-[2-(pyridin-2-yl)ethyl]piperazin-1-yl}-
[1,3]oxazolo[5,4-d]pyrimidine (9).
Yield: 200 mg, 76%; mp 188-190 ºС. 1H NMR (400
MHz, CDCl3) δ 8.55 (d, 2H, J 8.0 Hz, ArH), 8.42 (d, 2H, J
8.0 Hz, ArH), 8.21 (d, 2H, J 8.0 Hz, ArH), 7.75 (t, 1H, J 8.0
Hz, CHpyridine), 7.63-7.54 (m, 6H, ArH), 7.35 (d, 1H, J 8.0
Hz, CHpyridine), 7.25 (t, 1H, J 8.0 Hz, CHpyridine), 4.25 (br s,
4H, 2CH2), 2.97 (t, 2H, J 8.0 Hz, CH2), 2.75 (t, 2H, J 8.0
Hz, CH2), 2.57 (br s, 4H, 2CH2); 13C NMR (125 MHz,
DMSO-d6) δ 162.9, 160.6, 156.6, 155.5, 148.1, 147.8,
139.7, 136.7, 132.0, 130.8, 129.3, 129.1, 129.0, 128.1,
128.10, 127.8, 127.6, 127.4, 127.1, 123.2, 121.4, 115.6,
53.3, 52.2, 52.0, 47.7, 47.6, 32.6. LC-MS m/z Сalcd. for
C28H26N6O (M+H)+ 462,56. Found 463,5. Anal. calcd. For
C28H26N6O, %: C, 72.71; H, 5.67; N, 18.17. Found, %: C,
72.66; H, 5.61; N, 18.25.
One-Dose NCI-60 Human Tumor Cell Line Assay
The synthesized compounds 1-4, 8 were submitted to
the National Cancer Institute (NCI), Bethesda, Maryland,
USA, under the Developmental Therapeutics Program
(DTP) for in vitro anticancer screening. The NCI-60 cell
line panel comprises 60 different human tumor cell lines
representing nine cancer types: lung, colon, melanoma,
renal, ovarian, brain, leukemia, breast, and prostate.
In the one-dose primary screening, cells from each of
the 60 lines were inoculated into standard 96-well
microtiter plates at a density of 5,000-40,000 cells per well
in RPMI-1640 medium supplemented with 5% fetal bovine
serum and 2 mM L-glutamine (day 0). After a 24 h
preincubation at 37 °C and 5% CO₂ in the absence of the
test compounds, each compound was added at a single
concentration of 10⁻⁵ M (day 1), followed by an additional
48 h incubation under the same conditions. Subsequently,
the cells were fixed in situ, washed, and air-dried (day 3).
Cell density was determined using the sulforhodamine B
(SRB) assay, which quantifies total cellular protein content.
After fixation with 10% (w/v) trichloroacetic acid, cells
were stained for 30 min, washed repeatedly with 1% (v/v)
acetic acid, and the bound dye was resolubilized in 10 mM
Tris base solution. Absorbance was measured spectrophoto-
metrically at 510 nm using an automated microplate reader.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
66
Notes
Acknowledgments and finances. We thank the
National Cancer Institute, Bethesda, MD, USA, for the in
vitro evaluation of anticancer activity within the
Developmental Therapeutic Program and Enamine Ltd for
the material and technical support.
The authors declare no conflict of interest.
Author contributions. S.G.P.: synthesis of compounds,
investigation, writing experimental section, editing.
M.V.K.: investigation, formal analysis, writing most of the
manuscript. S.V.P.: formal analysis, conceptualization.
V.S.B.: supervision, writing, review & editing.
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Синтез та протиракова активність 2,5-діарил-оксазоло[5,4-d]піримідин-7-іл амінів
та відповідних амідів
С.Г. Пільо, М.В. Качаєва*, С.В. Попільніченко, В.С. Броварець
Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ, Україна
Резюме: Було синтезовано та оцінено протиракову активність серії нових похідних оксазоло[5,4-d]піримідину проти ракових клітинних ліній
NCI-60. Ця робота є продовженням нашого дослідження протиракової активності низки ізомерних оксазолопіримідинів та вивчення залежності
протиракового ефекту від структури. Раніше описані оксазоло[4,5-d]піримідини, що містять N-незаміщені піперазинові або діазепанові
фрагменти, демонстрували високу цитотоксичність із субмікромолярними значеннями IC₅₀ проти ліній клітин раку молочної залози (MDA-MB-
231), яєчників (OVCAR-3) та товстої кишки (HCT-116) у скринінгу NCI. Синтезовані 2,5-діарил-оксазоло[5,4-d]піримідин-7-іл аміни не
демонстрували значної протиракової дії, на відміну від раніше описаних ізомерних оксазоло[4,5 -d]піримідинів. Інгібуюча активність
спостерігалася для 7-аміно-2-феніл-5-(4-метилфеніл)оксазоло[5,4-d]піримідину (D-765554), зокрема проти ліній клітин MCF7 (79,6%), UO-31
(78,4%) та OVCAR-5 (88,1%), але протираковий потенціал серед протестованих похідних оксазоло[5,4-d]піримідину не був помітним. Результати
дослідження протипухлинної активності в оксазолопіримідиновому ряді, отримані в цій роботі та опубліковані раніше, можуть бути корисними
для вивчення біоактивності оксазолопіримідинів у майбутньому.
Ключові слова: оксазоло[5,4-d]піримідин-7-амін; аміди; протипухлинна активність.
https://onlinelibrary.wiley.com/doi/10.1002/jhet.4401
https://onlinelibrary.wiley.com/doi/10.1002/jhet.4401
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| id | oai:ojs2.bioorganica.com.ua:article-127 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:00:15Z |
| publishDate | 2025 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
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| spelling | oai:ojs2.bioorganica.com.ua:article-1272026-07-19T14:56:56Z Synthesis and anticancer activity of 2,5-diaryl-oxazolo[5,4-d]pyrimidin-7-amines and corresponding amides Синтез та протиракова активність 2,5-діарил-оксазоло[5,4-d]піримідин-7-амінів та відповідних амідів Pilyo, Stepan G. Kachaeva, Maryna V. Popilnichenko, Serhii V. Brovarets, Volodymyr S. oxazolo[5,4-d]pyrimidin-7-amine amides anticancer activity оксазоло[5,4-d]піримідин-7-амін аміди протипухлинна активність A series of novel oxazolo[5,4-d]pyrimidine derivatives were synthesized and evaluated for anticancer activity against NCI 60 cancer cell lines. This work is a continuation of our investigation of the anticancer activity of a number of isomeric oxazolopyrimidines, and the study of the dependence of structure on anticancer effect. Previously described oxazolo[4,5-d]pyrimidines containing N-unsubstituted amino groups of piperazine or diazepane exhibited high cytotoxicity, with submicromolar IC₅₀ values against breast (MDA-MB-231), ovarian (OVCAR-3), and colon (HCT-116) cancer cell lines in NCI screening. Synthesized 2,5-diaryl-oxazolo[5,4-d]pyrimidin-7-amines did not demonstrate significant anticancer effects, unlike the previously described isomeric oxazolo[4,5-d]pyrimidines. Inhibition activity was observed for 7-amino-2-phenyl-5-(4-methylphenyl)oxazolo[5,4-d]pyrimidine (D-765554), particularly against the MCF7 (79.6%), UO-31 (78.4%), and OVCAR-5 (88.1%) cell lines, but anticancer potential among the tested oxazolo[5,4-d]pyrimidine derivatives was not noticeable. The results of anticancer activity in the oxazolopyrimidine series, obtained in this work and published previously, may be useful for studying the bioactivity of oxazolopyrimidines in the future Було синтезовано та оцінено протиракову активність серії нових похідних оксазоло[5,4-d]піримідину проти ракових клітинних ліній NCI-60. Ця робота є продовженням нашого дослідження протиракової активності низки ізомерних оксазолопіримідинів та вивчення залежності структури від протиракового ефекту. Раніше описані оксазоло[4,5-d]піримідини, що містять N-незаміщені піперазинові або діазепанові фрагменти, демонстрували високу цитотоксичність із субмікромолярними значеннями IC₅₀ проти ліній клітин раку молочної залози (MDA-MB-231), яєчників (OVCAR-3) та товстої кишки (HCT-116) у скринінгу NCI. Синтезовані 2,5-діарил-оксазоло[5,4-d]піримідин-7-аміни не демонстрували значної протиракової дії, на відміну від раніше описаних ізомерних оксазоло[4,5-d]піримідинів. Інгібуюча активність спостерігалася для 7-аміно-2-феніл-5-(4-метилфеніл)оксазоло[5,4-d]піримідину (D-765554), зокрема проти ліній клітин MCF7 (79,6%), UO-31 (78,4%) та OVCAR-5 (88,1%), але протираковий потенціал серед протестованих похідних оксазоло[5,4-d]піримідину не був помітним. Результати дослідження протипухлинної активності в оксазолопіримідиновому ряді, отримані в цій роботі та опубліковані раніше, можуть бути корисними для вивчення біоактивності оксазолопіримідинів у майбутньому. V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2025-12-31 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/127 10.15407/bioorganica2025.02.060 Ukrainica Bioorganica Acta; Vol. 20 No. 2 (2025): Ukrainica Bioorganica Acta; 60-66 Ukrainica Bioorganica Acta; Том 20 № 2 (2025): Ukrainica Bioorganica Acta; 60-66 1814-9766 1814-9758 10.15407/bioorganica2025.02 en https://bioorganica.com.ua/index.php/journal/article/view/127/109 Copyright (c) 2025 Stepan G. Pilyo, Maryna V. Kachaeva, Serhii V. Popilnichenko, Volodymyr S. Brovarets https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | оксазоло[5,4-d]піримідин-7-амін аміди протипухлинна активність Pilyo, Stepan G. Kachaeva, Maryna V. Popilnichenko, Serhii V. Brovarets, Volodymyr S. Синтез та протиракова активність 2,5-діарил-оксазоло[5,4-d]піримідин-7-амінів та відповідних амідів |
| title | Синтез та протиракова активність 2,5-діарил-оксазоло[5,4-d]піримідин-7-амінів та відповідних амідів |
| title_alt | Synthesis and anticancer activity of 2,5-diaryl-oxazolo[5,4-d]pyrimidin-7-amines and corresponding amides |
| title_full | Синтез та протиракова активність 2,5-діарил-оксазоло[5,4-d]піримідин-7-амінів та відповідних амідів |
| title_fullStr | Синтез та протиракова активність 2,5-діарил-оксазоло[5,4-d]піримідин-7-амінів та відповідних амідів |
| title_full_unstemmed | Синтез та протиракова активність 2,5-діарил-оксазоло[5,4-d]піримідин-7-амінів та відповідних амідів |
| title_short | Синтез та протиракова активність 2,5-діарил-оксазоло[5,4-d]піримідин-7-амінів та відповідних амідів |
| title_sort | синтез та протиракова активність 2,5-діарил-оксазоло[5,4-d]піримідин-7-амінів та відповідних амідів |
| topic | оксазоло[5,4-d]піримідин-7-амін аміди протипухлинна активність |
| topic_facet | oxazolo[5,4-d]pyrimidin-7-amine amides anticancer activity оксазоло[5,4-d]піримідин-7-амін аміди протипухлинна активність |
| url | https://bioorganica.com.ua/index.php/journal/article/view/127 |
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