2,2-Дизаміщені 5- та 8-азахроман-4-они: вплив на ріст ракових клітин у порівнянні з хроманоновими аналогами
A series of 2,2-disubstituted 5-azachroman-4-ones (two examples) and isomeric 8-azachroman-4-ones (four derivatives) were evaluated for their in vitro anticancer activity on 60 cancer cell lines. The decreased proliferation of cancer cells was observed for the case of both types of isomeric azachrom...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2023
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Ukrainica Bioorganica Acta| _version_ | 1871193594779402240 |
|---|---|
| author | Malets, Yehor S. Golovchenko, Oleksandr V. |
| author_facet | Malets, Yehor S. Golovchenko, Oleksandr V. |
| author_institution_txt_mv | [
{
"author": "Yehor S. Malets",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Oleksandr V. Golovchenko",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
}
] |
| author_sort | Malets, Yehor S. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:54Z |
| description | A series of 2,2-disubstituted 5-azachroman-4-ones (two examples) and isomeric 8-azachroman-4-ones (four derivatives) were evaluated for their in vitro anticancer activity on 60 cancer cell lines. The decreased proliferation of cancer cells was observed for the case of both types of isomeric azachromanones with the highest activity for 2,3,5,6-tetrahydrospiro[pyran-4,2'-pyrano[2,3-b]pyridin]-4'(3'H)-one, which slows down the growth of 27 out of 60 cancer cell lines by more than half, including melanoma, colon and ovarian cancers. The structure-activity relationship in the hit spirocyclic 8-azachromanone was established by comparison with the parent chromanone analog (the least active) and the corresponding 8-fluorosubstituted derivative (showed moderate activity) |
| doi_str_mv | 10.15407/bioorganica2023.01.022 |
| first_indexed | 2025-07-17T12:19:53Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 1
UDC 547.853
DOI: https://doi.org/10.15407/bioorganica2023.01.022
22
Ukrainica Bioorganica Acta
w w w.b io or gani c a.o rg .ua
RESEARCH ARTICLE
2,2-Disubstituted 5- and 8-azachroman-4-ones: the effect on cancer
growth in contrast to chromanone analogs
Yehor S. Malets*, Oleksandr V. Golovchenko
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
Abstract: A series of 2,2-disubstituted 5-azachroman-4-ones (two examples) and isomeric 8-azachroman-4-ones (four derivatives) were
evaluated for their in vitro anticancer activity on 60 cancer cell lines. The decreased proliferation of cancer cells was observed for the case
of both types of isomeric azachromanones with the highest activity for 2,3,5,6-tetrahydrospiro[pyran-4,2'-pyrano[2,3-b]pyridin]-4'(3'H)-
one, which slows down the growth of 27 out of 60 cancer cell lines by more than half, including melanoma, colon and ovarian cancers .
The structure-activity relationship in the hit spirocyclic 8-azachromanone was established by comparison with the parent chromanone
analog (the least active) and the corresponding 8-fluorosubstituted derivative (showed moderate activity).
Keywords: heterocycles; chromanones; azachromanones; anticancer activity
Introduction
Chromones are among the most prominent oxygen
heterocycles represented by numerous natural products and
pharmaceutical agents [1-6]. In turn, one of the most
popular tools of chemists is the design of analogs; in the
case of chromones promising drug candidates with
improved ADMET profiles could be reached by the
introduction of a nitrogen atom into various positions
(Figure 1). In particular, 8-azachromone) have been studied
as anticancer [7] and antiviral [8] agents. A prominent
example is the anti-inflammatory and antiallergic
immunomodulatory drug Amlexanox (1), [9-16] which has
become marketed for the treatment of aphthous ulcers
(canker sores), asthma and allergic rhinitis by decreasing
healing time and pain symptoms [17-20]. Other biological
activities of Amlexanox include the inhibition of TANK-
binding kinase 1 (TBK1). Other example is nuclear factor
kappa-B kinase subunit (IKK).
Received:
Revised:
Accepted:
Published online:
20.03.2023
29.03.2023
26.04.2023
30.06.2023
Corresponding author. Tel.: +380-96-242-4818;
e-mail: yehor.malets@gmail.com (Ye.S. Malets)
ORCID: 0000-0002-3029-3065
O
NO NH2
CO2Hi-Pr
1
Amlexanox
O N
O
CN
NH2
O N
O
CONH2
NH2
F
NH2
3
E. coli IC50 = 0.9 mM
2
E. coli IC50 = 0.04 mM
O N
O
Ph
4
mGlu5 EC50 = 11.5 nM
Figure 1. Representative examples of pharmaceutically relevant
azachromones and azachromanones
The latter results in lower rates of glycated hemoglobin
(HbA1c) [21]. This outcome resulted in significant interest
in analogs of Amlexanox, which could be used for the
treatment of notorious type 2 diabetes and obesity [13, 14,
22]. Other pharmaceutically relevant compounds are
pyridochromanones 2 and 3 – potent inhibitors of NAD+-
dependent DNA ligase from Escherichia coli (Figure 1)
[23], which additionally show selective antibacterial
activity without affecting the eukaryotic cells (i.e. for the
case of pathogen Staphylococcus aureus) [24, 25].
Another example is 7-(phenylacetylenyl)-8-azachro-
manone 4 with positive allosteric modulation
© Ye.S. Malets 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.
mailto:yehor.malets@gmail.com
https://orcid.org/0000-0002-3029-3065
Y.S. Malets, O.V. Golovchenko
23
activity of metabotropic glutamate receptor 5 (mGlu5) [26],
which could be used as antipsychotic and antischizophrenic
agents [27-29].
In our previous works, we have developed efficient
synthetic approaches to isomeric azachromones,
particularly, 2,2-disubstituted 8-azachromanones (Scheme
1) [30].
N O
R1
R2
O
R1
R2O
1. NaH, THF
2. TMSCl,
NaI, MeCN
spirocyclic
8-azachromanones
N OMe
O
P
O
OMe
OMe
Scheme 1. Previously reported synthesis of azachroman-4-ones.
In this work we have aimed to study in vitro anticancer
activity of previously reported 5-azachromones [31]
(compound NCS 828792 5 [32] and NCS 828793 6 [33])
and aforementioned isomeric derivatives 7-10 on 60 cancer
cell lines, including colon, ovarian, prostate, renal, breast,
and non-small cell lung cancer types, as well as leukemia
and melanoma.
Results and Discussion
Biological assay
The anticancer activity of compounds 5-10 was tested
according to the Developmental Therapeutic Program
(DTP) of the National Cancer Institute (NCI, Bethesda,
Maryland, USA) on 60 cancer cell lines [20-21]. The most
representative data is shown as a percentage of inhibition of
the growth of cancer cells (Table 1).
The most active compound, i.e. 8-azachromanone 9,
slowed down the growth of a small number of cancer cell
lines (8 out of 60) by more than half, including melanoma,
colon, and ovarian cancers. The isomeric derivative 6 had
significant inhibition of one type of leukemia studied. Other
derivative 8 showed low anticancer activity towards
melanoma. At the same time, the inhibitory ability of all
other substances can be considered insignificant.
Overall, azachromone 9 NCS 828796 shows the highest
activity. In order to evaluate the importance of the pyridine
ring in azachromones, we have aimed to study the
anticancer activity of the corresponding benzoanalog 11
[34-37]. As it was found, derivative 11 significantly loses
its ability to slow down the growth of cancer cells and did
not show a noticeable anticancer effect (see Supplementary
Material for further details).
Figure 2. The target isomeric 5- and 8-azachroman-4-ones.
Figure 3. The hit azachromanone 9 and its benzoanalogs 11 and
12.
Synthesis
We aimed to evaluate the importance of the 8-position of
the chromanone scaffold in cancer cell inhibition. It was
envisaged that the presence of a small fluorine atom bearing
lone pairs in C(8)-position might increase the anticancer
OH
F
N
OMOM
F
N
O
OH
F
O
O
O
F OO
12
13 14
15
1. MeMgCl, THF, 0 oC,
30 min to reflux, 6 h
2. aq. HCl
CH2Cl2, rt,
overnight
66% (over two steps)
MOMCl,
DIPEA
1.
pyrrolidine,
THF, reflux, 8 h
2. aq. HCl
72%
Scheme 2. Sythesis of 8-fluoro-2',3',5',6'-tetrahydrospiro[chromane-2,4'-pyran]-4-one (12).
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 1
24
Table 1. Anticancer activity of 5-azachromanones 5-6, 8-azachromanones 7-10, and chromanones 11-12.
Compound (NCS code) GP, Mean GP, Rang N50 N0 The most significant inhibition, GP
5, NCS 828792 105.43 45.08 0 0 80.13 UO-31 (renal cancer)
80.06 SNB-75 (CNS cancer)
94.87 NCI-H522 (non-small cell lung cancer)
6, NCS 828793 105.20 85.49 1 0 42.59 CCRF-CEM (leukemia)
86.10 A498 (renal cancer)
96.12 UO-31 (renal cancer)
7, NCS 828794 106.36 28.15 0 0 93.92 TK-10 (renal cancer)
94.24 UO-31 (renal cancer)
95.34 UACC-62 (melanoma)
8, NCS 828795
104.99 62.12 0 0 62.16 MALME-3M (melanoma)
94.71 UACC-62 (melanoma)
96.12 UO-31 (renal cancer)
9, NCS 828796 49.78 198.66 27 8 -78.71 LOX IMVI (melanoma)
-62.58 HCT-15 (colon cancer)
-54.56 SW-620 (colon cancer)
-54.40 OVCAR-3 (ovarian cancer)
10, NCS 828798 105.45 31.06 0 0 94.34 A498 (renal cancer)
94.84 UACC-62 (melanoma)
96.31 NCI-H522 (non-small cell lung cancer)
11, NCS 836271 104.68 27.61 0 0 92.25 SNB-19 (CNS cancer)
93.81 UO-31 (renal caner)
94.86 SF-295 (CNS cancer)
12, NCS 842588 100.10 65.66 0 0 61.18 SNB-75 (CNS cancer)
69.54 UO-31 (renal caner)
76.53 CAKI-1 (renal cancer)
activity as compared to C(8)-unsubstituted analog 11. Thus,
we have designed the synthetic approach to the
corresponding derivative 12 starting from the 3-fluoro-2-
hydroxy-benzonitrile (13). Our initial attempt of using of
MeMgCl (in THF at 0 °C to reflux) for the straightforward
transfor-mation of the nitrile group to the acetyl moiety of
the target intermediate 15 was not successful. The following
O-protection with TMSCl, (with Et3N and DMAP in
CH2Cl2 at 0 °C to rt or NaH in THF at -10 °C to rt) was also
ineffective. Starting material was recovered in all the above
mentioned cases. Nevertheless, the use of MOMCl and
DIPEA in CH2Cl2 was a suitable and efficient approach for
the preparation of derivative 14, which was then
successfully involved in the reaction with Gringard reagent
to obtain intermediate 15 in 66% yield over two steps
(Scheme 2). To our delight, the condensation with
tetrahydropyran-4-one proceeded easily with the common
synthetic method to give the key fluorinated chromanone 12
in 72% yield.
Conclusions
In this work we have disclosed in vitro studies of the
anticancer activity of 8 derivatives (six isomeric
azachromanones and the corresponding benzoanalogs),
which revealed a promising anticancer effect of 2,3,5,6-tet-
rahydrospiro[pyran-4,2'-pyrano[2,3-b]pyridin]-4'(3'H)-one
(9) with the highest activity among other 2,2-disubstituted
compounds and 5-azachromones. This compound
demonstrated the decreased proliferation by more than half
in 8 out of 60 cancer cell lines, including melanoma, colon
and ovarian cancers. The presence of the pyridine fragment
is essential for the significant anticancer activity, which was
shown by a series of experiments with the corresponding
chromanone. The latter derivative has insignificant
influence on the cancer cell growth. In order to evaluate the
importance of 8-position of azachromones, we have
synthesized the novel 8-fluorinated spirocyclic chromanone,
which has shown higher activity than that of non-
fluorinated derivative and lower activity as compared to the
8-azachromanone hit.
Notes
Acknowledgments and finances. The authors thank all
the brave defenders of Ukraine that stood against the
russian full-scale invasion and made this publication
possible.
Experimental section
The solvents were purified according to the standard
procedures [38]. Compounds 5-11 and 13 were available
from Enamine Ltd. Melting points were measured on
MPA100 OptiMelt automated melting point system. 1H and
13C{H} NMR spectra were recorded on Bruker 170 Avance
500 spectrometer (at 500 MHz for 1H NMR and 126 MHz
for 13C{H} NMR) and Varian Unity Plus 400 spectrometer
(at 400 MHz for 1H NMR and 101 MHz for 13C{H} NMR).
NMR chemical shifts are reported in ppm (δ scale)
downfield from TMS as an internal standard and are
referenced using residual NMR solvent peaks at 7.26 and
77.16 ppm for 1H and 13C{H} in CDCl3, 2.50 and 39.52
ppm for 1H and 13C{H} in DMSO-d6, and 4.79 ppm for 1H
in D2O. Coupling constants (J) are shown in Hz. Spectra are
Y.S. Malets, O.V. Golovchenko
25
reported as follows: chemical shift (δ, ppm), multiplicity,
integration, and coupling constants (Hz).
1-(3-Fluoro-2-hydroxyphenyl)ethan-1-one (15)
MOMCl (15.1 g, 0.188 mol, 14.3 mL) was added dropwise
at rt to a mixture of phenol 13 (10.3 g, 75.1 mmol) and
DIPEA (38.8 g, 0.300 mol, 52.3 mL) in CH2Cl2 (100 mL)
under an argon atmosphere and stirred overnight. Saturated
aq NH4Cl (100 mL) was added to the resulting mixture,
which was then extracted with CH2Cl2 (6 × 50 mL), dried
over Na2SO4, filtered, and evaporated in vacuo. Yield ca.
13.0 g (ca. 96%); red crystals. The compound was used in
the next step without additional purification. A solution of
crude benzonitrile 14 (ca. 13.0 g, 71.8 mmol) in THF (360
mL) was added dropwise to a solution of 3 M MeMgCl
(20.6 g, 0.276 mol) in THF (180 mL) under argon
atmosphere at 0 °C. The reaction mixture was stirred for 30
min, warmed up to rt, then refluxed for 6 h. The resulting
mixture was stirred at rt overnight, then poured into of ice-
cold aq HCl (300 mL), extracted with CH2Cl2 (6 × 100 mL),
dried over Na2SO4, filtered, and evaporated in vacuo. Yield
7.6 g (66%). Colorless solid, mp 73-75 °C. 1H NMR (500
MHz, DMSO-d6) δ 11.94 (s, 1H), 7.69 (dd, J 8.2, 1.0 Hz,
1H), 7.58-7.39 (m, 1H), 7.03-6.85 (m, 1H), 2.64 (s, 3H).
13C NMR (126 MHz, DMSO-d6) δ 204.3 (d, J 2.5 Hz),
150.7 (d, J 244 Hz), 148.7 (d, J 13.1 Hz), 126.6 (d, J 3.4
Hz), 122.5 (d, J 2.7 Hz), 121.6 (d, J 17.4 Hz), 118.6 (d, J
6.9 Hz), 27.9. LC/MS (ES-API): m/z 155 [M+H]+. GC/MS
(EI): m/z 154 [M]+.
8-Fluoro-2',3',5',6'-tetrahydrospiro[chromane-2,4'-py-
ran]-4-one (12)
A solution of phenol 15 (1.10 g, 7.10 mmol),
tetrahydropyran-4-one (710 mg, 7.10 mmol, 0.66 mL) and
pyrrolidine (250 mg, 3.57 mmol, 0.29 mL) in THF (70 mL)
was refluxed for 8 h. The resulting mixture was cooled to rt,
poured into 1 M aq. HCl (200 mL), extract with CH2Cl2
(6 × 30 mL), dried over Na2SO4, filtered, and evaporated in
vacuo. The residue was dissolved in saturated aq. K2CO3,
and extracted with hexane – t-BuOMe (2:1, v/v, 3 × 50
mL), dried over Na2SO4, filtered, and evaporated in vacuo.
The compound was purified by the recrystallization from
i-PrOH. Yield 1.22 g (72%). Yellow solid, mp 88-89 °C.
1H NMR (500 MHz, DMSO-d6) δ 7.54 (t, J 8.8 Hz, 2H),
7.01 (td, J 8.0, 4.5 Hz, 1H), 3.69-3.61 (m, 4H), 2.91 (s, 2H),
1.89-1.81 (m, 2H), 1.77 (ddd, J 14.4, 9.7, 5.7 Hz, 2H).
13C NMR (126 MHz, DMSO-d6) δ 190.6 (d, J 3.2 Hz),
151.6 (d, J 246 Hz), 146.7 (d, J 11.2 Hz), 122.5, 122.2 (d, J
17.5 Hz), 121.2 (d, J 3.6 Hz), 120.6 (d, J 6.6 Hz), 78.8,
62.3, 46.0, 33.9. LC/MS (ES-API): m/z 237 [M+H]+.
HRMS (ESI-TOF) Calcd. for C13H14FO3 237.0921 [M+H]+.
Found 237.09242.
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2,2-Дизаміщені 5- та 8-азахроман-4-они: вплив на ріст ракових клітин у порівнянні
з хроманоновими аналогами
Є.С. Малець, О.В. Головченко
Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ, Україна
Резюме: Серія 2,2-дизаміщених 5-азахроман-4-онів (два приклади) та ізомерних 8-азахроман-4-онів (чотири похідні) була оцінена на
протипухлинну активність in vitro щодо 60 типів ракових клітин. Зменшення проліферації ракових клітин спостерігалося для 2,3,5,6-
тетрагідроспіро[піран-4,2'-пірано[2,3-b]піридин]-4'(3'Н)-ону, який значно уповільнює ріст 27 із 60 ракових клітин більш ніж наполовину,
включаючи меланому, рак товстої кишки та яєчників. Взаємозв'язок структури та активності даного спіроциклічного 8-азахроманону
встановлено шляхом порівняння з хроманоновим аналогом (найменша активність) і відповідною 8-флуорозаміщеною похідною, яка виявляла
помірну активність.
Ключові слова: гетероцикли; хроманони; азахроманони; протиракова активність.
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| id | oai:ojs2.bioorganica.com.ua:article-66 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:12Z |
| publishDate | 2023 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/14/0c922120ea3a4cc41b4d1a65e4652814.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-662026-07-19T14:56:54Z 2,2-Disubstituted 5- and 8-azachroman-4-ones: the effect on cancer growth in contrast to chromanone analogs 2,2-Дизаміщені 5- та 8-азахроман-4-они: вплив на ріст ракових клітин у порівнянні з хроманоновими аналогами Malets, Yehor S. Golovchenko, Oleksandr V. heterocycles chromanone azachromanones anticancer activity гетероцикли хроманони азахроманони протиракова активніст A series of 2,2-disubstituted 5-azachroman-4-ones (two examples) and isomeric 8-azachroman-4-ones (four derivatives) were evaluated for their in vitro anticancer activity on 60 cancer cell lines. The decreased proliferation of cancer cells was observed for the case of both types of isomeric azachromanones with the highest activity for 2,3,5,6-tetrahydrospiro[pyran-4,2'-pyrano[2,3-b]pyridin]-4'(3'H)-one, which slows down the growth of 27 out of 60 cancer cell lines by more than half, including melanoma, colon and ovarian cancers. The structure-activity relationship in the hit spirocyclic 8-azachromanone was established by comparison with the parent chromanone analog (the least active) and the corresponding 8-fluorosubstituted derivative (showed moderate activity) Серія 2,2-дизаміщених 5-азахроман-4-онів (два приклади) та ізомерних 8-азахроман-4-онів (чотири похідні) була оцінена на протипухлинну активність in vitro щодо 60 типів ракових клітин. Зменшення проліферації ракових клітин спостерігалося для 2,3,5,6-тетрагідроспіро[піран-4,2'-пірано[2,3-b]піридин]-4'(3'Н)-ону, який  значно уповільнює ріст 27 із 60 ракових клітин більш ніж наполовину, включаючи меланому, рак товстої кишки та яєчників. Взаємозв'язок структури та активності даного спіроциклічного 8-азахроманону встановлено шляхом порівняння з хроманоновим аналогом (найменша активність) і відповідною 8-флуорозаміщеною похідною, яка виявляла помірну активність V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2023-06-30 Article Article application/pdf application/pdf https://bioorganica.com.ua/index.php/journal/article/view/66 10.15407/bioorganica2023.01.022 Ukrainica Bioorganica Acta; Vol. 18 No. 1 (2023): Ukrainica Bioorganica Acta; 22-26 Ukrainica Bioorganica Acta; Том 18 № 1 (2023): Ukrainica Bioorganica Acta; 22-26 1814-9766 1814-9758 10.15407/bioorganica2023.01 en https://bioorganica.com.ua/index.php/journal/article/view/66/58 https://bioorganica.com.ua/index.php/journal/article/view/66/64 Copyright (c) 2023 Yehor S. Malets, Oleksandr V. Golovchenko https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | гетероцикли хроманони азахроманони протиракова активніст Malets, Yehor S. Golovchenko, Oleksandr V. 2,2-Дизаміщені 5- та 8-азахроман-4-они: вплив на ріст ракових клітин у порівнянні з хроманоновими аналогами |
| title | 2,2-Дизаміщені 5- та 8-азахроман-4-они: вплив на ріст ракових клітин у порівнянні з хроманоновими аналогами |
| title_alt | 2,2-Disubstituted 5- and 8-azachroman-4-ones: the effect on cancer growth in contrast to chromanone analogs |
| title_full | 2,2-Дизаміщені 5- та 8-азахроман-4-они: вплив на ріст ракових клітин у порівнянні з хроманоновими аналогами |
| title_fullStr | 2,2-Дизаміщені 5- та 8-азахроман-4-они: вплив на ріст ракових клітин у порівнянні з хроманоновими аналогами |
| title_full_unstemmed | 2,2-Дизаміщені 5- та 8-азахроман-4-они: вплив на ріст ракових клітин у порівнянні з хроманоновими аналогами |
| title_short | 2,2-Дизаміщені 5- та 8-азахроман-4-они: вплив на ріст ракових клітин у порівнянні з хроманоновими аналогами |
| title_sort | 2,2-дизаміщені 5- та 8-азахроман-4-они: вплив на ріст ракових клітин у порівнянні з хроманоновими аналогами |
| topic | гетероцикли хроманони азахроманони протиракова активніст |
| topic_facet | heterocycles chromanone azachromanones anticancer activity гетероцикли хроманони азахроманони протиракова активніст |
| url | https://bioorganica.com.ua/index.php/journal/article/view/66 |
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