Особливості синтезу та біологічної активності 3-(карбоксифеніл)хромонів
Flavonoids and their derivatives have historically been a source of therapeutic agents. Every year, more and more data is published on new flavonoid compounds, both synthetic and isolated from natural sources, and their innumerable physiological and pharmacological activities. This review presents s...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2020
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| author | Shablykina, Olga V. Moskvina, Viktoriia S. Khilya, Volodymyr P. |
| author_facet | Shablykina, Olga V. Moskvina, Viktoriia S. Khilya, Volodymyr P. |
| author_institution_txt_mv | [
{
"author": "Olga V. Shablykina",
"institution": "Taras Shevchenko National University of Kyiv, 60 Volodymyrska St., Kyiv, 01601, Ukraine"
},
{
"author": "Viktoriia S. Moskvina",
"institution": "Taras Shevchenko National University of Kyiv, 60 Volodymyrska St., Kyiv, 01601, Ukraine"
},
{
"author": "Volodymyr P. Khilya",
"institution": "Taras Shevchenko National University of Kyiv, 60 Volodymyrska St., Kyiv, 01601, Ukraine"
}
] |
| author_sort | Shablykina, Olga V. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:53Z |
| description | Flavonoids and their derivatives have historically been a source of therapeutic agents. Every year, more and more data is published on new flavonoid compounds, both synthetic and isolated from natural sources, and their innumerable physiological and pharmacological activities. This review presents synthetic routes towards 3-(carboxyphenyl)chromones and evaluation of their biological activity as published in both journal and patent literature. We have focused specifically on the 3-(carboxyphenyl)chromones, because while methods of synthesis and biological activity of 2(3)-substituted and 2,3-disubstituted chromones are well studied, literature data on isoflavones containing a carboxyl, ester, or amide group in ring B is scarce and fragmentary. The presented generalization of synthetic strategies and biological activity of 3-(carboxyphenyl)chromone derivatives demonstrates that this class of compounds can be targeted for discovery of new drugs and can be readily prepared owing to recent advances in synthetic organic and medicinal chemistry |
| doi_str_mv | 10.15407/bioorganica2020.02.003 |
| first_indexed | 2025-07-17T12:19:38Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
UDC 547.814.1
DOI: https://doi.org/10.15407/bioorganica2020.02.003
3
DIGEST PAPER
Features of the synthesis and biological evaluation of
3-(carboxyphenyl)chromones
Olga V. Shablykina, Viktoriia S. Moskvina*, Volodymyr P. Khilya
Taras Shevchenko National University of Kyiv, 60 Volodymyrska St., Kyiv, 01601, Ukraine
Abstract: Flavonoids and their derivatives have historically been a source of therapeutic agents. Every year, more and more data is
published on new flavonoid compounds, both synthetic and isolated from natural sources, and their innumerable physiological and
pharmacological activities. This review presents synthetic routes towards 3-(carboxyphenyl)chromones and evaluation of their biological
activity as published in both journal and patent literature. We have focused specifically on the 3-(carboxyphenyl)chromones, because
while methods of synthesis and biological activity of 2(3)-substituted and 2,3-disubstituted chromones are well studied, literature data on
isoflavones containing a carboxyl, ester, or amide group in ring B is scarce and fragmentary. The presented generalization of synthetic
strategies and biological activity of 3-(carboxyphenyl)chromone derivatives demonstrates that this class of compounds can be targeted for
discovery of new drugs and can be readily prepared owing to recent advances in synthetic organic and medicinal chemistry.
Keywords: chromones; isoflavones; biological activity; synthesis.
Chromones are important structural motifs that serve as
useful templates for а design of novel biologically
important compounds. The majority of research activity in
recent years has been focused on the synthesis of
2(3)-substituted (flavones and isoflavones respectively) and
2,3-disubstituted chromones [1-7]. The synthetic
approaches to chromone-pyrazole-fused compounds [8],
azachromones, and azachromanones [9] have been
summarized. Among numerous currently known isoflavone
derivatives, compounds 1 with a carboxyl group in the
ring B constitute a small group of compounds (Figure 1).
Isoflavones of natural origin, due to peculiarities of their
biogenesis, belong to the category of polyphenols. Аny
substituents in their structure other than hydroxyl, alkoxyl,
and methyl groups are extremely rare [10].
Preparative synthesis of isoflavones mainly focused on
making of natural compounds with biological activity
Received:
Revised:
Accepted:
Published online:
07.09.2020
25.09.2020
28.09.2020
30.12.2020
Corresponding author. Tel.: +380-44-239-3342;
e-mail: v.moskvina@gmail.com (V. S. Moskvina)
ORCID: 0000-0001-5556-9147
as well as the synthesis of analogues and heteroanalogues of
isoflavones – 3-hetarylchromones [11]. Methods to
synthesize derivatives of pharmaceutically active molecules
of 3-(carboxyphenyl)chromones and their synthetic
intermediates have also been reported.
Figure 1. Examples of pharmaceutically active 3-(carboxy-
phenyl)chromones.
© Shablykina O. V. 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.bioorganica.org.ua
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
4
For example, acids 2 are inhibitors of
S-nitrosoglutathione reductase and can be used as
immunomodulators, anti-inflammatory, and anti-asthma
drugs [12]; isoflavone amides of type 3 are antagonists of
the bradykinin B1 receptor [13]; and amides 4 are used to
prevent or cure hyperlipemia, obesity, and type II diabetes
(Figure 1) [14]. Yet, despite the obvious prospect, studies of
synthesis of isoflavones containing a carboxyl, ester, or
amide group in the B-ring have received little attention.
These compounds are usually briefly mentioned in widely
scoped publications and rarely feature as individual study
objects. In addition, studies of the impact of introducing a
highly acidic and reactive carboxyl group or its derivatives,
e.g., various amides, on biological activity and approaches
to constructing the isoflavone system are isolated.
In this brief review, we present a compilation of the
literature data published in the last years, concerning the
synthesis and biological activity of the
3-(carboxyphenyl)chromones. Analysis of the data
demonstrates that although the introduction of a carboxyl
group can complicate the construction of the isoflavone
system, these problems are easily overcome. Therefore, we
hope that this review will help draw attention to such
promising building blocks for medicinal chemistry as
3-(carboxyphenyl)chromones.
Biological activity of 3-(carboxyphenyl)chromones,
their esters and amides
The summary of 3-(carboxyphenyl)chromones biological
activity presented below illustrates that these compounds
can be readily employed as precursors to new drugs with
various pharmacological effects.
A series of acids 2 (Figure 2) was reported to inhibit
S-nitrosoglutathione reductase (GSNOR) [12], which
implied that these compounds were promising
immunomodulators, anti-inflammatory, and anti-asthma
drugs. Similar bioactivity was manifested by corresponding
1-thioisoflavones [15].
Figure 2. 4-(7-Hydroxy-4-oxo-4H-chromen-3-yl)benzoic acids 2
– inhibitors of S-nitrosoglutathione reductase.
A number of functionalized isoflavones, including those
with carboxyl and carboxamide groups in 4'-position, and
their heteroanalogues (at the ring A), featured as possible
agents for the treatment of various kinds of mental disorders
and addictions due to their ability to inhibit aldehyde
dehydrogenase 2 (ALDH-2) [16-17].
Amides 3a,b, produced from acids 5a,b, were
synthesized in the course of amide 6 modification in order
to obtain new antagonists of the bradykinin B1 receptor
(hB1) (Scheme 1) [13].
Despite p-isomer 3b being less effective than its
analogue with the phthalazinone cycle, it was selected as a
promising compound for a more detailed study. It is
interesting to note the significantly higher activity of
p-isomer 3b in comparison with m-isomer 3a. The same
pattern was observed not only for isoflavone derivatives but
also for structurally related phthalazinones.
Scheme 1. Isoflavone amides 3 – antagonists of the bradykinin B1
receptor.
Interestingly, subsequent studies of isoflavone amides
3a,b showed that their inhibitory activity significantly
depends on the presence of substituents in the A-ring of
isoflavone [18]: p-amide 3b with a F or Cl atom introduced
into the 5th position of the chromone ring is quite capable of
competing in terms of activity with the most successful
inhibitor 7 in a series of phthalazinones from a previous
study [13]. Table 1 shows the efficiency of the bradykinin
B1 receptor inhibition by the indicated compounds; as a
numerical parameter, the inhibitory constant (Ki) is used.
Table 1. The efficiency of inhibition of the hB1 receptor.
Compd R1 hB1
Ki (nM)
Compd R1 hB1
Ki (nM)
3aa H 64 ± 11 3ba H 184 ± 32
3ab 5-Cl 29 ± 12 3bb 5-Cl 4 ± 2
3ac 6-Cl 767 ± 225 3bc 6-Cl 1616 ± 498
3ad 6-F 398 ± 44 3bd 7-Cl 42 ± 4
3ae 8-Cl 322 ± 126 3be 8-Cl 481 ± 87
3bf 5-F 17 ± 8
3bg 5-Me 15 ± 2
A variety of amides 4 of 7-hydroxy-isoflavone
4'-carboxylic acid was presented in a patent development
[14] as medicines for preventing or curing hyperlipemia,
obesity, or type II diabetes (Figure 3).
O. V. Shablykina, V. S. Moskvina, V. P. Khilya
5
Figure 3. Isoflavone amides 4 – products for the treatment of
hyperlipemia, obesity, and type II diabetes.
Of the four synthesized amides (Figure 4), the amide 8d
exhibited transactivation activity and induced the
expression of farnesoid X receptor (FXR). The latter is
known to regulate a series of target genes, including short
heterodimer partner (SHP), bile salt export pump (BSEP)
and sterol regulatory element-binding protein 1c
(SREBP-1c).
Although the effect of 8d in modulating FXR gene
expression was less pronounced than that of GW4064 –
synthetic FXR agonist, 8d showed less toxicity in HepG2
cells. Overall, results obtained by the authors indicated that
8d could act as a promising lead compound for the design
of novel FXR modulators against dyslipidemia [19].
Moreover, amidation turned out to be a necessary condition
for the high level of biological activity as the acid itself and
its ester demonstrated much more modest performance.
Functionalized isoflavones similar to the depicted ones have
been patented for preventing or treating hyperlipidemia,
type II diabetes, atherosclerosis, and non-alcoholic fatty
hepatitis [20].
Figure 4. Isoflavone amides 8 – FXR modulators against
dyslipidemia.
Figure 5. Series of isoflavones 9 – a new class of apoptosis
inhibitors.
A large array of isoflavones modified with functional
groups, as well as additional aromatic and heterocyclic
fragments, were announced to be a new class of apoptosis
inhibitors [21]. Compounds with carboxyl and carboxamide
groups are represented mainly by structures 9 (Figure 5);
several structures with a carboxyl group at the 3'-position of
the isoflavone are shown.
Pyranoisoflavones were shown to function as
butyrylcholinesterase inhibitor and can therefore be used in
the treatment of Alzheimer's disease [22]; one of the studied
derivatives was compound 10 with an ester group, the
publication focused more on carbamate derivatives of
hydroxyisoflavones, in particular, compound 11 – one of
the most active substances (Figure 6).
The site docking data given in this work is interesting.
Calculations showed that multiple ways of binding
pyranoisoflavones to the active site of the enzyme exist
depending on the nature and location of the substituents. In
one of them, the carbonyl fragment of the chromone ring
and π-interaction with the isoflavone ring B plays an
important role, which is another argument in favor of the
pharmacophoric potential of the isoflavone system. It
should also be noted that the removal of the annelated pyran
ring led to a noticeable drop in isoflavone activity, while the
variation of substituents in ring B was not critical. This
confirms the assumption that the B ring substituents can be
easily varied (in particular, by obtaining amides of the
carboxyl group) in order to introduce required
physicochemical properties into a compound, while at the
same time preserving the active action of the heterocyclic
system itself.
Figure 6. Pyranoisoflavones as butyrylcholinesterase inhibitor.
The inhibition activities are expressed as IC50 (μM) or as a
percentage of inhibition at 10 μM, and the IC50 values are the
mean of three independent experiments ± SEM; SI represents
selectivity index which is determined as ratio AChE IC50 / BChE
IC50; AChE – Acetylcholinesterase, BChE – butyrylcholinesterase.
Biological activity of 3-(carboxyphenyl)chromone
derivatives
Approaches to obtaining biologically active substances
from isoflavones can be based not only on the modification
of functional groups but also on the recyclization of the
labile pyrone fragment. For example, article [23] proposed
pyrazoles 13 as an alternative to substance H23 – a
previously known inhibitor of glycogen synthase. The
pyrazoles 13, including a compound with an ester group in
the ring B (R1 = ОН, R2 = Me, R3 = 4-CO2Me, Scheme 2),
were obtained via recyclization of 2-substituted (R1 = Н,
Me, CF3) isoflavones 12. The p-hydroxy derivative 13a
exhibited the highest activity (Scheme 2, inhibitory IC50
values against human glycogen synthase GS 1 (hGYS1)).
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
6
Scheme 2. Isoflavones 12 – precursor inhibitors of glycogen
synthase.
Saturated analogs of isoflavones with carboxyl,
carboxamide, and ester groups are also mentioned among
biologically active substances. Isoflavans 14, in particular,
were investigated as compounds that exhibited valuable
pharmacological properties, especially for the treatment of
vascular diseases (Figure 7) [24].
Figure 7. Isoflavans 14 – products for the treatment of vascular
diseases.
It was also discovered that the antineoplastic activity on
human malignant cell lines and antileishmanial activity on
Leishmania amazonensis [25] is inherent in quinoid
pterocarpans, including substance 15 with an ester group
(Table 2).
Table 2. Comparison of antileishmanial activity of
compound 15 and pentamidine (P*) on promastigote and
amastigote forms of L. amazonensis and toxicity for M J774
cells (IC50 in µM).
15 P*
Promastigote 2.8 2.2
Amastigote 0.5 1.5
MJ774 22.5 70
M J774/amastigote 45 46
Synthesis of 3-(carboxyphenyl)chromones, their esters
and amides
The most obvious "classical" solution to the problem of
obtaining isoflavones with a carboxyl group in ring B is the
Houben-Hoesch reaction using (carboxyphenyl)acetonitriles
as key reagents, followed by formylation and ring-closure
of the chromone system. However, the reactivity of phenyl-
acetonitriles with a carboxyl function is questionable and,
when ester protection of the carboxyl group is used, the
ester fragment stability in both reaction and subsequent
isolation conditions is of concern. Paper [26] described the
preparation of 2-hydroxyphenylbenzyl ketones 18a,b (and
their analogues with alkoxy, CF3, and CO2Et groups) via the
classical Houben-Hoesch reaction. Substituted phenols 16
and 3-(carboxyphenyl)acetonitrile (17) reacted under the
action of ZnCl2 in Et2O, and underwent subsequent ring-
closure into the corresponding isoflavones 19a,b according
to the method described by Bass – with BF3·Et2O followed
by formylation with MeSO2Cl-DMF reagent (Scheme 3)
[27].
Scheme 3. Synthesis of 3-(carboxyphenyl)chromones 19a,b.
In two cases when Houben-Hoesch reaction of ethyl
3-(cyanomethyl) benzoate with 2,6-dihydroxytoluene or
1,2,3-trihydroxybenzene was used, the isolation of reaction
products was accompanied by partial hydrolysis and the
formation of a mixture of ester and acid 18. Isolation and
purification of the main product were based on the acid’s
solubility in the aqueous solution of NaHCO3. The main
product was the ester 18а in the first case and the acid 18b
in the second. During formylation and heterocyclization,
despite treating the reaction mixture with water at a certain
stage of the process, hydrolysis of the ester group of
derivative 19a did not occur.
Notably, the conversion of deoxybenzoin to isoflavone is
accompanied by partial or complete acylation of free OH-
groups, and subsequent addition of water is necessary to
remove the acyl residue from the hydroxyl group.
Therefore, it can be assumed that the hydrolytic stability of
the ester group in ring B is significantly higher; several
similar examples are given later in the review.
O. V. Shablykina, V. S. Moskvina, V. P. Khilya
7
Scheme 4. Synthesis of isoflavans 24.
The previously mentioned bioactive isoflavans 14
(Figure 7) were synthesized by a catalytic reduction of
corresponding isoflavones [24]. The latter, in turn, were
obtained via the Houben-Hoesch reaction which was carried
out at a rather low temperature. This significantly increased
the reaction time but was obviously justified, because the
authors successfully obtained a wide series of
polyfunctional compounds, including those with a free
carboxyl group. The synthetic sequence to these carboxy
derivatives is shown in Scheme 4 (on the example of
compounds 24 synthesis).
Using a corresponding arylacetic acid 26 instead of a
nitrile in the Houben-Hoesch reaction allows to avoid the
hydrolysis of the imine fragment and to treat the reaction
mixture in milder conditions, which reduces the likelihood
of hydrolysis of functional groups present in the main
fragment (including ester). If the target product is an
isoflavone with a free carboxyl group, the hydrolysis of the
ester fragment is expediently carried out after the ring-
closure of the pyrone ring. Such sequence of reactions was
proposed by the authors of [12], devoted to the synthesis of
a large array of bioactive isoflavones with a 4'-carboxyl
group, shown in Figure 2. Scheme 5 shows the synthesis of
a key compound – methyl 4-(2-(2,4-dihydroxyphenyl)-2-
oxoethyl)benzoate (27).
Scheme 5. Synthesis of methyl 4-(2-(2,4-dihydroxyphenyl)-2-
oxoethyl)benzoate (27).
As an alternative to the Houben-Hoesch reaction
between (ethoxycarbonylphenyl)acetic acid 29 and
1,3-dimethoxybenzene 28 in BF3·Et2O medium, the authors
of [12] studied in detail the Friedel-Crafts acylation of 28
with (ethoxycarbonylphenyl)acetic acid chlorides in the
presence of AlCl3 with subsequent removal of methyl
groups of ВBr3. This approach provided higher yields of the
target product 31 in comparison to the Houben-Hoesch
reaction (Scheme 6).
Scheme 6. Synthesis of ethyl 4-(2-(2,4-dihydroxyphenyl)-2-
oxoethyl)benzoate (31).
Additionally, two approaches have been successfully
used to introduce a carboxyl group in the p-position of
phenylacetic acid: the Friedel-Crafts acetylation of
phenylacetic acid 32 with subsequent oxidation of the acetyl
fragment in the iodoform reaction (Scheme 7а;
unfortunately, the total yield of product 37 for four stages
was minuscule); or the catalyzed carbonylation of
p-bromophenylacetic acid 33 with yields of target product
38 of 76% (Scheme 7b).
Scheme 7. Synthesis of (ethoxycarbonylphenyl)acetic acid 37 and
(methoxycarbonylphenyl)acetic acid 38.
This study is also noteworthy for its use of anhydrides
and chloroanhydrides of various carboxylic acids (aliphatic,
aromatic, and heteroaromatic, as well as alkoxy and
fluorine-substituted) in the cyclization of deoxybenzoins 39
– the products of the Houben-Hoesch reaction. This allowed
to obtain isoflavones 40 with various substituents at
position 2 of the chromone ring (the list of substituents
R1-R3 is given in Figure 2 above). Depending on the activity
of reagents, the cyclization of deoxybenzoins 39 to flavones
40 took place either with an equivalent amount of Et3N at
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
8
room temperature in a dichloromethane solution or under
reflux (Scheme 8). Of course, acylation of the additional
hydroxyl group occurred simultaneously with the
cyclization. Two methods were also developed for the
hydrolysis of the O-acyl fragment: heating products 40 in
an acidic medium, or treating with LiOH at room
temperature, resulting in the formation of corresponding
acids 2 with yields of up to 94%.
Scheme 8. Synthesis of 4-(7-hydroxy-4-oxo-4H-chromen-3-
yl)benzoic acids 2.
Tang et al. demonstrated that the conditions of the
Houben-Hoesch reaction should be varied depending on the
activity of arylacetic acids or nitriles [23]. Various reagents
were used to conduct the cyclization of the chromone ring,
allowing for variation of the substituent at position 2 of the
system. The data on the synthesis of a derivative with an
ester group – compound 44 – is presented in Scheme 9.
Scheme 9. Synthesis of isoflavone 44 – a precursor of inhibitors of
glycogen synthase.
7-Alkoxyisoflavone 4'-carboxylic acid, subsequently
converted into various amides 4 (see the list in Figure 3),
was synthesized using the Houben-Hoesch reaction as well
[14]; the synthesis of 2-(4-(methoxycarbonyl)phenyl)acetic
acid required for the reaction was carried out using an
approach similar to that shown in Scheme 7a. The authors
did not reported a hydrolysis of the ester group neither
during the Houben-Hoesch reaction nor during the isolation
and subsequent cyclization to isoflavone (Scheme 10).
BF3
.
Et2O, DMF
MeSO2Cl,
95 °C, 2 h
O
O
CO2Me
HO
(58% for 2 steps)
conc. HCl,
1,4-dioxane
105 °C, 4h CO2H
O
O
H
N
O
O
R2
R1
4
27
46
Scheme 10. Synthesis of isoflavone amides 4 – products for the
treatment of hyperlipemia, obesity, or type II diabetes.
Isoflavone amides with an isoxazole moiety –
compounds 8 – were synthesized in a similar manner; slight
differences were related to the temperature regime of the
Houben-Hoesch reaction, the conditions of hydrolysis of the
ester, and the formation of the amide bond (Scheme 11)
[19-20].
Scheme 11. Synthesis of isoflavone amides 8 – FXR modulators
against dyslipidemia.
Another promising modern method for producing
isoflavones is the catalytic arylation of 3-halogeno-
chromones. One of the undoubted advantages of this
approach is the possibility of using reagents with fragments
that are unstable under the conditions of "classical"
schemes. Using this method, tert-butyl esters 51a of the
acids mentioned above (Scheme 1) were obtained by the
Suzuki-Miyaura reaction [13]. It should be noted that the
ester fragment remained intact, despite the rather high
reaction temperature (Scheme 12).
Scheme 12. Synthesis of isoflavones 51a,b – precursors for
antagonists of the bradykinin B1 receptor.
O. V. Shablykina, V. S. Moskvina, V. P. Khilya
9
Bioactive isoflavones 3a,b with amide group (see
Table 1 above for a list of substituents) can be easily
synthesized from methyl esters 51b (Scheme 13), as was
done in [18].
Scheme 13. Synthesis of amides 3a,b – antagonists of the
bradykinin B1 receptor.
In the preparation of pyranoisoflavones, the pyran ring
was first annealed to 7-hydroxy-3-iodochromone 58, and
only then was it combined with boronic acids [22]. At the
coupling stage, standard conditions were used – palladium
catalyst with triphenylphosphine ligands, aqueous organic
medium, sodium carbonate as a base. In this way, an
extensive list of 3-substituted pyranoisoflavones was
synthesized, mainly with hydroxy and alkoxy groups in the
B ring, as well as some 3-pyridylisoflavones. The yield of
compound 61 with the ester group is shown in Scheme 14.
Scheme 14. Synthesis of pyranoisoflavone 61.
The literature contains plenty of examples of the Suzuki
reaction’s preparative possibilities for the synthesis of
isoflavones that are functionalized, among other things,
with a carboxyl group. In fact, the main difficulties in this
method are associated not so much with the implementation
of the combination itself, but with the synthesis of the
starting 3-halochromones.
For example, the authors of [28] carried out coupling of
3-iodochromone 69 and arylboronic acid 70 with a free
carboxyl group with a yield of 75%, but the synthesis of the
starting 3-iodochromone 69 from 3,4,5-trimethoxyphenol
62 required 6 stages (Scheme 15).
Scheme 15. Synthesis of isoflavone 71 via coupling of
3-iodochromone 69 and arylboronic acid 70.
In the same manner, the same group obtained isoflavone-
3'(4')-carboxylic acids with alkyl substituents at positions 2
and 8 and hydroxy groups at positions 5-7, which were used
for the synthesis of a large group of amides – potential
inhibitors of Bcl-2 (Figure 5) [21].
A more recent approach to catalytic heterocyclization of
various systems (2H-benzo-[e][1,2]-thiazine 1,1-dioxides
(benzosultams), benzoselenophenes, benzothiophenes,
4H-chromen-4-ones (flavones), 3H-indoles, 1H-isochro-
men-1-ones (isocoumarins), and 4H-thiochromen-4-ones
(thioflavones)) was a photopromoted gold-catalyzed
arylative heterocyclization of alkynes [29]. This method
was tolerant towards many functional groups, including
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
10
esters functional groups, and the yield of corresponding
3-aryl-2-phenylchromone 75 with a 4-CO2Et substituent did
not differ significantly from the yield of Cl-, Br-,
CF3-derivatives (Scheme 16). Unfortunately, this technique
has so far been developed only for 2,3-diarylchromones,
and attempts to obtain 2-unsubstituted isoflavones by
introducing silyl derivatives into the reaction have not been
successful.
Scheme 16. Synthesis of 3-aryl-2-phenylchromone 75.
Unusual polycyclic structures – condensed benzo--
pyrones – were obtained by a domino reaction between
3-acetyl-2-methylchromone 77 and various 3-(2-R-vinyl)-
chromones (R = EWG) 78 [30]. In this specific method of
constructing isoflavones 79, the diene fragment of
3-vinylchromone 78 and the acetal group of acethyl-
chromone 77 participated in the formation of the benzene
ring (Scheme 17).
Scheme 17. Synthesis of isoflavone 79 via domino reaction.
The patent [24] mentioned the possibility of obtaining
4'-carboxyisoflavone 81 by the hydrolysis of the
corresponding nitrile in an acidic medium (Scheme 18).
Scheme 18. Synthesis of isoflavone 81.
Synthesis of 3-(carboxyphenyl)chromone derivatives
Compound 84 – isoflavanone with an ester group – was
obtained by the catalytic arylation of the α-position of
chromanone [31]; the high enantioselectivity of this
reaction is remarkable (Scheme 19).
Scheme 19. Synthesis of isoflavanone 84.
As it was mentioned earlier (Figure 7), the adducts that
were obtained during a palladium-catalyzed oxyarylation of
the multiple bonds of chromanes contained the structural
fragment of isoflavane [25, 32-33]. Although such
pterocarpans maintain interest as biologically active
substances [25], the synthetic method was not very effective
because the reaction yield never reached above 65% even
under microwave irradiation for 40 min.
Nevertheless, the ability to use of a wide variety of
substituents, as well as the successful use of electron-
deficient quinone 87, are worth mentioning as the reaction’s
advantages. Not only compounds with ester groups but their
analogues with chloro-, nitro- and methoxy- groups were
obtained as well (Scheme 20) [33]. The latter reaction led to
the formation of biologically active derivatives (Figure 7).
The quinone cyclic system also was obtained by the
oxidation of dimethoxy derivatives [25].
Scheme 20. Synthesis of pterocarpans 15, 89-90.
The carboxylation of the heterocyclic system itself as a
method for modifying an isoflavonoid with a carboxyl
group was carried out only for pterocarpans [34]. The
bromination of the (+)-medicarpin 91 under free-radical
O. V. Shablykina, V. S. Moskvina, V. P. Khilya
11
conditions with NBS (N-bromosuccinimide) in methyl
acetate led to the formation of the 8-bromoderivative 92
(Scheme 21). The protected 8-bromo derivative 92
was treated with butyllithium and TMEDA
(N,N,N',N'-tetramethylethylenediamine) at low temperature
(-110 °C) followed by quenching of the lithio derivative
with ethyl chloroformate to give the ethyl ester 93. This
approach, however, is not applicable to isoflavones.
Scheme 21. Synthesis of pterocarpan 93.
Conclusions
The literature data reveals numerous practical applica-
tions for 3-(carboxyphenyl)chromones and their derivatives.
A carboxyl group modifications were the main synthetic
routs to chromones’ derivatives. Although the number of
compounds of this class is still relatively small, most of
them appeared in many biological studies where they
demonstrated a fairly high level of biological activity. The
existing data allows us to consider 3-(carboxyphenyl)-
chromones as synthetically available compounds. In some
cases the presence of the carboxyl group in the molecules
necessitated adjustments to the "classical" synthetic
protocols. Most of these derivatives were obtained using
popular approaches in the synthesis of isoflavones – the
Houben-Hoesch reaction or catalytic arylation of
3-halogenochromones. It should be noted that the number
of publications on this topic has been steadily increasing
since 2000. Moreover, the reports on the preparative
synthesis of new 3-(carboxyphenyl)chromones facilitated
studies of their biological activity, which undoubtedly will
significantly improve the prospects of creating new drugs
and other practically useful substances based on this class
of compounds.
Notes
Acknowledgments and finances. The work was funded
by the Ministry of Education and Science of Ukraine (Grant
No. 19БФ037-03).
The authors declare no conflict of interest.
Author contributions. The manuscript was written
through the contributions of all authors. All authors have
given approval to the final version of the manuscript.
References
1. Edwards, A. M.; Howell, J. B. L. The chromones: history, chemistry
and clinical development. A tribute to the work of Dr R. E. C.
Altounyan. Clin Exp Allergy. Clin. Exp. Allergy 2000, 30, 756-774.
2. Wilk, W.; Waldmann, H.; Kaiser, M. Gamma-pyrone natural
products - a privileged compound class provided by nature. Bioorg.
Med. Chem. 2009, 17, 2304-2309.
3. Khadem, S.; Marles, R. J. Chromone and Flavonoid Alkaloids:
Occurrence and Bioactivity. Molecules 2012, 17, 191-206.
4. Silva, C. F. M.; Batista, V. F.; Pinto, D. C. G. A.; Silva, A. M. S.
Challenges with chromone as a privileged scaffold in drug discovery.
Exp. Opinion Drug Disc. 2018, 13, 795-798.
5. Reis, J.; Gaspar, A.; Milhazes, N.; Borges, F. Chromone as a
Privileged Scaffold in Drug Discovery: Recent Advances. J. Med.
Chem. 2017, 60, 7941-7957.
6. Gaspar, A.; Matos, M. J.; Garrido, J.; Uriarte, Eu.; Borges, F.
Cromone: A Valid Scaffold in Medicinal Chemistry. Chem. Rev.
2014, 114, 4960-4992.
7. Keri, R. S.; Budagumpi, S.; Pai, R. K.; Balakrishna, R. G.
Chromones as a privileged scaffold in drug discovery: a review.Eur.
J. Med. Chem. 2014, 78, 340-374.
8. Santos, C. M. M.; Silva, V. L. M.; Silva, A. M. S. Synthesis of
Chromone-Related Pyrazole Compounds. Molecules 2017, 22, 1665-
1711.
9. Malets, Y. S.; Moskvina, V. S.; Grygorenko, O. O.; Brovarets, V. S.
Synthesis of azachromones and azachromanones. Chem. Heterocycl.
Comp. 2019, 55, 1007-1012.
10. Dictionary of Flavonoids, Buckingham, J.; Munasinghe, V. R. N.,
Eds., CRC Press, Taylor & Francis Group: Boca Raton, FL, USA,
2015.
11. Flavonoids. Chemistry, Biochemistry and Applications;
Andersen, Ø. M.; Markham, K. R., Eds., CRC Press, Taylor &
Francis Group: Boca Raton, FL, USA, 2005.
12. WO Patent No WO2011/099978 A1. Chromone inhibitors of S-
nitrosoglutathione reductase / Sun, X.; Qiu, J.; Wasley, J. Patent appl.
No PCT/US2010/024035 12.02.2010. Publ. 18.08.2011.
13. Biswas, K.; Peterkin, T. A. N.; Bryan, M. C.; Arik, L.; Lehto, S. G.;
Sun, H.; Hsieh, F. Y.; Xu, C.; Fremeau, R. T.; Allen, J. R. Discovery
of Potent, Orally Bioavailable Phthalazinone Bradykinin B1
Receptor Antagonists. J. Med. Chem. 2011, 54, 7232-7246.
14. CN Patent No CN105541777 A. Isoflavone amide type derivative,
preparation method and medical application thereof / Xiang, H.;
Xu, P.; Wang, W.; Qian, Z.; Chen, M.; You, Q. Patent appl. No
CN201610064415.4A 29.01.2016. Publ. 04.05.2016 (in Chinese).
15. WO Patent No WO2011/100433 A1. Novel S-nitrosoglutathione
reductase inhibitors / Sun, X.; Qiu, J. Patent appl. No
PCT/US2011/024353 10.02.2011. Publ. 18.08.2011.
16. US Patent No 2009/0124672 A1. Aldh-2 inhibitors in the treatment
of psychiatric disorders / Diamond, I.; Overstreet, D. Patent appl. No
12/266288 06.11.2008. Publ. 14.05.2009.
17. WO Patent No WO2009/094028 A1. Aldh-2 inhibitors in the
treatment of addiction / Bilokin, Y.; Elzein, E.; Zablocki, J.; Organ,
M.; Perry, T.; Kobayashi, T.; Abelman, M.; Kalla, R.; Fan, P.;
Diamond, I.; Jiang, R.; Arolfo, M. P.; Li, X.; Yao, L.; Jiang, Z.;
Keung, W. M.; Tao, G. Patent appl. No PCT/US2008/051862
24.01.2008. Publ. 30.07.2009.
18. Bryan, M. C.; Biswas, K.; Peterkin, T. A. N.; Rzasa, R. M.; Arik, L.;
Lehto, S. G.; Sun, H.; Hsieh, F. Y.; Xu, C.; Fremeau, R. T.;
Allen, J. R. Chromenones as potent bradykinin B1 antagonists.
Bioorg. Med. Chem. Lett. 2012, 22, 619-622.
19. Qiu, R.; Luo, G.; Cai, X.; Liu, L.; Chen, M.; Chen, D.; You, Q.;
Xiang, H. Structure-guided design and synthesis of isoflavone
analogs of GW4064 with potent lipid accumulation inhibitory
activities. Bioorg. Med. Chem. Lett. 2018, 28, 3726-3730.
20. CN Patent No CN108264506 A. Novel isoflavone derivative,
preparation method and medical usage / Chen, D.; Chen, M.; Hu, W.;
Li, H.; Liu, M.; Qiu, R.; Tao, R.; Xiang, H.; Yang, Q.; You, Q.;
Zhang, J.; Zheng, F. Patent appl. No CN201810061682.5A
17.01.2018. Publ. 10.07.2018 (in Chinese).
21. WO Patent No WO2006/099193 A2. Chromen-4-one inhibitors of
anti-apoptotic bcl-2 family members and the uses thereof / Wang, S.;
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
12
Ding, K.; Tang, G.; Wang, R.; Yang, C. Y.; Nikolovska-Coleska, Z.
Patent appl. No PCT/US2006/008690 13.03.2006. Publ. 11.01.2007.
22. Wu, C.; Tu, Y. B.; Li, Z.; Li, Y. F. Highly selective carbamate-based
butyrylcholinesterase inhibitors derived from a naturally occurring
pyranoisoflavone. Bioorg. Chem. 2019, 88, 102949.
23. Tang, B.; Frasinyuk, M. S.; Chikwana, V. M.; Mahalingan, K. K.;
Morgan, C. A.; Segvich, D. M.; Bondarenko, S. P.; Mrug, G. P.;
Wyrebek, P.; Watt, D. S.; DePaoli-Roach, A. A.; Roach, P. J.;
Hurley, T. D. Discovery and Development of Small-Molecule
Inhibitors of Glycogen Synthase. J. Med. Chem. 2020, 63, 3538-
3551.
24. US Patent No 4814346 A. Benzopyrans and use thereof in treating
vascular diseases / Albert, A. I.; Zilliken. Patent appl. No 116737
04.11.1987. Publ. 21.03.1989.
25. Buarque, C. D.; Militão, G. C. G.; Lima, D. J. B.; Costa-Lotufo, L.
V.; Pessoa, C.; De Moraes, M. O.; Cunha-Junior, E. F.; Torres-
Santos, E. C.; Netto, C. D.; Costa, P. R. R. Pterocarpanquinones, aza-
pterocarpanquinone and derivatives: synthesis, antineoplasic activity
on human malignant cell lines and antileishmanial activity on
Leishmania amazonensis. Bioorg. Med. Chem. 2011, 19, 6885-6891.
26. Sepulveda-Boza, S.; Walizei, G. H.; Rezende, M. C.; Vasquez, Y.;
Mascayano, C.; Mejıas, L. The preparation of new isoflavones.
Synth. Commun. 2001, 31, 1933-1940.
27. Bass, R. J. Synthesis of chromones by cyclization of
2-hydroxyphenyl ketones with boron trifluoride-diethyl ether and
methanesulphonyl chloride. J. Chem. Soc., Chem. Commun. 1976,
78-79.
28. Ding, K.; Wang, S. Efficient synthesis of isoflavone analogues via a
Suzuki coupling reaction. Tetrahedron Lett. 2005, 46, 3707-3709.
29. Alcaide, B.; Almendros, P.; Busto, E.; Herrera, F.; Lázaro-Milla, C.;
Luna, A. Photopromoted Entry to Benzothiophenes,
Benzoselenophenes, 3H‐Indoles, Isocoumarins, Benzosultams, and
(Thio)flavones by Gold‐Catalyzed Arylative Heterocyclization of
Alkynes. Adv. Synth. Catal. 2017, 359, 2640-2652.
30. Gong, J.; Xie, F.; Ren, W.; Chen, H.; Hu, Y. Domino reactions of 2-
methyl chromones containing an electron withdrawing group with
chromone-fused dienes. Org. Biomol. Chem. 2012, 10, 486-489.
31. Huang, Z.; Lim, L. H.; Chen, Z.; Li, Y.; Zhou, F.; Su, H.; Zhou, J. S.
Arene CH-O hydrogen bonding: a stereocontrolling tool in
palladium-catalyzed arylation and vinylation of ketones. Angew.
Chem. Int. Ed. 2013, 52, 4906-4911.
32. Buarque, C. D.; Pinho, V. D.; Vaz, B. G.; Eberlin, M. N.; Da Silva,
A. J. M.; Costa, P. R. R. Palladium-catalyzed oxyarylation of olefins
using silver carbonate as the base. Probing the mechanism by
electrospray ionization mass spectrometry. J. Organomet. Chem.
2010, 695, 2062-2067.
33. Leão, R. A. C.; Pinho, V. D.; Coelho, A. S.; Buarque, C. D.; Moraes,
P. F.; Alonso, D. A.; Nájera, C.; Costa, P. R. R. Micro-
wave‐Promoted Palladium‐Catalysed Oxyarylation of
Dihydronaphthalene and Chromenes by o‐Iodophenols and Its
Acetates. Eur. J. Org. Chem. 2011, 2011, 3313-3316.
34. Ferreira, J. A.; Nel, J. W.; Brandt, E. V.; Bezuidenhoudt, B. C. B.;
Ferreira, D. Oligomeric isoflavonoids. Part 3. Daljanelins A-D, the
first pterocarpan- and isoflavanoid-neoflavonoid analogues. J. Chem.
Soc., Perkin Trans. 1 1995, 33, 1049-1056.
Особливості синтезу та біологічної активності 3-(карбоксифеніл)хромонів
О. В. Шабликіна, В. С. Москвіна*, В. П. Хиля
Київський національний університет імені Тараса Шевченка, вул. Володимирська, 60, Київ, 01601, Україна
Резюме: Флавоноїди та їх похідні історично були джерелами терапевтичних засобів. З кожним роком публікується все більше даних про нові
флавоноїдні сполуки (як виділені з природних джерел, так і синтезовані) та їх різноманітну фізіологічну та фармакологічну активність. У цьому
огляді представлена інформація щодо синтезу 3-(карбоксифеніл)хромонів та їх біологічної активності, опублікована як у періодичних виданнях,
так і в патентній літературі. Наш інтерес до 3-(карбоксифеніл)хромонів, було викликано насамперед тим, що є багато літературних даних про
методи синтезу та біологічну активність 2(3)-заміщених та 2,3-дизаміщених хромонів, але дані про ізофлавони, що містять карбоксильну, естерну
або амідну групу в кільці В обмежені та фрагментарні. Тим не менше, інтенсивність роботи над цією темою в 2000 рр. почала зростати, в першу
чергу, завдяки виявленню цікавих біологічних властивостей карбоксиізофлавонів та їх похідних; і це, в свою чергу активізувало розробки
оригінальних методів синтезу таких сполук. Представлений огляд літератури дозволяє вважати 3-(карбоксифеніл)хромони та їх похідні
синтетично доступними сполуками, хоча в деяких випадках присутність карбоксильної групи в субстраті вимагає певних удосконалень
"класичних" методів. Більшість із представлених у огляді 3-(карбоксифеніл)хромонів були отримані з використанням підходів, популярних у
синтезі ізофлавонів – реакції Губена-Хеша з наступною циклізацією або каталітичного арилювання 3-галогенохромонів. Структура
3-(карбоксифеніл)хромону має також багато можливостей для модифікації, зокрема: синтез амідів за карбоксильною функцією, анелювання
додаткових гетероциклічних фрагментів, одержання частково насичених за кільцем С похідних та продуктів рециклізації хромонової системи.
Перелічені перетворення були реалізовані на практиці і привели до створення нових біологічно активних сполук, що беззаперечно підтверджує
потенціал подальшого розвитку хімії 3-(карбоксифеніл)хромонів.
Ключові слова: хромони; ізофлавони; біологічна активність; синтез.
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| id | oai:ojs2.bioorganica.com.ua:article-35 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:00:50Z |
| publishDate | 2020 |
| 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/06/0cfead9b84782776dbeceb8a2c52e606.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-352026-07-19T14:56:53Z Features of the synthesis and biological evaluation of 3-(carboxyphenyl)chromones Особливості синтезу та біологічної активності 3-(карбоксифеніл)хромонів Shablykina, Olga V. Moskvina, Viktoriia S. Khilya, Volodymyr P. chromones isoflavones biological activity synthesis хромони ізофлавони біологічна активність синтез Flavonoids and their derivatives have historically been a source of therapeutic agents. Every year, more and more data is published on new flavonoid compounds, both synthetic and isolated from natural sources, and their innumerable physiological and pharmacological activities. This review presents synthetic routes towards 3-(carboxyphenyl)chromones and evaluation of their biological activity as published in both journal and patent literature. We have focused specifically on the 3-(carboxyphenyl)chromones, because while methods of synthesis and biological activity of 2(3)-substituted and 2,3-disubstituted chromones are well studied, literature data on isoflavones containing a carboxyl, ester, or amide group in ring B is scarce and fragmentary. The presented generalization of synthetic strategies and biological activity of 3-(carboxyphenyl)chromone derivatives demonstrates that this class of compounds can be targeted for discovery of new drugs and can be readily prepared owing to recent advances in synthetic organic and medicinal chemistry Флавоноїди та їх похідні історично були джерелами терапевтичних засобів. З кожним роком публікується все більше даних про нові флавоноїдні сполуки (як виділені з природних джерел, так і синтезовані) та їх різноманітну фізіологічну та фармакологічну активність. У цьому огляді представлена інформація щодо синтезу 3-(карбоксифеніл)хромонів та їх біологічної активності, опублікована як у періодичних виданнях, так і в патентній літературі. Наш інтерес до 3-(карбоксифеніл)хромонів, було викликано насамперед тим, що є багато літературних даних про методи синтезу та біологічну активність 2(3)-заміщених та 2,3-дизаміщених хромонів, але дані про ізофлавони, що містять карбоксильну, естерну або амідну групу в кільці В обмежені та фрагментарні. Тим не менше, інтенсивність роботи над цією темою в 2000 рр. почала зростати, в першу чергу, завдяки виявленню цікавих біологічних властивостей карбоксиізофлавонів та їх похідних; і це, в свою чергу активізувало розробки оригінальних методів синтезу таких сполук. Представлений огляд літератури дозволяє вважати 3-(карбоксифеніл)хромони та їх похідні синтетично доступними сполуками, хоча в деяких випадках присутність карбоксильної групи в субстраті вимагає певних удосконалень "класичних" методів. Більшість із представлених у огляді 3-(карбоксифеніл)хромонів були отримані з використанням підходів, популярних у синтезі ізофлавонів – реакції Губена-Хеша з наступною циклізацією або каталітичного арилювання 3-галогенохромонів. Структура 3-(карбоксифеніл)хромону має також багато можливостей для модифікації, зокрема: синтез амідів за карбоксильною функцією, анелювання додаткових гетероциклічних фрагментів, одержання частково насичених за кільцем С похідних та продуктів рециклізації хромонової системи. Перелічені перетворення були реалізовані на практиці і привели до створення нових біологічно активних сполук, що беззаперечно підтверджує потенціал подальшого розвитку хімії 3-(карбоксифеніл)хромонів V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2020-12-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/35 10.15407/bioorganica2020.02.003 Ukrainica Bioorganica Acta; Vol. 15 No. 2 (2020): Ukrainica Bioorganica Acta; 3-12 Ukrainica Bioorganica Acta; Том 15 № 2 (2020): Ukrainica Bioorganica Acta; 3-12 1814-9766 1814-9758 10.15407/bioorganica2020.02 en https://bioorganica.com.ua/index.php/journal/article/view/35/33 Copyright (c) 2020 Olga V. Shablykina, Viktoriia S. Moskvina, Volodymyr P. Khilya https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | хромони ізофлавони біологічна активність синтез Shablykina, Olga V. Moskvina, Viktoriia S. Khilya, Volodymyr P. Особливості синтезу та біологічної активності 3-(карбоксифеніл)хромонів |
| title | Особливості синтезу та біологічної активності 3-(карбоксифеніл)хромонів |
| title_alt | Features of the synthesis and biological evaluation of 3-(carboxyphenyl)chromones |
| title_full | Особливості синтезу та біологічної активності 3-(карбоксифеніл)хромонів |
| title_fullStr | Особливості синтезу та біологічної активності 3-(карбоксифеніл)хромонів |
| title_full_unstemmed | Особливості синтезу та біологічної активності 3-(карбоксифеніл)хромонів |
| title_short | Особливості синтезу та біологічної активності 3-(карбоксифеніл)хромонів |
| title_sort | особливості синтезу та біологічної активності 3-(карбоксифеніл)хромонів |
| topic | хромони ізофлавони біологічна активність синтез |
| topic_facet | chromones isoflavones biological activity synthesis хромони ізофлавони біологічна активність синтез |
| url | https://bioorganica.com.ua/index.php/journal/article/view/35 |
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