Хроман-4-онові каркаси як платформа для пошуку протиракових та противірусних сполук-лідерів
Chroman-4-one derivatives, a class of oxygen-containing heterocycles commonly found in biologically active natural products, continue to attract significant attention for their potential in anticancer and antiviral drug discovery. In this study, a small library of eight chroman-4-one compounds was s...
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| Date: | 2025 |
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| Language: | English |
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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_ | 1871193623208394752 |
|---|---|
| author | Timokhin, Oleksii S. Moskvina, Viktoriia S. Kucher, Olexandr V. Keith, Kathy A. Harden, Emma A. Hartline, Caroll B. James, Scott H. Brovarets, Volodymyr S. |
| author_facet | Timokhin, Oleksii S. Moskvina, Viktoriia S. Kucher, Olexandr V. Keith, Kathy A. Harden, Emma A. Hartline, Caroll B. James, Scott H. Brovarets, Volodymyr S. |
| author_institution_txt_mv | [
{
"author": "Oleksii S. Timokhin",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine; Enamine Ltd., Kyiv, Ukraine"
},
{
"author": " Viktoriia S. Moskvina",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine; Taras Shevchenko National University of Kyiv, Kyiv, Ukraine "
},
{
"author": "Olexandr V. Kucher",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine; Enamine Ltd., Kyiv, Ukraine"
},
{
"author": "Kathy A. Keith",
"institution": "University of Alabama at Birmingham, Birmingham, Alabama, USA"
},
{
"author": "Emma A. Harden",
"institution": "University of Alabama at Birmingham, Birmingham, Alabama, USA"
},
{
"author": "Caroll B. Hartline",
"institution": "University of Alabama at Birmingham, Birmingham, Alabama, USA"
},
{
"author": "Scott H. James",
"institution": "University of Alabama at Birmingham, Birmingham, Alabama, USA"
},
{
"author": "Volodymyr S. Brovarets",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
}
] |
| author_sort | Timokhin, Oleksii S. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:55Z |
| description | Chroman-4-one derivatives, a class of oxygen-containing heterocycles commonly found in biologically active natural products, continue to attract significant attention for their potential in anticancer and antiviral drug discovery. In this study, a small library of eight chroman-4-one compounds was synthesized via Kabbe condensation and screened for antiproliferative activity against the NCI-60 human cancer cell line panel. Most compounds demonstrated low cytotoxicity at a concentration of 10 μM; however, several derivatives exhibited selective growth-inhibitory effects against specific tumor cell lines, including non-small cell lung cancer and melanoma. In parallel, 7-hydroxyspiro[chromane-2,1'-cyclohexan]-4-one (compound 6) was evaluated for antiviral activity against a panel of DNA and RNA viruses. While it showed no significant activity against RNA viruses such as herpesviruses, it demonstrated selective antiviral activity against HPV-11 (EC50 = 3.35 µM, SI50 >45) and moderate activity against BK virus (EC50 = 15.88 µM, SI50 >9), with low associated cytotoxicity. These findings support the chroman-4-one scaffold as a promising chemotype for the development of biologically active agents and identify compound 6 as a preliminary lead for further investigation of its antiviral potential |
| doi_str_mv | 10.15407/bioorganica2025.01.019 |
| first_indexed | 2025-07-17T12:20:08Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 1
UDC 547.814.1
DOI: https://doi.org/10.15407/bioorganica2025.01.019
19
RESEARCH ARTICLE
Chroman-4-one scaffolds as a platform for anticancer and
antiviral lead discovery
Oleksii S. Timokhin1,2, Viktoriia S. Moskvina1,3*, Olexandr V. Kucher1,2, Kathy A. Keith4,
Emma A. Harden4, Caroll B. Hartline4, Scott H. James4, Volodymyr S. Brovarets1
1 V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
2 Enamine Ltd. (www.enamine.net), Kyiv, Ukraine
3 Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
4 University of Alabama at Birmingham, Birmingham, Alabama, USA
Abstract: Chroman-4-one derivatives, a class of oxygen-containing heterocycles commonly found in biologically active natural products,
continue to attract significant attention for their potential in anticancer and antiviral drug discovery. In this study, a small library of eight
chroman-4-one compounds was synthesized via Kabbe condensation and screened for antiproliferative activity against the NCI-60 human
cancer cell line panel. Most compounds demonstrated low cytotoxicity at a concentration of 10 μM; however, several derivatives exhibited
selective growth-inhibitory effects against specific tumor cell lines, including non-small cell lung cancer and melanoma. In parallel,
7-hydroxyspiro[chromane-2,1'-cyclohexan]-4-one (compound 6) was evaluated for antiviral activity against a panel of DNA and RNA
viruses. While it showed no significant activity against RNA viruses such as herpesviruses, it demonstrated selective antiviral activity
against HPV-11 (EC50 = 3.35 µM, SI50 >45) and moderate activity against BK virus (EC50 = 15.88 µM, SI50 >9), with low associated
cytotoxicity. These findings support the chroman-4-one scaffold as a promising chemotype for the development of biologically active
agents and identify compound 6 as a preliminary lead for further investigation of its antiviral potential.
Keywords: oxygen-containing heterocycles; chroman-4-ones; antiproliferative activity; anticancer activity; antiviral activity.
Introduction
Natural products have long served as a prolific source of
therapeutic agents and continue to inspire the development
of novel molecular architectures with significant biomedical
potential. Their structural diversity and biological relevance
make them indispensable in the search for new lead
compounds for drug discovery. Even in the era of modern
high-throughput screening and rational design, nature-
derived molecules remain central in the pharmaceutical
landscape, contributing to some of the most commercially
and clinically successful drugs to date [1].
Received:
Revised:
Accepted:
Published online:
21.04.2025
28.04.2025
14.05.2025
30.06.2025
Corresponding author. Tel.: +38066-791-09-21;
e-mail: v.moskvina@gmail.com (V.S. Moskvina)
ORCID: 0000-0001-5556-9147
Among the diverse families of oxygen-containing
heterocycles, chroman-4-ones (2,3-dihydro-1-benzopyran-
4-ones) represent a particularly important scaffold.
Structurally related to chromones, chroman-4-ones are
widely distributed in nature and are integral to many
biologically active secondary metabolites found in plants
and fungi [2]. These compounds are involved in key
physiological processes such as growth regulation, defense
mechanisms, and reproduction in plants. More importantly,
both natural and synthetic derivatives of chroman-4-ones
have demonstrated a broad spectrum of pharmacological
activities, including anticancer, antioxidant, anti-
inflammatory, antimicrobial, antiviral, antihyperlipidemic,
and neuroprotective effects [3, 4].
The chroman-4-one core is considered a privileged
scaffold in medicinal chemistry due to its ability to engage
in diverse biological interactions. Several chroman-4-one
derivatives are under clinical or preclinical investigation for
various indications. For instance, hesperetin, a natural
flavanone, exhibits cholesterol-lowering, antioxidant, and
anti-inflammatory activities; dihydroquercetin (taxifolin)
© Moskvina V.S. 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.
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 1
20
demonstrates strong antioxidant and antitumor effects and is
being explored for cardiovascular and anticancer therapies;
and related flavonoids such as naringenin and kaempferol
show antidiabetic and anticancer potential. Moreover, well-
known drugs containing chroman-based moieties highlight
the clinical importance of this scaffold: tocopherols
(vitamin E) are potent lipophilic antioxidants; nebivolol is a
β1-selective adrenergic receptor blocker with additional
vasodilating and antioxidant properties; troglitazone was
used as an antidiabetic agent acting as a PPARγ agonist; and
ormeloxifene is a selective estrogen receptor modulator
(SERM) with anticancer and contraceptive activity (Figure
1). Collectively, these examples underscore the broad
therapeutic relevance of chroman-4-one derivatives across
diverse pharmacological domains.
Hesperetin
O
OH
HO
O
OH
OMe
O
O
Dihydroquercetin
(Taxifolin)
OH
OH
HO
OH
OH
Kaempferol
O
OH
HO
O
OH
OH
Naringenin
O
OH
HO
O
OH
a-Tocopherol (Vitamin E)
O
O
HO
Nebivolol
O
Troglitazone
Ormeloxifene
O
F
H
O
HO MeO
O
N
OH
N
H
OH
O
F
H
O
S
NH
O
O
Figure 1. Representative biologically active chroman-4-one
derivatives.
The structural versatility of chroman-4-ones allows for
targeted modifications to enhance pharmacokinetic profiles,
increase selectivity toward biological targets, and overcome
limitations of natural analogues. Consequently, chroman-4-
ones continue to draw attention not only for their inherent
biological activity but also as synthetic intermediates and
templates for further derivatization. Despite the well-
established significance of chroman-4-ones, further
investigation into their biological potential remains crucial,
particularly in the context of pressing therapeutic needs
such as cancer and viral infections.
In this study, we present the results of comprehensive
biological evaluation of a series of chroman-4-one
derivatives, with a focus on their anticancer and antiviral
activities. The compounds under investigation were
synthesized using methodologies previously developed and
published by our group. Building upon this synthetic
foundation, the current work provides new insights into the
pharmacological profile of chroman-4-ones, thereby
expanding and complementing our earlier findings. These
results contribute to the growing understanding of chroman-
4-one scaffolds as promising platforms for the development
of bioactive agents with potential clinical relevance.
Results and Discussion
The set of chroman-4-one derivatives evaluated for
anticancer and antiviral activities is presented in Figure 2.
Compounds 1-8 were synthesized via the Kabbe
condensation of 2-hydroxyacetophenones with the
corresponding carbonyl compounds, as outlined in
Scheme 1. The detailed synthetic procedures,
physicochemical properties, and spectral data for these
compounds have been described in our previous
publications [5, 6]. All compounds were obtained with a
purity greater than 98%, as confirmed by NMR and LC-MS
analyses. Notably, chroman-4-one derivatives 3 and 7 were
isolated and investigated in the form of their hydrochloride
salts, which were obtained by treating the corresponding
Boc-protected intermediates with 4 M HCl in dioxane.
Figure 2. Chemical structures of chroman-4-one derivatives
studied for anticancer and antiviral activities.
General cytotoxicity profile of tested chroman-4-one
derivatives.
The anticancer activity of synthesized compounds was
tested according to the International Program of the
National Institutes of Health – DTP (Developmental
Therapeutic Program) of the National Cancer Institute
O.S. Timokhin, V.S. Moskvina et al.
21
(NCI, Bethesda, Maryland, USA) on 60 cancer cell lines at
a single concentration of 1×10–5 M [7].
As presented in Table 1, most compounds demonstrated
mean growth percentages above 100%, indicating a general
Scheme 1. General synthetic route to chroman-4-one derivatives
1-8.
lack of significant cytostatic or cytotoxic effects at this
screening dose. Notably, compound 2 (NSC 852298)
exhibited the lowest mean growth percent (90.67%),
suggesting the most promising overall antiproliferative
potential within the tested set. In contrast, compounds 4
(NSC 852299) and 8 (NSC 852300) showed elevated
growth values (111.80% and 110.52%, respectively), which
may reflect not only weak antiproliferative activity but also
potential growth-stimulatory effects in specific tumor cell
lines. This phenomenon, occasionally observed in NCI-60
single-dose screenings, underscores the importance of
cautious interpretation of growth percent data and
highlights the need for dose-response follow-up studies.
The delta values ranged from 16.03% to 39.58%, and the
growth percent range varied between 42.80% and 82.06%,
reflecting a high degree of variability across the panel and
highlighting the heterogeneity of tumor cell responses. Such
variability suggests that certain compounds may exhibit
selective activity profiles, warranting more detailed analysis
across individual cell lines.
Table 1. Percent of cancer cell growth in 1×10–5 M solution
of the test compound compared to the control (according to
one doses full NCI 60 cell panel assay).
Compound
NSC
code
Mean
Growth
Percent,
%
Delta,
%
Range,
%
1 852296 101.72 39.58 65.45
2 852298 90.67 28.40 51.65
3 852297 99.31 21.84 42.80
4 852299 111.80 32.18 82.06
5 852301 109.44 22.98 47.67
6 846127 104.47 25.50 69.78
7 852302 107.00 28.95 60.20
8 852300 110.52 16.03 45.78
Antiproliferative activity against selected human cancer
cell lines.
Table 2 summarizes the most responsive cell lines for
each tested chroman-4-one derivative. Several compounds
demonstrated selective antiproliferative activity against
specific cancer types:
• compound 1 (NSC 852296) showed the most
pronounced growth inhibition in the non-small cell lung
cancer cell line NCI-H522 with a growth percentage of
62.14%, indicating moderate activity.
• compound 2 (NSC 852298) exhibited selective
inhibitory potential against melanoma UACC-257 cells
(62.27%), aligning with its favorable mean growth profile
reported Table 1.
• compound 7 (NSC 852302) demonstrated a degree of
selectivity toward melanoma LOX IMVI cells (78.05%);
however, its relatively high mean growth value (107.00%)
suggests limited overall cytotoxic efficacy.
• other compounds, such as 6 (NSC 846127), showed
only modest growth inhibition against renal cancer UO-31
(78.97%), which may not warrant further investigation at
this stage.
Table 2. The best results of each compounds against
different cell lines.
Compound
NSC
code
Panel Line
Cell
Line
Growth
Percent,
%
1 852296
Non-Small Cell
Lung Cancer
NCI-
H522
62.14
2 852298 Melanoma
UACC-
257
62.27
3 852297
Non-Small Cell
Lung Cancer
NCI-
H226
77.47
4 852299
Non-Small Cell
Lung Cancer
NCI-
H522
79.62
5 852301 Melanoma
LOX
IMVI
86.46
6 846127 Renal Cancer UO-31 78.97
7 852302 Melanoma
LOX
IMVI
78.05
8 852300 Melanoma
UACC-
257
94.49
To better understand the cell line-selectivity, additional
analysis revealed the top three most responsive cell lines for
each compound based on growth percent values. For
instance, compound 2 inhibited UACC-257 (melanoma),
HT29 (colon cancer), and MDA-MB-231/ATCC (breast
cancer) more strongly than others, while compound 1 was
active against NCI-H522, SN12C (renal), and LOX IMVI
(melanoma).
These findings suggest that despite the generally low
overall cytotoxicity, certain compounds exhibit preferential
activity toward specific tumor subtypes. These observations
are supported by extended comparative data provided in
Supporting Information Table S1.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 1
22
Although a comprehensive structure-activity relationship
(SAR) analysis is beyond the current scope, preliminary
observations can be made. Compound 2, which
demonstrated the most favorable overall profile, may
contain structural features conducive to melanoma cell
inhibition. Conversely, compounds such as 8 and 5, which
exhibited weaker activity across multiple lines including
melanoma, suggest that even minor structural variations can
significantly influence biological outcomes. While a full
SAR analysis is beyond the scope of this study, the
observed differences in activity suggest that ring size and
substitution pattern may influence tumor-type selectivity,
and these aspects warrant more detailed targeted
investigation.
Evaluation of antiviral activity against DNA and RNA
viruses.
The antiviral activity of chroman-4-one derivative 6 was
assessed across a panel of eight viruses representing both
DNA and RNA types, including human cytomegalovirus
(HCMV), poliovirus type 1 (POV-1), herpes simplex virus
1 (HSV-1), varicella-zoster virus (VZV), BK virus, and
three genotypes of human papillomavirus (HPV-11, HPV-
18, and HPV-31). No relevant antiviral activity was
observed against HCMV, POV-1, HSV-1, or VZV, with
EC50 values exceeding 100 or even 150 μM in all cases. The
reference drugs – ganciclovir, enviroxime, and acyclovir –
showed expected levels of potency, validating the assays. In
contrast, more promising results were obtained for BK
virus, where 6 exhibited an EC50 of 15.88 μM, with a
selectivity index (SI50) exceeding 9, indicating low
cytotoxicity and moderate antiviral potential. This activity
is substantially weaker than the control drug cidofovir (EC50
= 0.97 μM), but still warrants consideration for further
structural optimization. The most notable antiviral effect
was observed against HPV-11, where 6 demonstrated an
EC50 of 3.35 μM and an SI50 >45, closely approaching the
potency of the reference drug 9-[2-phosphonomethoxy-
ethyl]guanine (EC50 = 2.56 μM). Encouraged by this result,
further testing was conducted against HPV-18 and HPV-31.
While the activity was significantly reduced for these
genotypes (EC50 = 167.87 μM and 128.42 μM, respective-
ly), the compound maintained low cytotoxicity (CC50 >250
μM), yielding SI values slightly above 1. Taken together,
these findings suggest that 6 exhibits selective antiviral
activity, particularly against HPV-11 and BK virus, with a
favorable cytotoxicity profile. Although its broad-spectrum
efficacy appears limited, the selective inhibition of certain
DNA viruses highlights the chroman-4-one scaffold as a
viable platform for future development of targeted antiviral
agents. Further structural refinement and mechanistic
studies are warranted to optimize potency and expand viral
selectivity.
Table 3. Evaluation of antiviral activity of chroman-4-one derivative 6 across a virus panel.
Compound
Control
Assay
Order
Control Assay Name
EC50,
μM
EC90,
μM
CC50,
μM
SI50 SI90
Human cytomegalovirus
Ganciclovir a) Primary
CellTiter-Glo (Cytopathic
effect / Toxicity)
1.01 >150.00 >150.00 >148 1
6 Primary
CellTiter-Glo (Cytopathic
effect / Toxicity)
>150.00 >150.00 >150.00 1 1
POV-1
Enviroxime b) Primary
CellTiter-Glo (Cytopathic
effect / Toxicity)
0.082 n/a 7.4 90 n/a
6 Primary
CellTiter-Glo (Cytopathic
effect / Toxicity)
>100.00 n/a >100.00 0 n/a
Herpes simplex virus 1
Acyclovir c) Primary
CellTiter-Glo (Cytopathic
effect / Toxicity)
3.39 >150.00 >150.00 >44 1
6 Primary
CellTiter-Glo (Cytopathic
effect / Toxicity)
>150.00 >150.00 >150.00 1 1
Varicella-Zoster virus
Acyclovir d) Primary
CellTiter-Glo (Cytopathic
effect / Toxicity)
5.53 145.87 >150.00 >27 >1
6 Primary
CellTiter-Glo (Cytopathic
effect / Toxicity)
>30.00 >30.00 124.74 <4 <4
BK virus
Cidofovir e) Primary
Quantitative polymerase chain
reaction (DNA)/CellTiter-Glo
(Toxicity)
0.97 83.60 >150.00 >154 >2
O.S. Timokhin, V.S. Moskvina et al.
23
Table 3. (Contd.)
Compound Control
Assay
Order
Control Assay Name
EC50,
μM
EC90,
μM
CC50,
μM
SI50 SI90
BK virus
6 Primary
Quantitative polymerase chain
reaction (DNA)/CellTiter-Glo
(Toxicity)
15.88 121.86 >150.00 >9 >1
Human papillomavirus 11
9-[2-Phosphono-
methoxy)ethyl]guanine f)
Primary
Nano-Glo Luciferase
(Nanoluc)/CellTiter-Glo
(Toxicity)
2.56 >150.00 >150.00 >59 1
6 Primary
Nano-Glo Luciferase
(Nanoluc)/CellTiter-Glo
(Toxicity)
3.35 >150.00 >150.00 >45 1
Human papillomavirus 18
9-[2-Phosphono-
methoxy)ethyl]guanineg)
Secondary
Nano-Glo Luciferase
(Nanoluc)/CellTiter-Glo
(Toxicity)
2.93 9.06 >250.00 >85 >28
6 Secondary
Nano-Glo Luciferase
(Nanoluc)/CellTiter-Glo
(Toxicity)
167.87 213.64 >250.00 >1 >1
Human papillomavirus 31
9-[2-Phosphono-
methoxy)ethyl]guanineh)
Secondary
Nano-Glo Luciferase
(Nanoluc)/CellTiter-Glo
(Toxicity)
1.57 20.34 >250.00 >159 >12
6 Secondary
Nano-Glo Luciferase
(Nanoluc)/CellTiter-Glo
(Toxicity)
128.42 226.81 >250.00 >1 >1
a) Control drug compound. Virus screened: Human cytomegalovirus; virus strain: AD169; cell line: HFF; vehicle: DMSO; drug conc. range: 0.048-150 μM;
control conc. range: 0.048-150 μM; b) Control drug compound. Virus screened: POV-1; virus strain: Mahoney; cell line: Vero 76; vehicle: DMSO; drug
conc. range: 0.1-100 μM; control conc. range: 0.1-100 μM; c) Control drug compound. Virus screened: Herpes simplex virus 1; virus strain: E-377; cell line:
HFF; vehicle: DMSO; drug conc. range: 0.048-150 μM; control conc. range: 0.048-150 μM; d) Control drug compound. Virus screened: Varicella-Zoster
virus; virus strain: Ellen; cell line: HFF; vehicle: DMSO; drug conc. range: 0.048-150 μM; control conc. range: 0.048-150 μM; e) Control drug compound.
Virus screened: BK virus; virus strain: Gardner; cell line: HFF; vehicle: DMSO; drug conc. range: 0.048-150 μM; control conc. range: 0.048-150 μM; f)
Control drug compound. Virus screened: Human papillomavirus 11; virus strain: HE611260.1; cell line: C-33 A; vehicle: DMSO; drug conc. range: 0.048-
150 μM; control conc. range: 0.048-150 μM; g) Control drug compound. Virus screened: Human papillomavirus 18; virus strain: KC470230.1; cell line:
C-33 A; vehicle: DMSO; drug conc. range: 0.001-250 μM; control conc. range: 0.001-250 μM; h) Control drug compound. Virus screened: Human
papillomavirus 31; virus strain: HQ53768.1; cell line: C-33 A; vehicle: DMSO; drug conc. range: 0.001-250 μM; control conc. range: 0.001-250 μM;
Conclusions
A series of chroman-4-one derivatives was synthesized
and evaluated for their antiproliferative and antiviral
activities. Screening against the NCI-60 cancer cell line
panel showed that most compounds exhibited low
cytotoxicity, with some derivatives demonstrated modest,
cell line-specific growth inhibition, particularly against
melanoma and non-small cell lung cancer. While these
preliminary observations are not sufficient to define a
structure-activity relationship, they may serve as a sterting
point for future exploration. In the context of antiviral
evaluation, 7-hydroxyspiro[chromane-2,1'-cyclohexan]-4-
one (compound 6) emerged as a selective inhibitor of HPV-
11 and a moderate inhibitor of BK virus, with favorable
selectivity indices and low cytotoxicity. Overall, this study
highlights the chroman-4-one scaffold as a valuable
platform for the development of both anticancer and
antiviral agents, warranting further exploration of structure-
activity relationships and biological mechanisms of action.
Experimental section
Chemistry
The synthesis, physicochemical properties, and 1H and
13C NMR data of 2,2-dimethylchroman-4-one (1), spiro-
[chromane-2,1'-cyclobutan]-4-one (2), spiro[chromane-2,1'-
cyclopentan]-4-one (4), spiro[chromane-2,1'-cyclohexan]-4-
one (5), and 2',3',5',6'-tetrahydrospiro-[chromane-2,4'-thio-
pyran]-4-one (8) have been described in detail in our
previous publication [5], while those of 7-hydroxyspiro-
[chromane-2,1'-cyclohexan]-4-one (6) were reported in
publication [6]. The synthesis of spiro[azetidine-3,2'-
chroman]-4'-one (3) and spiro[chromane-2,4'-piperidin]-4-
one (7) involved the preparation of the corresponding Boc-
protected chromanone intermediates according to the
methodology described in detail in publication [5], followed
by acid-mediated Boc-deprotection to afford the target
compounds.
General procedure for acid-mediated Boc-deprotection.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 1
24
The corresponding Boc-protected chromanone derivative
(1 equiv., 500 mg) was dissolved in methyl tert-butyl ether
(MTBE, 5 mL per 1 equiv.) and cooled to 0 °C. A solution
of 4 M HCl in dioxane (3 mL per 1 equiv.) was added
dropwise under stirring. The reaction mixture was allowed
to warm to room temperature and stirred overnight. After
completion, additional MTBE was added, and the resulting
precipitate was collected by filtration, washed thoroughly
with cold MTBE, and dried under reduced pressure to
afford the deprotected product.
Spiro[azetidine-3,2'-chroman]-4'-one hydrochloride (3).
Yield: 330 mg, 85%. Mp 175 °C. 1H NMR (400 MHz,
DMSO-d6) δ 3.29 (s, 2H), 4.25-3.95 (m, 5H), 7.08-7.22 (m,
2H), 7.66 (t, J = 7.7 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 9.57
(br s , 2H). 13C NMR (101 MHz, DMSO-d6) δ 43.99, 56.00,
77.75, 118.96, 120.85, 123.01, 126.75, 137.4, 158.32,
189.88. MS (ESI+) m/z: 190.0 [M+H]+.
Spiro[chromane-2,4'-piperidin]-4-one hydrochloride (7).
Yield: 360 mg, 90%. Mp 219 °C. 1H NMR (400 MHz,
DMSO-d6) δ 2.04-1.81 (m, 2H), 2.18-2.04 (m, 2H), 2.9 (s,
2H), 2.99-3.27 (m, 5H), 6.95-7.2 (m, 2H), 7.61 (t, J = 7.8
Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 9.1 (br s, 2H). 13C NMR
(101 MHz, DMSO-d6) δ 30.59, 39.21, 46.87, 76.44, 118.9,
120.69, 122.02, 126.43, 137.13, 158.59, 191.38. MS (ESI+)
m/z: 218.0 [M+H]+.
Biology
All test compounds were prepared as 10 μM stock
solutions in DMSO (biological assay grade) and submitted
for biological screening under the NCI Developmental
Therapeutics Program.
One doses full NCI 60 cell panel assay.
The newly synthesized compounds were submitted to
National Cancer Institute NCI, Bethesda, Maryland, U.S.A.,
under the Developmental Therapeutic Program DTP [7].
The cell line panel engaged a total of 60 different human
tumor cell lines derived from nine cancer types. The
selected compounds 1-8 were assigned with the NCI codes
(see Tables 1-2), respectively. Primary in vitro one-dose
anticancer screening was initiated, in which the full NCI 60
panel lines were inoculated onto a series of standard 96-
well microtiter plates on day 0 at 5000-40000 cells per well
in RPMI 1640 medium containing 5 % fetal bovine serum
and 2 mM L-glutamine, and then preincubated in absence of
drug at 37 °C, and 5 % CO2 for 24 h. Test compounds were
then added at one concentration of 10−5 M in all 60 cell
lines (stock solution preparing see in [8]), and incubated for
a further 48 h at the same incubation conditions. Following
this, the media were removed, the cells were fixed in situ,
washed, and dried. The sulforhodamine B assay was used
for cell density determination, based on the measurement of
cellular protein content. After an incubation period, cell
monolayers were fixed with 10 % (wt/vol) trichloroacetic
acid and stained for 30 min, after which the excess dye was
removed by washing repeatedly with 1 % (vol/vol) acetic
acid. The bound stain was resolubilized in 10 mM Tris base
solution and measured spectrophotometric ally on
automated microplate readers for OD determination at
510 nm.
Antiviral and cytotoxicity assays
The antiviral activity of compound 6 was evaluated
against a panel of eight viruses representing both DNA and
RNA viruses: human cytomegalovirus (HCMV), poliovirus
type 1 (POV-1), herpes simplex virus type 1 (HSV-1),
varicella-zoster virus (VZV), BK polyomavirus (BKPyV),
and human papillomavirus types 11, 18, and 31 (HPV-11,
HPV-18, HPV-31). Antiviral assays were performed in
monolayers of appropriate host cells under standard
conditions. Viral replication inhibition was assessed via
quantification of viral genome copies or cytopathic effect,
depending on the virus system. For BKPyV, plasmid
pMP526 was used as a DNA standard for viral genome
quantification by qPCR.
Cell viability and compound cytotoxicity were determin-
ed in parallel using the CellTiter-Glo luminescent cell
viability assay (Promega, Madison, WI), and the 50%
cytotoxic concentration (СC50) was calculated. Selectivity
index (SI50) values were determined as the ratio of СC50 to
EC50. Cidofovir, acyclovir, enviroxime, ganciclovir, and
9-[2-phosphonomethoxyethyl]guanine were used as
reference antiviral compounds depending on the virus.
Notes
Acknowledgments and finances. The authors thank all
brave defenders of Ukraine who made this publication
possible. The authors also acknowledge the U.S. Public
Health Service and the National Cancer Institute (NCI),
USA, for the in vitro anticancer screening (NCI-60
cell panel assay) conducted within the frame-
work of the Developmental Therapeutic Program
(http://dtp.cancer.gov). We are grateful to Enamine Ltd. for
providing material and technical support for the synthetic
part of this study. These research was funded in whole or in
part with Federal funds from the National Institute of
Allergy and Infectious Diseases (NIAID), National
Institutes of Health (NIH), U.S. Department of Health
and Human Services, under Contract No.
HHSN75N93019D00016 (SHJ).
Disclaimer. This material should not be interpreted as
representing the viewpoint of the U.S. National Institutes of
Health, the National Cancer Institute, the National Institute
of Allergy and Infectious Diseases, or its Collaborative
Antiviral Testing Group.
The authors declare no conflict of interest.
Author contributions. O.S.T.: synthesis of compounds,
investigation, formal analysis, editing. V.S.M.:
investigation, formal analysis, writing most of the
manuscript, editing. O.V.K.: investigation, formal analysis,
editing. K.A.K.: investigation, formal analysis. E.A.H.:
investigation, formal analysis. C.B.H.: investigation, formal
analysis. S.H.J.: investigation, formal analysis. V.S.B.:
conceptualization, supervision, writing - review & editing.
http://dtp.cancer.gov/
O.S. Timokhin, V.S. Moskvina et al.
25
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27.07.2015. (in Ukrainian)
Хроман-4-онові каркаси як платформа для пошуку протиракових та противірусних
сполук-лідерів
О.С. Тімохін1,2*, В.С. Москвіна 1,3, О.В. Кучер 1,2, K.A. Kіт 4, E.A. Харден 4, К.B. Гартлайн 4,
С.H. Джеймс 4, В.С. Броварець 1
1 Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ, Україна
2 ТОВ НВП «Енамін», Київ, Україна
3 Київський національний університет імені Тараса Шевченка, Київ, Україна
4 Університет Алабами в Бірмінгемі, Бірмінгем, Алабама, США
Резюме: Похідні хроман-4-ону – клас оксигеновмісних гетероциклів, що широко представлений біологічно активними природними сполуками,
які продовжують привертати значну увагу як перспективні структури у пошуку протиракових і противірусних препаратів. У цьому дослідженні
було синтезовано невелику бібліотеку з восьми представників хроман-4-онів шляхом конденсації Каббе та проведено їх скринінг на
антипроліферативну активність на панелі з 60 ліній ракових клітин людини (NCI-60). Більшість сполук виявили низьку цитотоксичність при
концентрації 10 μM, а окремі похідні проявили вибіркову інгібувальну дію щодо пухлинних клітин, зокрема недрібноклітинного раку легень і
меланоми. Паралельно було досліджено антивірусну активність 7-гідрокси-спіро[хроман-2,1'-циклогексан]-4-ону (сполука 6) проти панелі ДНК-
та РНК-вірусів. Попри відсутність значущої активності щодо РНК-вірусів і герпесвірусів, сполука продемонструвала вибіркову противірусну дію
проти вірусу папіломи людини типу 11 (HPV-11, EC50 = 3.35 μM, SI50 >45) і помірну активність проти BK-вірусу (EC50 = 15.88 μM, SI50 >9), зі
збереженням низької цитотоксичності. Отримані результати підтверджують, що хроман-4-оновий каркас є перспективним хемотипом для
створення біологічно активних сполук і виокремлюють сполуку 6 як кандидата для подальших досліджень противірусного потенціалу.
Ключові слова: оксигеновмісні гетероцикли; хроман-4-они; антипроліферативна активність; протиракова активність; противірусна активність.
https://dtp.cancer.gov/discovery_development/nci-60/default.htm
Evaluation of antiviral activity against DNA and RNA viruses.
|
| id | oai:ojs2.bioorganica.com.ua:article-96 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:39Z |
| publishDate | 2025 |
| 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/3e/9983b5abbb7e363371033d6a56423f3e.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-962026-07-19T14:56:55Z Chroman-4-one scaffolds as a platform for anticancer and antiviral lead discovery Хроман-4-онові каркаси як платформа для пошуку протиракових та противірусних сполук-лідерів Timokhin, Oleksii S. Moskvina, Viktoriia S. Kucher, Olexandr V. Keith, Kathy A. Harden, Emma A. Hartline, Caroll B. James, Scott H. Brovarets, Volodymyr S. oxygen-containing heterocycles chroman-4-ones antiproliferative activity anticancer activity antiviral activity оксигеновмісні гетероцикли хроман-4-они антипроліферативна активність протиракова активність противірусна активність Chroman-4-one derivatives, a class of oxygen-containing heterocycles commonly found in biologically active natural products, continue to attract significant attention for their potential in anticancer and antiviral drug discovery. In this study, a small library of eight chroman-4-one compounds was synthesized via Kabbe condensation and screened for antiproliferative activity against the NCI-60 human cancer cell line panel. Most compounds demonstrated low cytotoxicity at a concentration of 10 μM; however, several derivatives exhibited selective growth-inhibitory effects against specific tumor cell lines, including non-small cell lung cancer and melanoma. In parallel, 7-hydroxyspiro[chromane-2,1'-cyclohexan]-4-one (compound 6) was evaluated for antiviral activity against a panel of DNA and RNA viruses. While it showed no significant activity against RNA viruses such as herpesviruses, it demonstrated selective antiviral activity against HPV-11 (EC50 = 3.35 µM, SI50 &gt;45) and moderate activity against BK virus (EC50 = 15.88 µM, SI50 &gt;9), with low associated cytotoxicity. These findings support the chroman-4-one scaffold as a promising chemotype for the development of biologically active agents and identify compound 6 as a preliminary lead for further investigation of its antiviral potential Похідні хроман-4-ону – клас оксигеновмісних гетероциклів, що широко представлений біологічно активними природніми сполуками, які продовжують привертати значну увагу як перспективні структури у пошуку протиракових і противірусних препаратів. У цьому дослідженні було синтезовано невелику бібліотеку з восьми представників хроман-4-онів шляхом конденсації Каббе та проведено їх скринінг на антипроліферативну активність на панелі з 60 ліній ракових клітин людини (NCI-60). Більшість сполук виявили низьку цитотоксичність при концентрації 10 μM, а окремі похідні проявили вибіркову інгібувальну дію щодо пухлинних клітин, зокрема недрібноклітинного раку легень і меланоми. Паралельно було досліджено антивірусну активність 7-гідрокси-спіро[хроман-2,1'-циклогексан]-4-ону (сполука 6) проти панелі ДНК- та РНК-вірусів. Попри відсутність значущої активності щодо РНК-вірусів і герпесвірусів, сполука продемонструвала вибіркову противірусну дію проти вірусу папіломи людини типу 11 (HPV-11, EC50 = 3.35 μM, SI50 &gt;45) і помірну активність проти BK-вірусу (EC50 = 15.88 μM, SI50 &gt;9), зі збереженням низької цитотоксичності. Отримані результати підтверджують, що хроман-4-оновий каркас є перспективним хемотипом для створення біологічно активних сполук і виокремлюють сполуку 6 як перспективного кандидата для подальших досліджень противірусного потенціалу V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2025-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/96 10.15407/bioorganica2025.01.019 Ukrainica Bioorganica Acta; Vol. 20 No. 1 (2025): Ukrainica Bioorganica Acta; 19-25 Ukrainica Bioorganica Acta; Том 20 № 1 (2025): Ukrainica Bioorganica Acta; 19-25 1814-9766 1814-9758 10.15407/bioorganica2025.01 en https://bioorganica.com.ua/index.php/journal/article/view/96/93 Copyright (c) 2025 Oleksii S. Timokhin, Viktoriia S. Moskvina, Olexandr V. Kucher, Kathy A. Keith, Emma A. Harden, Caroll B. Hartline, Scott H. James, Volodymyr S. Brovarets https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | оксигеновмісні гетероцикли хроман-4-они антипроліферативна активність протиракова активність противірусна активність Timokhin, Oleksii S. Moskvina, Viktoriia S. Kucher, Olexandr V. Keith, Kathy A. Harden, Emma A. Hartline, Caroll B. James, Scott H. Brovarets, Volodymyr S. Хроман-4-онові каркаси як платформа для пошуку протиракових та противірусних сполук-лідерів |
| title | Хроман-4-онові каркаси як платформа для пошуку протиракових та противірусних сполук-лідерів |
| title_alt | Chroman-4-one scaffolds as a platform for anticancer and antiviral lead discovery |
| title_full | Хроман-4-онові каркаси як платформа для пошуку протиракових та противірусних сполук-лідерів |
| title_fullStr | Хроман-4-онові каркаси як платформа для пошуку протиракових та противірусних сполук-лідерів |
| title_full_unstemmed | Хроман-4-онові каркаси як платформа для пошуку протиракових та противірусних сполук-лідерів |
| title_short | Хроман-4-онові каркаси як платформа для пошуку протиракових та противірусних сполук-лідерів |
| title_sort | хроман-4-онові каркаси як платформа для пошуку протиракових та противірусних сполук-лідерів |
| topic | оксигеновмісні гетероцикли хроман-4-они антипроліферативна активність протиракова активність противірусна активність |
| topic_facet | oxygen-containing heterocycles chroman-4-ones antiproliferative activity anticancer activity antiviral activity оксигеновмісні гетероцикли хроман-4-они антипроліферативна активність протиракова активність противірусна активність |
| url | https://bioorganica.com.ua/index.php/journal/article/view/96 |
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