Біологічно активні каліксаренфосфонові кислоти
Phosphorylated derivatives of organic compounds are known to be capable of inhibiting the activities of enzymes and other proteins responsible for key metabolic pathways. In this connection, the calixarene phosphonic acids are of interest as macrocyclic agents interacting with targets that may be in...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2022
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Ukrainica Bioorganica Acta| _version_ | 1871193563607334912 |
|---|---|
| author | Kobzar, Oleksandr L. Cherenok, Sergiy O. Kosterin, Sergiy O. Kalchenko, Vitaly I. Vovk, Andriy I. |
| author_facet | Kobzar, Oleksandr L. Cherenok, Sergiy O. Kosterin, Sergiy O. Kalchenko, Vitaly I. Vovk, Andriy I. |
| author_institution_txt_mv | [
{
"author": "Oleksandr L. Kobzar",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Sergiy O. Cherenok",
"institution": "Institute of Organic Chemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Sergiy O. Kosterin",
"institution": "Palladin Institute of Biochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Vitaly I. Kalchenko",
"institution": "Institute of Organic Chemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Andriy I. Vovk",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
}
] |
| author_sort | Kobzar, Oleksandr L. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:53Z |
| description | Phosphorylated derivatives of organic compounds are known to be capable of inhibiting the activities of enzymes and other proteins responsible for key metabolic pathways. In this connection, the calixarene phosphonic acids are of interest as macrocyclic agents interacting with targets that may be involved in pathological cellular processes. This review presents a literature survey on the synthesis and properties of calix[4]arene phosphonic acids as inhibitors of alkaline phosphatases, protein tyrosine phosphatases, Na,K-ATPase, nucleotide pyrophosphatase/phosphodiesterase 1, and some other enzymes and proteins. Brief information is also given about the inhibitory activity of calix[4]arene derivatives bearing alkyl phosphonate or phosphinic acid groups |
| doi_str_mv | 10.15407/bioorganica2022.02.003 |
| first_indexed | 2025-07-17T12:19:34Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 2
UDC 547.789+ 577.152.2+577.152.3
DOI: https://doi.org/10.15407/bioorganica2022.02.003
3
REVIEW
Biologically active calixarene phosphonic acids
Oleksandr L. Kobzar1, Sergii O. Cherenok2, Sergiy O. Kosterin3, Vitaly I. Kalchenko2,
Andriy I. Vovk1*
1 V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
2 Institute of Organic Chemistry of the NAS of Ukraine, Kyiv, Ukraine
3 Palladin Institute of Biochemistry of the NAS of Ukraine, Kyiv, Ukraine
Abstract: Phosphorylated derivatives of organic compounds are known to be capable of inhibiting the activities of enzymes and other
proteins responsible for key metabolic pathways. In this connection, the calixarene phosphonic acids are of interest as macrocyclic agents
interacting with targets that may be involved in pathological cellular processes. This review presents a literature survey on the synthesis
and properties of calix[4]arene phosphonic acids as inhibitors of alkaline phosphatases, protein tyrosine phosphatases, Na,K-ATPase,
nucleotide pyrophosphatase/phosphodiesterase 1, and some other enzymes and proteins. Brief information is also given about the
inhibitory activity of calix[4]arene derivatives bearing alkyl phosphonate or phosphinic acid groups.
Keywords: calix[4]arene; phosphonic acids; enzymes; proteins; inhibition.
Introduction
Calixarenes are synthetically available nano-sized
macrocyclic compounds with a cup-like structure [1]. Due
to the unique receptor properties of calixarenes to
biologically important cations and anions, neutral bio-
molecules, as well as biopolymers, they have broad
prospects for biomedical applications [2, 3]. These
macrocyclic molecules are considered as potential
therapeutic agents [4] with antimicrobial [5] antibacterial
[6], antiviral, anticoagulant, and antifungal activities [3].
The anticancer activity of functionalized calixarenes has
been reported by several research groups [7].
One of the leading places in the field of calixarene
chemistry is occupied by their phosphorylated derivatives
[8, 9]. Phosphonic acid fragments of the synthetic
compounds can be considered as non-hydrolyzable
Received:
Revised:
Accepted:
Published online:
05.08.2022
16.09.2022
29.09.2022
30.12.2022
Corresponding author. Tel.: +380-44-558-5388;
e-mail: vovk@bpci.kiev.ua (A.I. Vovk)
ORCID: 0000-0001-6167-076X
mimetics of phosphate groups of low-molecular bioorganic
substrates and phosphate groups of proteins [10, 11]. The
phosphonic acid derivatives of organic compounds are
known to inhibit the activity of enzymes and some other
biomolecules responsible for key metabolic pathways [12,
13].
Although several phosphonate inhibitors are known in
the literature, these studies are still ongoing, including
synthesis and investigation of bioorganic properties of
various phosphorylated macrocycles [14, 15]. In this
connection, the calixarene phosphonic acids are of interest
as possible chemical agents interacting with targets
involved in pathological cellular processes.
In this review, we summarize information on
calix[4]arene phosphonic acids as inhibitors of biologically
relevant enzymes such as alkaline phosphatases, protein
tyrosine phosphatases, nucleotide pyrophosphatase/phos-
phodiesterase 1, ATPases, as well as glutathione S-trans-
ferase. In addition to the phosphonic acids, the activities of
their mono- and diester forms as well as properties of
calix[4]arene-based phosphinic acids are discussed. The
analysis of possible mechanisms of inhibitory activity and
details of the synthesis of the phosphorylated macrocycles
can be found in the original papers which are referred to in
the review.
© Kobzar O.L. 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, 2022, Vol. 17, N 2
4
Inhibition of alkaline phosphatases
Alkaline phosphatases belong to the substrate non-
specific enzymes catalyzing hydrolysis of phosphate
monoesters and reactions of transphosphorylation [16].
Overexpression of these enzymes was observed in patients
with bone diseases and some cancer types [17].
The inhibitory activity of calix[4]arene methylene-
bisphosphonic acids 1 and 2 (Figure 1) towards alkaline
phosphatases was investigated using in vitro enzymatic
hydrolysis of p-nitrophenyl phosphate. Compounds 1 and 2
were synthesized in two steps. In the first stage, ethyl esters
of calix[4]arene methylenebisphosphonic acids were
obtained by the Arbuzov reaction of formyl calix[4]arenes
with triethyl phosphite. The treatment of the phosphate
esters with bromotrimethylsilane and methanol afforded the
calix[4]arene methylenebisphosphonic acids [18].
Figure 1. Calix[4]arene methylenebisphosphonic acids 1, 2 and
model compound 3.
It was established that calix[4]arene methylene-
bisphosphonic acids were stronger inhibitors of the calf
intestine alkaline phosphatase in comparison with porcine
kidney alkaline phosphatase and E. coli alkaline
phosphatase. 4-Hydroxyphenyl methylenebisphosphonic
acid 3 and methylenebisphosphonic acid exhibited
significantly lower activity. The inhibition effects of bis-
substituted calix[4]arene derivative 2 observed for alkaline
phosphatase from calf intestine were more pronounced than
in the case of compound 1. The influence of compounds 1
and 2 on the enzyme activities is in agreement with mixed-
type or partial mixed-type inhibition. According to this, the
inhibitor competes with the substrate for binding to the
enzyme's active site and binds with the enzyme-substrate
complex. The competitive component in the inhibition
mechanism prevailed over the non-competition one. The
inhibition constants Ki of calix[4]arene
methylenebisphosphonic acids 1 and 2 are 2.5 μМ and
0.38 μМ for calf intestine alkaline phosphatase, 6.3 μМ and
0.40 μМ for bovine intestine alkaline phosphatase, 8.8 μМ,
and 12 μМ for bovine kidney alkaline phosphatase, and
230 μМ and 190 μМ for E. coli alkaline phosphatase. The
strong inhibitory activity of calixarene 2 can be the
consequence of the preorganization of two methylene-
bisphosphonic acid moieties. The efficient coordination
with the metal cations in the enzyme active site and the
additional van der Waals interactions brought about by the
macrocycle scaffold itself are probably responsible for the
high activity of the compound 2 [18, 19].
The investigation of chiral calix[4]arene α-amino-
phosphonic acids 4 and 5 (Figure 2) towards porcine kidney
alkaline phosphatase was carried out. The macrocyclic
derivatives were synthesized by the Pudovik reaction of
chiral iminocalix[4]arenes with sodium diethyl phosphite
and further dialkylation of obtained calix[4]arene
aminophosphonates with bromotrimethylsilane and
methanol [20].
Calix[4]arene derivatives 4 and 5 were found to be
reversible inhibitors of porcine kidney alkaline phosphatase
with a mixed-type inhibition mechanism. The alkaline
phosphatase was shown to be sensitive to the absolute
configuration of the chiral carbon atom of the calix[4]arene
α-aminophosphonic acids. The Ki value for S-isomer 4b was
about two times smaller than for its R-counterpart 4a. The
inhibition of the enzyme increased drastically in the case of
diastereomeric bis-aminophosphonic acids 5a and 5b. The
binding affinity of the RR-diastereomer 5a to the porcine
kidney alkaline phosphatase with an inhibition constant
of 1.7 μМ was about 50 times higher than that of
SS-diastereomer 5b, which corresponds to a difference in
free energy of 2.3 kcal/mol. However, a less pronounced
enantioselectivity of inhibition by calix[4]arenes 5a and 5b
was observed in the case of bovine intestinal alkaline
phosphatase. The S-isomer of model compound 6 (Figure 2)
showed significantly less inhibitory effect.
Figure 2. Calix[4]arene α-aminophosphonic acids 4, 5 and model
compound 6.
The inhibitory properties of functionalized calixarenes
can be dependent not only on the modification of lower rim
substituents but also on a change in scaffold structure. The
effect of the thiacalix[4]arene platform on the inhibition of
O. L. Kobzar, S. O. Cherenok et al.
5
alkaline phosphatases was demonstrated on the example of
tetrakis-dihydroxyphosphorylmethyl derivatives of
thiacalix[4]arene and calix[4]arene. The derivatives 7 and 8
(Figure 3) were obtained by the Arbuzov reaction of the
chloromethylated macrocycles with triethyl phosphite
followed by transformation of the obtained esters into
corresponding acids by treatment with hydrochloric acid
solution [21].
As expected, the tetrakis-dihydroxyphosphorylmethyl
thiacalix[4]arene 7 was an effective inhibitor of bovine
intestinal alkaline phosphatase, while showing lower
inhibitory effects against human placental alkaline
phosphatase and shrimp alkaline phosphatase. The activity
of calix[4]arene 8 against these enzymes was less
pronounced as compared to that of compound 7. The value
of inhibition constant for thiacalix[4]arene 8 as an inhibitor
of bovine intestinal alkaline phosphatase was approximately
one order of magnitude lower than for calix[4]arene
methylenebisphosphonic acid 2. Both compounds were
found to be mixed-type inhibitors of the enzymes from
human placenta and bovine intestinal mucosa with a larger
contribution of the competitive component. At the same
time, these compounds were competitive inhibitors of the
alkaline phosphatase from shrimp. Based on molecular
docking results, it was suggested that the properties inherent
to thiacalix[4]arene scaffold can provide a more extensive
network of hydrogen bonds between phosphonate groups
and amino acid residues of the active site [21].
Figure 3. Thiacalix[4]arene and calix[4]arene tetrakis-methyl-
phosphonic acids 7 and 8.
Inhibition of ATPases
Na,K-ATPase is a membrane protein that catalyzes the
hydrolysis of ATP and pumps Na+ and K+ ions across the
cellular membranes. This enzyme is responsible for
generating the membrane potential and maintaining the
osmotic equilibrium [22]. Numerous attempts have been
made to elucidate the inhibitory properties of calix[4]arene
phosphonic acids as possible regulators of ATPase
activities. In this field, the effects of calix[4]arene
derivatives 1, 9, and 10 (Figures 1 and 4) with methylene-
bisphosphonic, aminophosphonic, and α-hydroxyphospho-
nic acid groups on the enzymatic activity of ouabain-
sensitive Na,K-ATPase and ouabain resistant basal Mg-
ATPase were studied. In suspension of myometrium cell
plasma membranes, the calix[4]arene phosphonic acids in
the concentration of 100 µM inhibited the enzymatic
activity of Na,K-ATPase by 86-98% and did not practically
affect the activity of Mg-ATPase. These calix[4]arenes
were more effective than ouabain in suppressing the
enzymatic activity of the sodium pump. Among the
compounds studied, calix[4]arene methylenebisphosphonic
acid 1 exhibited the best inhibitory effect on Na,K-ATPase
with I50 of 33 nM [23].The synthesis of calix[4]arene 9 and
10 were described in papers [23, 24].
Figure 4. Calix[4]arene 9 and 10 studied as inhibitors of ATPases.
Other experimental results showed that compound 9 at a
concentration of 100 μM can activate the actomyosin
ATPase. At the same time, 100 μM calixarenes 1 and 10
inhibited the activity of this ATPase by 70% and 50%,
respectively. In the case of myosin subfragment-1 ATPase,
calix[4]arene 9 (100 μM) increased ATP hydrolysis more
than twice, while 100 μM calix[4]arene 1 inhibited activity
by 77% (I0.5 = 43 μM) [25]. Calix[4]arene 9 is also able
to inhibit myometrium Na,K-ATPase (I50 = 54 nM) with
selectively over other ATPases of the plasma membrane
and simultaneously activated the enzymatic activity of the
myosin ATPase of smooth muscles (A50 = 9.6 μM). It was
shown that inhibition of Na,K-ATPase and activation of
myosin ATPase by calix[4]arene 9 cause stimulation of
isolated smooth muscle contractile activity [26]. It was also
shown that the inhibitors of plasma membrane Сa,Mg-
АТРase have been identified among sulfonylamidine
derivatives of calix[4]arenes [27, 28].
Inhibition of protein tyrosine phosphatases
The first investigation of calix[4]arene phosphonic acids
as inhibitors of PTPases was undertaken on the Yersinia
protein tyrosine phosphatase [29]. This enzyme is an
essential virulence factor of Yersinia pestis in infected cells
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 2
6
causing dephosphorylation of multiple focal adhesion
proteins to disrupt the signaling pathways and to escape the
immune responses [30]. The in vitro study revealed that
calix[4]arene methylenebisphosphonic acids 1, 2, and 11
(Figures 1 and 5) as well as thiacalix[4]arene tetrakis-
methylphosphonic acid 7 and calix[4]arene tetrakis-
methylphosphonic acids 8 (Figure 3) are competitive
inhibitors of Yersinia PTPase. The inhibition constants of
the calix[4]arene methylene-bisphosphonic acid 1 and
calix[4]arene bis-methylene-bisphosphonic acid 2 were 7.1
µM and 1.4 µM, respecti-vely, which are approximately 80-
fold and 400-fold better than of 4-hydroxyphenyl
methylenebisphosphonic acid 4 (Figure 2). At the same
time, compound 11 bearing four methylenbisphosphonic
acid fragments at the wide rim of the calix[4]arene scaffold
showed decreased inhibition of the enzyme compared with
the effects of compounds 1 and 2. The most effective
inhibitors of Yersinia phosphatase were thiacalix[4]arene-
and calix[4]arene-based tetrakis-methylphosphonic acids 7
and 8 with Ki values of 0.92 µM and 0.22 µM, respectively.
According to molecular docking results, the calix[4]arene
inhibitors may occupy the active site region of the enzyme,
thereby preventing substrate binding [29].
Figure 5. Calix[4]arene tetrakis-methylenebisphosphonic acid 11.
Further systematic studies of calix[4]arene phosphonic
acids have been conducted using protein tyrosine
phosphatase 1B (PTP1B), T-cell protein tyrosine
phosphatase (TC-PTP), megakaryocyte protein tyrosine
phosphatases 1 and 2 (MEG1 and MEG2), Src homology
region 2 containing protein tyrosine phosphatase (SHP2),
leukocyte common antigen protein tyrosine phosphatase
(CD45), and receptor-type protein tyrosine phosphatase
beta (PTPβ), also known as vascular endothelial-protein
tyrosine phosphatase (VE-PTP). PTP1B is involved in the
insulin and leptin signal transduction by dephosphorylation
of activated insulin receptor or leptin receptor-associated
kinase JAK2. As a negative regulator of insulin and leptin
signaling, this enzyme is one of the most promising
therapeutic targets for the treatment of type 2 diabetes and
obesity [31, 32]. TC-PTP having a sequence identity of the
catalytic domain to PTP1B of 74% [33] plays a role in
inflammation control [34]. MEG2 is a regulator of
hematopoietic signaling and blood glucose homeostasis and
is considered a potential therapeutic target in the treatment
of myeloproliferative disorders and type 2 diabetes [35-37].
Activation of SHP-2 was observed in many pathological
conditions including different cancer types [38]. CD45 is
implicated in immune system function and therefore can be
involved in the development of autoimmune diseases [39].
Overactivity of PTPβ upregulated by hypoxia can lead to a
variety of endothelial dysfunctions in patients with diabetes
[40]. These data suggest that the inhibitors of PTPs may be
developed as possible therapeutic agents.
The syntheses of calix[4]arene α-hydroxymethylene-
bisphosphonic acids 12 and 13 (Figure 6) were performed
starting from calix[4]arene carboxylic acids and their acyl
chlorides. Corresponding α-ketophosphonic acid silyl esters
obtained in the Arbusov reaction were transformed into silyl
esters of α-hydroxymethylenebisphosphonic acid, which
gave free acids 12 and 13 after treatment by methanol [41].
Figure 6. Calix[4]arene α-hydroxymethylenebisphosphonic acids
12-14.
Calix[4]arene methylenebisphosphonic acids 1 and 2 and
calix[4]arene α-hydroxymethylenebisphosphonic acids 12
and 13 were found to be micromolar inhibitors of PTP1B.
Comparison of IC50 values of the compounds 1, 2, 12, and
13 (Figures 1 and 6) showed that the replacement of one or
two α-hydroxy-methylenebisphosphonate fragments by
methylene-bisphosphonate ones leads to a decrease in
enzyme inhibition. The macrocyclic inhibitors of PTP1B
showed good selectivity over PTPβ (with exception of bis-
α-hydroxymethylenebisphosphonic acid 13) and 4-9-fold
selectivity over CD45. Mono-substituted calix[4]arenes 1
and 12 exhibited 8- and 14-fold selectivity over TCPTP.
Kinetic studies revealed that the calix[4]arene derivative 1
is a slow-binding inhibitor of PTP1B with a competitive-
type inhibition mechanism. Docking results suggested that
the macrocyclic inhibitors are capable of occupying the
active site region of PTP1B with the predicted free energies
that were in agreement with experimental data [41].
The inhibitory effects of the calix[4]arene α-hydroxy-
methylphosphonic acids 14 (in racemic form; Figure 6) and
bis-substituted derivative 10 (as (RS)-stereoisomer; Figure
4) against PTPs were found to be similar to the inhibitory
effects of calix[4]arene methylenebisphosphonic acids 1
and 2. However, compound 14 exhibited high inhibitory
activity against CD45 (IC50 values of 0.64 µM) with
selectivity over TC-PTP and modest selectivity over
PTP1B, PTPβ, and SHP2 [42]. As compared to this the
described activities of α-hydroxyphosphonates screened
against CD45 were much lower [43].
O. L. Kobzar, S. O. Cherenok et al.
7
Calix[4]arene α-ketophosphonic acids 15 and 16 (Figure
7) turned out to be slightly less effective inhibitors of the
PTPases than the calix[4]arene methylenebisphosphonic
acids 1 and 2 (Figure 1). At the same time, they showed
preferred inhibition of PTP1B over TC-PTP, MEG1,
MEG2, SHP2, and LAR. The position of the α-ketophos-
phonate fragment of the inhibitor 15 mimics the substrate
binding at the active site of PTP1B [44].
Figure 7. Calix[4]arene α-ketophosphonic acids 15 and 16.
The IC50 values of thiacalix[4]arene tetrakis-
methylphosphonic acid 7 and calix[4]arene tetrakis-
methylphosphonic acid 8 for PTP1B with IC50 values of
0.17 µM and 1.3 µM were comparable with the values
obtained for PTPβ (0.13 µM and 3.8 µM, respectively). The
activity of sulfonylcalix[4]arene 17 (Figure 8) with four
phosphonic acid groups introduced at the upper rim was the
same as compared to its thiacalix[4]arene analog 7 (Figure
3), without selectivity over other PTPases such as TC-PTP,
MEG1, MEG2, SHP2, and PTPβ [45]. Synthesis of
sulfonylcalix[4]arene phosphonic acid 17 was performed by
oxidation of thiacalix[4]arene scaffold followed by
hydrolysis of the alkyl phosphonate groups of the obtained
sulfonylcalix[4]arene derivative [46].
Quite unexpectedly, the tetraethyl ester of the tetrakis-
methylphonic acid was found to exhibit inhibitory activity
against PTP1B and MEG2 with IC50 values of 0.7 µM
and 0.8 µM, respectively [45]. Unsubstituted sulfonyl-
calix[4]arene was also able to inhibit protein tyrosine
phosphatase MEG2 with an IC50 value of 9.1 µM
demonstrating lower activity against PTP1B, MEG1, TC-
PTP, SHP2, and PTPβ [47]. Sulfonylcalix[4]arene 18
functionalized by the tert-butyl group was a weak inhibitor
of PTP1B, MEG2, SHP2, and PTPβ and did not influence
the activity of TC-PTP, MEG1. Modification of
sulfonylcalix[4]arene scaffold with trifluoroacetamide
substituents (compound 20) led to inhibition of PTP1B with
IC50 of 1.4 μM and 4- to 28-fold selectivity over the other
PTPs [45].
Given that thiacalix[4]arene-based full ester 22 (Figure
8) was non-active against PTPases at a concentration of 10
µM, the thiacalix[4]arene tetrakis-methylphosphonate
monoesters 20 and 21 were designed as compounds which
have the improved bioavailability and do not lose the
capacity to interact with polar regions of PTPs active sites.
These monoesters were synthesized by consecutive
treatment of octaesters 22 with lithium bromide and
hydrochloric acid according to previously developed
synthetic protocols [46]. The derivatives 20 and 21 were
Figure 8. Derivatives of sulfonylcalix[4]arene (17-20) and
thiacalix[4]arene (20-22).
slow-binding selective inhibitors of PTP1B with IC50 values
of 0.34 µM and 0.32 µM, respectively, which were
more than 5 times better than IC50 values obtained for TC-
PTP, MEG1, MEG2, and SHP2. Kinetic studies revealed
that thiacalix[4]arene tetrakis-methylphosphonate mono-
ester 20 was a competitive inhibitor of PTP1B. As in the
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 2
8
case of acids 7 and 8, compound 20 is more favorable to
bind to the closed conformation of PTP1B [48].
Thiacalix[4]arene phosphinic acid 24 (Figure 9) can be
considered a structural analog of the monoester form of
tetrakis-methylphosphonate 20. It is known that phosphinic
acid derivatives are widely used in designing biologically
active compounds, in particular, enzyme inhibitors [49, 50].
Calix[4]arene phosphinic acid 23 and its thiacalix[4]arene
and sulfonylcalix[4]arene analogs 24 and 25, respectively
(Figure 9), were synthesized from chloromethyl
calix[4]arene or chloromethyl thiacalix[4]arene by the
Arbuzov reaction of the corresponding chloromethyl
derivatives with phenyl diisopropyl phosphonite in dry
chloroform. The oxidation of thiacalix[4]arene intermediate
with sodium perborate in absolute trifluoroacetic acid gave
sulfonylcalix[4]arene derivative in form of isopropyl esters.
The dealkylation of corresponding isopropyl esters with
trimethylbromosilane and methanolysis of the silyl
intermediates provided the methyl-phenylphosphinic acid
derivatives of calix[4]arene, thiacalix[4]arene, and
sulfonylcalix[4]arene (compounds 23-25, respectively) [51].
Figure 9. Calix[4]arene, thiacalix[4]arene, and sylfonyl-
calix[4]arene phosphinic acids 23-25.
The compound 24 and corresponding calix[4]arene 23
and sulfonylcalix[4]arene 26 turned out to be effective
inhibitors of PTP1B with IC50 values in the micromolar to
nanomolar concentration range depending on the scaffold
type. The inhibition effects towards PTPases increased from
calix[4]arene 23 to thiacalix[4]arene 24 and sulfonyl-
calix[4]arene 25, however, the selectivity of inhibition of
PTP1B decreased. Thiacalix[4]arene and sulfonyl-
calix[4]arene phosphinic acids 24 and 25 were competitive
inhibitors of PTP1B with Ki values of 0.14 µM and 0.032
µM. Modeling data revealed that the compounds can
occupy the active site region of the open conformation of
PTP1B forming many hydrogen bonds [51].
Considering the results obtained by the studies of
calix[4]arene phosphonic acids as inhibitors of PTPases, it
is worth emphasizing the role of macrocyclic scaffold for
obtaining selectivity for individual enzymes such as PTP1B.
The structural factors of scaffolds responsible for selectivity
to PTP1B can be illustrated by the comparison of
calix[4]arene, thiacalix[4]arene, and sulfonylcalix[4]arene
derivatives [45, 51]. At the same time, some anionic
fullerene derivatives considered a new class of protein
tyrosine phosphatase inhibitors are potent inhibitors of
CD45 showing IC50 values in the low micromolar to the
high nanomolar range and also exhibiting less inhibitory
activities against PTP1B [52]. ,-Difluoro--ketophos-
phonate derivatives of tetraazamacrocycles were found to
be potential inhibitors of T-cell protein tyrosine phos-
phatase with IC50 values in micromolar to nanomolar range
and selectivity over PTP1B, CD45, SHP2, and PTPβ [15].
Inhibition of nucleotide
pyrophosphatase/phosphodiesterase 1
Thiacalix[4]arene and calix[4]arene tetrakis-
methylphosphonic acids 7 and 8 (Figure 3) were found to
inhibit nucleotide pyrophosphatase/phosphodiesterase 1
(NPP/PDE1). This enzyme hydrolyzes a wide range of
phosphodiester bonds being involved in various biological
processes such as bone mineralization or cancer cell
proliferation [53]. The inhibition constants of compounds 7
and 8 as inhibitors of NPP/PDE1 were in the low
micromolar range [54]. However, the influence of these
inhibitors on the enzyme activity was sufficiently lower
than their effects on alkaline phosphatase from bovine
intestinal mucosa. At the same time, methylphosphonic acid
derivative 17 bearing sulfonylcalix[4]arene skeleton (Figure
8) demonstrated inhibitory activity only against NPP/PDE1
and did not influence the activity of alkaline phosphatases.
These results indicated that the selectivity of
sulfonylcalix[4]arene derivative 17 as an inhibitor of NPP1
can be attributed to the modified macrocyclic scaffold. The
inhibition of NPP/PDE1 by sulfonylcalix[4]arene tetrakis-
methylphosphonic acids 17 was found to be of the
competitive type with a Ki value of 0.39 µM. Tetrakis-tert-
butyl sulfonylcalix[4]arene 18 showed a low inhibition
effect on NPP/PDE1, while tetrakis-3-fluoromethyl-
acetamide sulfonylcalix[4]arene 19 had an IC50 value of 0.2
μM with selectivity over alkaline phosphatases.
Glutathione S-transferase as a target for
calix[4]arene-based phosphonic acids
Glutathione S-transferases (GSTases) belong to the phase
II detoxification system, catalyzing the conjugation of
glutathione with a variety of endogenous and exogenous
electrophilic compounds, including chemotherapeutic
O. L. Kobzar, S. O. Cherenok et al.
9
drugs. Overexpression of GSTases can be observed in
cancer cells [55].
Calix[4]arene α-hydroxymethylphosphonic acids 26-28
(Figure 10) were found to be inhibitors of GSTases showing
different effects on the enzymes from equine liver and
human placenta. These compounds as a mixture of stereo-
isomers or meso-form for bis-substituted derivative 27 can
be obtained by the reaction of formylcalix[4]arenes with
triisopropyl phosphite or diisopropylphosphite sodium salt,
and further treatment of alkylphosphonate esters by trime-
thylbromosilane and methanol [24]. The inhibition activities
of calix[4]arene α-hydroxymethylphosphonic acids against
GSTases, especially in the case of GST from equine liver,
were higher than those of corresponding methylenebis-
phosphonic or α-aminophosphonic acids [24, 56].
Figure 10. Calix[4]arene α-hydroxymethylphosphonic acids 26-
28.
Calix[4]arene-, thiacalix[4]arene-, and sulfonyl-
calix[4]arene-based phosphinic acids 23-25 turned out to be
more effective inhibitors of the GST from equine liver and
human recombinant GSTA1-1 than calix[4]arene α-hydr-
oxymethylphosphonic acids 26-28. At the same time, the
inhibitory effects of these compounds were negligible for
GST from the human placenta and GSTP1-1. The
thiacalix[4]arene phosphinic acid inhibitor 24 that showed
IC50 values of 0.085µM and 0.05 µM for GST from equine
liver and GSTA1-1, respectively, was one order magnitude
better than calix[4]arene or sulfonylcalix[4]arene
derivatives. Docking results suggest that the thia-
calix[4]arene being noncompetitive inhibitor of the GSTs
can bind at the bottom of a V-shaped cleft formed between
subunits of the homodimer structure of the enzyme [57].
It is known that peptides containing the benzoyl-
phosphonate group were found to exhibit photoactive
inhibitory effects towards PTP1B, MptpA, and STAT5b
[58, 59]. The photoactive effects of low-molecular alkyl and
aryl α-ketophosphonates were also observed in the case of
GSTases [60]. Assuming that the UV-induced inhibition by
the α-ketophosphonic acid group can be improved by
macrocyclic scaffold, the calix[4]arene α-ketophosphonic
acids 15, 16, 29-32, and diethyl ester 33 (Figures 7 and 11)
were studied as light-activated irreversible inhibitors of
GSTases [61].
The α-ketophosphonic acid fragments were inserted at
the calix[4]arene upper rim by the interaction of
corresponding dialkoxycalix[4]arene acyl chlorides with
triethylphosphite in the Arbusov reaction condition. The
mono- or bis-substituted calix[4]arene ethyl α-ketophospho-
nates gave corresponding acids 15, 16, 29-31 by treatment
with trimethylbromosilane and methanol. In the case of
compound 32 one of the α-ketophosphonate substituents of
calix[4]arene was transformed into α-hydroxymethylene
bisphosphonate group using triethylphosphite in the
presence of pyridinium perchlorate [44, 61].
O HO
O
OH
PO
OH
OHP
O OH
OH
29
O
O
O HO
O
OH
PO
OH
OHP
O OH
OH
30
O
O HO
O
OH
PO
OH
OHP
O OH
OH
O
31
O HO
O
OH
PO
O
OP
O O
O
33
O
O HO
O
OH
PO
OH
OH
P
O OH
OH
32
O
P
O
OH
OH
O
O
O
Figure 11. Calix[4]arene α-ketophosphonic acids 29-32 and
tetraethyl calix[4]arene α-ketophosphonate 33.
Without irradiation, the α-ketophosphonic acids 15, 16,
and 29-32 demonstrated low to high inhibitory potency
against GST from equine liver and GSTA1-1. Lengthening
of alkyl substituents of calix[4]arene scaffold to n-octyl and
n-dodecyl (compounds 30 and 31) increased their inhibitory
activity against GST from equine liver and GSTA1-1,
providing micromolar IC50 values. At the same time, these
calix[4]arene derivatives were devoid of such activity
against GST from human placenta and GSTP1-1. Under UV
irradiation at 365 nm, the inhibitory properties of some of
the calix[4]arenes were significantly improved, showing
IC50 values in the low micromolar range. Inactivation of the
enzymes was described by pseudo-first-order rate constants.
The calculated second-order rate constants indicated that the
photoactivated inhibitors were more effective towards GST
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 2
10
from human placenta than GST from equine liver. The most
potent UV-activated inhibitor was compound 16 with IC50
of 0.21 µM. The second-order rate constant for this
calix[4]arene is up to 10 times higher than that for other
derivatives. It was suggested that the mechanism of the
inactivation by photoactive calix[4]arenes includes
formation of reversible complex with the enzyme followed
by irreversible radical transformation of some of
catalytically important amino acid residues [61].
Interaction with proteins
Molecular interactions between the calix[4]arene
phosphonic acids and human serum albumin (HSA)
influence the possible mechanisms of their bioavailability.
Using the fluorescence-quenching method, the albumin-
binding properties of thiacalix[4]arene tetrakis-methyl-
phosphonic acid 7 and its phosphonate monoester 20
(Figures 3 and 8) were studied [48]. HSA is the most
abundant protein, responsible for drug delivery and
transport of metabolites and other molecules [62]. The
results obtained indicate that fluorescence quenching of
HSA by the thiacalix[4]arene derivatives 7 and 20 can be
initiated by complex formation rather than by dynamic
collision. Double logarithmic Stern-Volmer plot allowed
determining stoichiometry and apparent binding constants
of the ligands to HSA. According to this, the binding
capacity (at least one binding site) of thiacalix[4]arene
tetrakis-methylphosphonic acid 7 to HSA was enhanced
with the increasing temperature. In the case of monoester
derivative 20, the values of Kb and n decreased with
increasing temperature, indicating the reduction of the
stability of the ligand-protein complex. Such differences
between the binding modes may be explained by the nature
of binding forces playing a major role in the binding
process. According to the ∆G values calculated from van’t
Hoff equation, the binding of compounds 7 and 20 to HSA
is a spontaneous process. The hydrophobic interaction
forces might play a major role in the interaction of free acid
7 with the protein as confirmed by positive values of ∆S and
∆H. In the case of monoester derivative 20, negative values
of ∆H and ∆S suggest that hydrogen bonds and van der
Waals forces are dominant.
It was previously established that water-soluble anionic
calix[n]arenes with sulfo groups exhibit anti-thrombotic
activity [63]. According to the results of other researches,
the phosphorylated calix[4]arene derivatives turned out to
be inhibitors of fibrin polymerization [64]. The influence of
calix[4]arene tetrakis-methylenebisphosphonic acid 11
(Figure 5) [65, 66] led to a decrease in the maximum rate in
the fibrinogen–thrombin reaction with IC50 value of 0.52
µM at a molar ratio of compound to starting fibrinogen of
1.7 : 1. The IC50 value of 1.26 µM was obtained in case of
desAABB fibrin polymerization at a molar ratio of
compound 11 to fibrin monomer of 4 : 1. In human blood
plasma, the calixarene tetrakis-methylenebisphosphonic
acid 11 increased both the prothrombin time and the
activated partial thromboplastin time. Electron microscopy
confirmed that compound 11 inhibits the formation of
protofibrils in the first stage of fibrin polymerization. At the
same time, calix[4]arene bis-methylenebisphosphonic acid
2 (Figure 1) inhibited fibrin desAABB polymerization with
an IC50 of 131 µM. This data showed that
methylenebisphosphonic acid derivative 11 can be a
specific inhibitor of fibrin polymerization and blood
coagulation and may be useful for designing new
antithrombotic agents.
Recently, the inhibition of nucleocapsid protein
chaperone activity by calixarene phosphonic acids have
been described [67]. The nucleocapsid protein is a highly
conserved protein that plays key roles in HIV-1 replication
and is a promising target for antiviral therapy. The
phosphonate derivatives of thiacalix[4]arene were found to
be able to compete with nucleic acids for the binding to
nucleocapsid protein. In addition, the thiacalix[4]arene
tetrakis-methylphosphonate (tetrasodium salt of compound
7; Figure 3) at low micromolar concentrations inhibited in
cells the infectivity of wild-type and drug-resistant HIV-1
strains, primarily targeting the early steps of HIV-1
replication. It was shown also that the thiacalix[4]arene 7
can inhibit the flipping and polymerization activity of
reverse transcriptase. Thus the calix[4]arene phosphonic
acids can represent a new class of nucleocapsid protein
inhibitors with multitarget antiviral activity.
Figure 12. Amphiphilic calix[4]arene derivatives 34 and 35.
Newly synthesized calixarenes 34 and 35 (Figure 12)
bearing four phosphonate groups at the upper rim and two
or four long alkyl chains at the lower rim of the macrocycle
were found to complex with oligo-lysine and biologically
relevant HIV-1 nucleocapsid peptide forming small
nanoparticles (20-40 nm). At the same time, anionic
calixarene with short alkyl chains (compound 13; Figure 6)
did not form small nanoparticles with peptides, highlighting
the importance of micellar assembly of the amphiphilic
macrocycles for peptide complexation. Thus anionic
O. L. Kobzar, S. O. Cherenok et al.
11
amphiphilic macrocycles can be considered as promising
building blocks for the preparation of peptide delivery
vehicles [68].
Conclusions
The main works in the literature on the bioactivity of
calix[4]arenes were carried out during the last 25 years.
These studies became possible due to the development of
new synthetic methods for obtaining the various
functionalized macrocycles. A series of the new derivatives
carrying a calix[4]arene scaffold were synthesized for
assays of their biological properties. These investigations
afforded new information about calix[4]arenes which
demonstrated activity in vitro. However, many efforts are
still required to identify the advantages of the calix[4]arenes
in comparison with known agents with the same activity,
including investigation of efficacy, toxicity, resistance, and
other biomedical profiles. Further studies should also be
directed to elucidate the mechanisms of action for
compounds of this class.
The studies of calix[4]arene phosphonic acids are quite
attractive since their phosphonate motif as a phosphate
bioisoster in the structure of these compounds can regulate
the enzymatic phosphorylation and the cellular signaling
pathways. The examples of the inhibitory activity of the
calix[4]arene phosphonic acids against the alkaline
phosphatases, ATPases, protein tyrosine phosphatases, and
nucleotide pyrophosphatase phosphodiesterase, which are
represented in this review, can only outline some targets in
a wide list of protein structures with potential affinity to
phosphorylated macrocycles. Some other enzymes such as
glutathione S-transferase and proteins were also considered
here. It can be suggested that many new possible targets
will be identified soon. All these data can be used as a tool
for a more detailed study of the physiological role of the
calix[4]arene phosphonic acids to search for compounds
with selective action in cells. However, this also requires
the development of new approaches to the synthesis of
the diverse derivatives of phosphorus-containing
calix[4]arenes. These synthetic approaches can include
modification of macrocyclic scaffold, separation of
stereoisomers in case of molecules functionalized with
chiral substituents or inherently chiral calix[4]arenes, and
introduction of other structurally motivated functional
fragments in addition to phosphonate ones.
Notes
Acknowledgments. This work was supported by the
National Academy of Sciences of Ukraine.
The authors declare no conflict of interest.
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Біологічно активні каліксаренфосфонові кислоти
О.Л. Кобзар1, С.О. Черенок2, С.О. Костерін3, В.І. Кальченко2, А.І. Вовк1
1 Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря Національної академії наук України, Київ, Україна
2 Інститут органічної хімії Національної академії наук України, Київ, Україна
3 Інститут біохімії ім. О.В. Палладіна Національної академії наук України, Київ, Україна
Резюме: Відомо, що фосфорильовані похідні органічних сполук здатні інгібувати активність ензимів та інших протеїнів, відповідальних за
перебіг ключових метаболічних перетворень. У цьому зв'язку каліксаренфосфонові кислоти є цікавими як макроциклічні агенти, які взаємодіють
з мішенями, що можуть брати участь в патологічних клітинних процесах. У цьому огляді наведено літературні дані щодо синтезу та властивостей
калікс[4]аренфосфонових кислот як інгібіторів лужних фосфатаз, протеїнтирозинфосфатаз, Na,K-АТФази, нуклеотидпіро-
фосфатази/фосфодіестерази 1 та деяких інших ензимів і протеїнів. Також подано короткі відомості про інгібувальні властивості похідних
калікс[4]арену, що містять залишки фосфінової кислоти або алкілфосфонатні групи.
Ключові слова: калікс[4]арен; фосфонові кислоти; ензими; протеїни; інгібування.
50. Vassiliou, S.; Pagoni, A.; Węglarz-Tomczak, E.; Talma, M.; Tabor, W.; Grabowiecka, A.; Berlicki, Ł.; Much, A. Phosphinic acid-based enzyme inhibitors. Phosphorus Sulfur Silicon Relat. Elem. 2022, 197, 451-456.
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| id | oai:ojs2.bioorganica.com.ua:article-29 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:00:42Z |
| publishDate | 2022 |
| 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/01/88708034d65ffc1b441be18230544a01.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-292026-07-19T14:56:53Z Biologically active calixarene phosphonic acids Біологічно активні каліксаренфосфонові кислоти Kobzar, Oleksandr L. Cherenok, Sergiy O. Kosterin, Sergiy O. Kalchenko, Vitaly I. Vovk, Andriy I. calix[4]arene phosphonic acids enzymes proteins inhibition калікс[4]арени фосфонові кислоти ензими протеїни інгібування Phosphorylated derivatives of organic compounds are known to be capable of inhibiting the activities of enzymes and other proteins responsible for key metabolic pathways. In this connection, the calixarene phosphonic acids are of interest as macrocyclic agents interacting with targets that may be involved in pathological cellular processes. This review presents a literature survey on the synthesis and properties of calix[4]arene phosphonic acids as inhibitors of alkaline phosphatases, protein tyrosine phosphatases, Na,K-ATPase, nucleotide pyrophosphatase/phosphodiesterase 1, and some other enzymes and proteins. Brief information is also given about the inhibitory activity of calix[4]arene derivatives bearing alkyl phosphonate or phosphinic acid groups Відомо, що фосфорильовані похідні органічних сполук здатні інгібувати активність ензимів та інших протеїнів, відповідальних за перебіг ключових метаболічних перетворень. У цьому зв'язку каліксаренфосфонові кислоти є цікавими як макроциклічні агенти, які взаємодіють з мішенями, що можуть брати участь в патологічних клітинних процесах. У цьому огляді наведено літературні дані щодо синтезу та властивостей калікс[4]аренфосфонових кислот як інгібіторів лужних фосфатаз, протеїнтирозинфосфатаз, Na,K-АТФази, нуклеотидпіро-фосфатази/фосфодіестерази 1 та деяких інших ензимів і протеїнів. Також подано короткі відомості про інгібувальні властивості похідних калікс[4]арену, що містять залишки фосфінової кислоти або алкілфосфонатні групи V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2022-12-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/29 10.15407/bioorganica2022.02.003 Ukrainica Bioorganica Acta; Vol. 17 No. 2 (2022): Ukrainica Bioorganica Acta; 3-13 Ukrainica Bioorganica Acta; Том 17 № 2 (2022): Ukrainica Bioorganica Acta; 3-13 1814-9766 1814-9758 10.15407/bioorganica2022.02 en https://bioorganica.com.ua/index.php/journal/article/view/29/48 Copyright (c) 2022 Oleksandr L. Kobzar, Sergiy O. Cherenok, Sergiy O. Kosterin, Vitaly I. Kalchenko, Andriy I. Vovk https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | калікс[4]арени фосфонові кислоти ензими протеїни інгібування Kobzar, Oleksandr L. Cherenok, Sergiy O. Kosterin, Sergiy O. Kalchenko, Vitaly I. Vovk, Andriy I. Біологічно активні каліксаренфосфонові кислоти |
| title | Біологічно активні каліксаренфосфонові кислоти |
| title_alt | Biologically active calixarene phosphonic acids |
| title_full | Біологічно активні каліксаренфосфонові кислоти |
| title_fullStr | Біологічно активні каліксаренфосфонові кислоти |
| title_full_unstemmed | Біологічно активні каліксаренфосфонові кислоти |
| title_short | Біологічно активні каліксаренфосфонові кислоти |
| title_sort | біологічно активні каліксаренфосфонові кислоти |
| topic | калікс[4]арени фосфонові кислоти ензими протеїни інгібування |
| topic_facet | calix[4]arene phosphonic acids enzymes proteins inhibition калікс[4]арени фосфонові кислоти ензими протеїни інгібування |
| url | https://bioorganica.com.ua/index.php/journal/article/view/29 |
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