Selenolesterase enzyme activity of carbonic anhydrases

Article abstract of DOI:10.1039/d0cc00995d

Carbonic anhydrases (CAs, E.C. 4.2.1.1) are metalloenzymes expressed on a variety of cell types. Their overexpression leads to serious pathologies, including cancer. The discovery of a series of selenolesters with high structural diversity as novel CA inh

Full text of DOI:10.1039/d0cc00995d

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A Selenolesterase Enzyme Activity of Carbonic Anhydrases
Andrea Angeli,[a],[b] Fabrizio Carta,[a] Selene Donnini,[c] Antonella Capperucci,[c] Marta Ferraroni,[c]
Damiano Tanini,*[c] and Claudiu T. Supuran,*[a]
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Carbonic Anhydrases (CAs, E.C. 4.2.1.1) are metalloenzymes environment makes them difficult to be considered for
expressed on a variety of cell types. Their overexpression leads to biomedical purposes. To overcome such an issue we envisaged
serious pathologies, including cancer. The discovery of a series of to design and synthesise variously substituted selenolesters as
selenolesters with high structural diversity as novel CA inhibitors masked selenols, which we hypothesized that might be
is reported here. These compounds showed a remarkable in vitro activated by hydrolytic processes of CAs, considering the fact
inhibition against a panel of human CA isoforms such as hCA I, II, that these enzymes also possess esterase,8a,b thioesterase,8c
IX and XII. We observed that they undergo a CA mediated sulfatase,8d and phosphatase8e activities.
hydrolysis, releasing different active selenol fragments, which act Since the above mentioned hCA properties were also well
as CA inhibitors. Notably, to the best of our knowledge, this is the suited with the versatility and the reactivity of
first example of an enzyme with selenolesterase activity. In chalcogenoesters9 our idea of selenolesters as prodrugs of the
addition, X-ray crystallographic data support the proposed recently discovered selenol CAI moieties was sustained.7
mechanism, proving selenolesters as novel pro-drug inhibitors In this context, it is worthwhile mentioning that, owing to their
with potential pharmacological applications.
peculiar properties and reactivity, organoselenium compounds
play a key role in chemical sciences, finding wide applications
in organic synthesis,10 material science,11 polymer chemistry,12
medicinal chemistry, and biology.13 A number of selenium-
containing organic molecules have been indeed demonstrated
to possess antioxidant,14 anticancer,15 and cells growth
inhibitor16 properties. Therefore, the study of novel
biologically active selenium-containing systems would be
highly desirable in order to develop new drug candidates.
Hereby, we report our findings on the synthesis and the study
in vitro of the CA inhibitory activity of a wide variety of
differently substituted and functionalised aryl- and alkyl-
selenolesters. X-ray studies were thereafter undertaken in
order to unravel the mechanism by which these new selenium
containing potential prodrugs are activated by the enzymes.
The unique reactivity of the SeH group allowed its
functionalization under very mild reaction conditions with a
wide variety of electrophiles.17 In order to develop a general
and direct route towards selenolesters, we were attracted by
the possibility of using aromatic and aliphatic selenols as
valuable precursors of selenolate anions that, in the presence
of a weak base, would react with acyl chlorides to afford the
desired compounds. Indeed, the harsh reaction conditions
(strong reducing agents or strong bases)18 represent, together
with the use of metal catalysts, one of the main drawbacks of
the existing methodologies towards selenolesters.19
Carbonic Anhydrases (CAs, E.C. 4.2.1.1) are ubiquitous
metalloenzymes expressed in all life kingdoms.1 Eight different
and non-related gene families were discovered to date1,2 and
all reversibly catalyse the hydration of carbon dioxide to
carbonic acid.3 This reaction plays a pivotal role in several
biological systems such as pH and CO2 homeostasis as the
main ones.4 Inhibition of CAs was used since 70 years to treat a
range of diseases including oedema, glaucoma, obesity,
epilepsy, osteoporosis and, recently, hypoxic tumors in which
CA IX is overexpressed.5 The diverse kinetic profiles of 12
human CA isoforms (i.e. 3 are devoid of any activity) are the
basis of the clinical applications of several kind of inhibitors. In
this spot is the new born research on organoselenium
compounds as modulators of CAs6 and, selenols were shown
to act as a new and potent inhibitory chemotype.7 However
the relative instability of selenols into
a physiological
a. University of Florence, NEUROFARBA Department, Sezione di Scienze
Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
b. Centre of Advanced Research in Bionanoconjugates and Biopolymers
Department “Petru Poni” Institute of Macromolecular Chemistry
Iasi, Romania
c. University of Florence, Department of Chemistry "Ugo Schiff", Via della
Lastruccia 3-13, I-50019 Sesto Fiorentino, Italy.
damiano.tanini@unifi.it; claudiu.supuran@unifi.it.
Electronic supplementary information (ESI) available: Full experimental details,
products characterisation, in vitro kinetic procedure, X-ray statistics, control
experiments, and copy of NMR spectra. See DOI: 10.1039/x0xx00000x
We began by studying the synthesis of derivative 2a from
benzeneselenol 1a and benzoyl chloride. On the basis of our
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recent reports,20 weak organic (Et3N and iPr2EtN) and inorganic synthesis of derivatives 2k,l (Scheme 1).Functionalised alkyl
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DOI: 10.1039/D0CC00995D
(Cs2CO3) bases were evaluated in order to promote the desired selenols could also be efficiently employed in this reaction,
selenoacylation reaction. Different solvents (THF, DMF, CH2Cl2) thus providing access to unprecedented classes of substituted
and temperatures (-78 °C, 0 °C, and r.t.) were also investigated selenolesters. -Hydroxy-selenolesters 2m-o were obtained
to optimise the formation of 2a. The optimal conditions through selective selenoacylation of the corresponding
proved to be those reported in Scheme 1 with treatment of 1a selenols 1d,e under slightly modified conditions (see Scheme 1
with Et3N and benzoyl chloride in CH2Cl2 to provide the Se- and ESI for details). Interestingly, treatment of -hydroxy-
phenyl benzoselenoate 2a in 91% yield. Having in hands the selenols 1d,f with an excess of acyl chloride led to the
optimised conditions, we next pursued the scope of this formation of compounds 2p-r through the esterification of
reaction with respect to the acyl chloride partner. A variety of both the selenol and the hydroxyl groups (see Scheme 1 and
acyl chlorides bearing electron-deficient and electron-rich ESI for details). Similarly, this procedure allowed the synthesis
aromatics smoothly reacted with benzeneselenol 1a to afford of derivative 2s, bearing a selenolester and a thiolester group.
the corresponding selenolesters 2a-f in good yields (Scheme Notably, labile and further functionalisable epichlorohydrin
1). The reaction was also amenable to benzyl- and saturated or and glycidol derivatives could also be synthesised by using this
unsaturated alkyl-substituted acyl chlorides. Natural-product- mild protocol. Finally, this approach was also extended to
derived stearoyl- and oleoyl- chlorides were successfully amino-substituted selenols; the enantioenriched -
converted into the corresponding phenylseleno-esters 2i,j aminoselenol 1h was selectively converted into the
(Scheme 1).
corresponding selenolester 2t under standard conditions.
To the best of our knowledge the selenolesterase activity of
any known metalloenzyme has not yet been investigated, even
if this process has similar reaction mechanism to the hydrolysis
of esters and thioesters.
O
O
Et3N (1.2 eq.)
Alk/Ar
Ar1/Alk1
2a-t
Se
+
Ar1/Alk1
Cl
Ar/AlkSeH
dry CH2Cl2
0 °C to r.t., 4 h
1a-h
O
O
O
O
Figure 1 showed selenolesters 2a,i,n,q having time-dependent
inhibition constant (Ki) values when incubated with hCA II. The
Ki continued to decrease until an incubation period of 6 h was
reached. Such data suggest that the compound 2a undergoes a
chemical transformation promoted by the enzyme,
presumably similar to other prodrug CA inhibitors such as
coumarins and sulfocoumarins which do require a minimum of
6 h incubation time to exert the inhibitory activity.21 Exposure
of 2a under the same conditions of solvent and temperature
used for the kinetic assays up to 18 h with no enzyme, allowed
to recover the starting material in quantitative yields. No
traces of cleaved by-products were detected by inspection of
the 1H-NMR spectra of raw material. (see ESI).
SePh
SePh
SePh
Ph
SePh
2a, 91%
O2N
2b, 86%
2c, 74%
2d, 76%
Cl
O
O
F
O
O
O
F3C
O
SePh
SePh
2h, 72%
SePh
SePh
2e, 67%
2f, 81%
2g, 76%
CF3
O
Se
Se
Ph
O
6
SePh
O
O
SePh
16
6
O
2i, 85%
2j, 78%
2k, 83%
2l, 75%
OH
OH
OH
O
Se
Ph
O
Se
Ph
Cl
Se
2o, 73%a
2m, 65%a
2n, 68%a
O
O
O
O
O
O
O
O
O
Ph
Se
O
Ph
Se
Se
BnO
O
Ph
O
BnO
2r, 62%b
2p, 56%b
2q, 57%b
O
O
NHTs
S
Ph
Se
Ph
Se
BnO
Ph
O
2s, 71%b
2t, 74%
O
Scheme 1. Synthesis of selenolesters from selenols and acyl
chlorides. Isolated yields are reported. a 0.8 eq. of acyl chloride
were used. b 2.5 eq. of acyl chloride were used.
Figure 1. Inhibition constant (Ki) change for compounds
2a,I,n,q versus time, incubated with hCA II for 1−18 h(s). Errors
in the range of ± 5% of the reported values, from three
different stopped-flow assays.22
Notably, pharmacologically relevant fluorinated moieties could
also be employed in this chemistry, enabling the synthesis of
compounds 2f,g. Having demonstrated the versatility of the
reaction towards a variety of acyl chlorides, we turned our
attention to evaluating the scope of this methodology with
respect to the selenol partner. Substituted aromatic selenols
1b,c performed well under standard conditions, enabling the
In light of such results, the in vitro CA inhibition activities of
compounds 2a-t in comparison to the sulfonamide reference
acetazolamide (AAZ) were measured against four
2 | J. Name., 2012, 00, 1-3
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physiologically relevant hCA isozymes (i.e. the aboundant hCA X-ray investigations of compound 2a with hCA II demonstrated
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DOI: 10.1039/D0CC00995D
I, II and the cancer-related isoforms hCA IX, XII) at 6 h in detail the real binding species within the active site of the
incubation (Table 1).
enzyme.
Overall compounds 2a-t inhibited the hCAs tested with KI We performed the experiments by soaking the native hCA II
values in the low or submicromolar range with few exceptions crystals in the mother liquor solution containing 2a for 1 day.
and a rather complex structure–activity relationship (SAR). On Data were collected and the electron density maps clearly
focusing on the most potent data in Table 1, 2e and 2i showed the selenolate species and deeply bound within the
inhibited the hCA I isoform 2.8 and 3.1 fold more potently than enzymatic cleft adjacent to the zinc atom establishing
the reference AAZ followed by the seleno acyl derivatives 2h hydrophobic interactions mainly with Val122 and Leu198
and 2l which showed KI values comparable to the same (Figures 2a and 2b). Since we reported the benzeneselenol in
sulphonamide standard CAI. As for the hCA II the 2c, 2e, 2h, adduct with hCA II in our previous report6 a superimposition of
2k, 2l, 2m, 2n and 2q were the most effective among the both complex was operated and showed perfect matching
series in inhibiting such an isoform with submicromolar KI between the adducts (Figure 2c).
values. 2h, 2k, 2l were also very effective inhibitors of the hCA
IX isoform along with 2d and 2g. The second tumor associated
hCA XII revealed to be strongly inhibited from all the
compounds 2a-t with an almost flat kinetic profile. On the
basis of the kinetic data in Table 1 it is clear that the inhibitory
activity seems unaffected by the electron-donating or
electron-withdrawing nature of the substituents introduced as
well as by steric considerations. The high diversity of Ki values
among the series opens new possibilities for the application of
these compounds to biomedical purposes by making use of the
CA expressions.
Figure 2. a) Active site region of hCA II/2a adduct (PDB: 6XWZ).
Inhibitor showed as σA-weighted |Fo−Fc| density map at 2.0 σ.
b) Van der Waals interactions and the active site Zn2+-ion
coordination are shown and labelled in blue. c) hCA II structure
with bound 2a was superposed on to the hCA II structure with
bound selenol previously reported.6 The structure of the 2a
complex is colored with magenta whereas the structure of the
selenol complex as green with the zinc cation shown as a gray
sphere.
Table 1: Inhibition data of compounds 2a-t and AAZ against
four human CA isoforms (hCA I, II, IX and XII) by a stopped flow
CO2 hydrase assay.15
Ki (µM)a
Cmp
2a
2b
2c
hCA I
55.7
64.1
>100
>100
0.09
4.6
hCA II
5.1
hCA IX
26.9
14.1
5.0
hCA XII
3.9
8.9
0.56
0.09
0.41
2.1
In conclusion, under our experimental conditions, most of the
compounds here reported, displayed comparable in vitro
inhibition potency with respect to parent selenols,6 which
were previously used as CA inhibitors. In fact, we explored the
feasibility to design stable organoselenium compounds which,
after enzyme-mediated hydrolysis, afford the corresponding
differently functionalised selenols which act as carbonic
anhydrase inhibitors. A wide range of differently substituted
and functionalised selenolesters was synthesised their CA
inhibition profile was studied. The unprecedented
selenolesterase activity of different CA isoforms confirmed
these compounds as potential pro-drugs. X-ray co-
crystallography was also employed to further study the
mechanism of such a novel CAs inhibitors.
0.09
3.2
2d
2e
2f
1.1
0.05
0.45
2.0
21.3
30.2
0.21
1.3
7.6
2g
2h
2i
8.3
0.08
7.0
0.34
0.08
6.5
0.05
0.63
8.4
>100
24.6
0.99
1.1
0.09
0.41
0.09
0.08
0.3
2j
2k
2l
>100
0.37
7.6
0.08
0.55
0.09
0.04
55.4
44.7
0.52
63.6
73.7
>100
0.012
2m
2n
2o
2p
2q
2r
23.2
>100
22.6
>100
>100
13.9
>100
26.6
0.026
0.66
31.5
>100
0.71
>100
7.2
8.9
0.09
0.86
9.0
This work was supported by a grant of the Romanian Ministry
of Research and Innovation, CNCS–UEFISCDI, project number
PN-III-P4-ID-PCCF-2016–0050, within PNCDI II.
We acknowledge the Elettra-Sincrotrone for provision of
synchrotron radiation facilities and we would like to thank
Nicola Demitri for assistance in using beamline XRD2.
5.2
2s
6.5
2t
>100
0.25
0.77
0.006
AAZ
aMean from 3 different assays, by a stopped flow technique (errors were in the
range of  5-10 % of reported values).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Synthesis, Biological and Therapeutic Treatments, ed. V. K.
Jain, K. I. Priyadarsini, Royal Society of ChemVisietwryA,rtiLcolenOdnolinne,
2018, chapter 3 and references citedDtOhIe: r1e0i.1n0;3(9b/)DL0.CDC.00C9a9rr5oDl
and M. J. Davies, in Organoselenium Compounds in Biology
and Medicine: Synthesis, Biological and Therapeutic
Treatments, ed. V. K. Jain, K. I. Priyadarsini, Royal Society of
Chemistry, London, 2018, chapter 9 and references cited
therein. Inter alia: F. Kumakura, B. Mishra, K. I. Priyadarsini
and M. Iwaoka, Eur. J. Org. Chem., 2010, 440.
Conflicts of interest
There are no conflicts to declare.
Notes and references
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Organoselenium Compounds in Biology and Medicine:
4 | J. Name., 2012, 00, 1-3
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