Sulfur, selenium and tellurium containing amines act as effective carbonic anhydrase activators

Article abstract of DOI:10.1016/j.bioorg.2019.03.062

A new series of β-aminochalcogenides were designed and synthesized to identify new carbonic anhydrase activator (CAA) agents as novel tools for the management of several neurodegenerative and metabolic disorders which represent a clinical challenge withou

Full text of DOI:10.1016/j.bioorg.2019.03.062

BioorganicChemistry87(2019)516–522
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Sulfur, selenium and tellurium containing amines act as effective carbonic
anhydrase activators
⁎
⁎
Damiano Taninia, Antonella Capperuccia, Claudiu T. Supuranb, , Andrea Angelib,
a University of Florence, Department of Chemistry “Ugo Schiff”, Via della Lastruccia 3-13, I-50019 Sesto Fiorentino, Italy
b University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy
A R T I C L E I N F O
A B S T R A C T
Keywords:
A new series of β-aminochalcogenides were designed and synthesized to identify new carbonic anhydrase ac-
tivator (CAA) agents as novel tools for the management of several neurodegenerative and metabolic disorders
which represent a clinical challenge without effective therapies available. Some β-aminoselenides and β-ami-
notellurides showed effective CA activating effects and a potent antioxidant activity. CAAs may have applica-
tions for memory therapy and CA deficiency syndromes.
Carbonic Anhydrases (CAs)
Carbonic Anhydrase Activators (CAAs)
Selenium
Metalloenzymes
Tellurium
1. Introduction
unactivated aziridines in reactions with suitable nucleophiles for pre-
paring these derivatives. Indeed, ring opening reactions of strained
Carbonic anhydrases (CAs; EC 4.2.1.1) are ubiquitous me-
talloenzymes known for decades to be involved in the reversible hy-
dration of CO2 to bicarbonate and H+ ions [1,2]. This simple reaction
plays a key role in many crucial physiologic functions connected to
metabolic pathways in which CO2 is implicated [3–6]. For this reason,
their modulation is used for a long time in the treatment of different
diseases such as glaucoma, [7] edema, [8] epilepsy [9] and, more re-
cently, inhibitors of CAs are used as a new approach for treatment of
neuropathic pain, [10,11] cerebral ischemia [12] and different forms of
tumor [13]. The activation of CA, to date, does not yet have a clinical
application and has been a subject of debate for a long time. Only re-
cently their pharmacological exploration started [2,14]. Histamine
(Fig. 1) was one of the first CA activators (CAAs) discovered [15] and
also one of the most investigated scaffolds [16,17]. X-ray crystal
structure of CA-Histamine has been reported in the 90′s showing the
mechanism of activation, where the molecule participates to the rate-
determining step of the catalytic cycle, facilitating the formation of the
nucleophilic species of the enzyme [15]. In the last years, our group
focused on new molecules with activating propriety against CAs, most
of which amines of the general formula Ar–CH2CH(R)NHR’ [18–20]. In
a recent study from our group, [21] psychoactive drugs such as am-
phetamine and related compounds (Fig. 1) showed strong activating
proprieties against different CA isoforms.
heterocycles with chalcogen nucleophiles, including silyl chalcogenides
[22–27] represents a versatile way to obtain a large variety of biolo-
gically and synthetically valuable organosulfur, [28] organoselenium,
[29] and organotellurium [30] compounds.
2. Results and discussion
2.1. Compounds design and synthesis
We began our investigations by establishing the conditions required
to obtain aminosulfide 2a through the ring opening reaction of 2-me-
thylaziridine 2a with thiophenol 1a. Among several organic or in-
organic bases (Et3N, DMAP, Cs2CO3/TBAI) and solvents (THF, CH2Cl2)
evaluated, the use of KOH in DMF proved to be the most effective
conditions in promoting the desired transformation, allowing to access
3a in acceptable yield. Evaluation of different temperatures (−15 °C,
r.t.) gave no yield improvement. Having found suitable conditions for
the synthesis of β-aminosulfides bearing a free amino function, we next
explored the scope of this procedure. Thus, o-, m-, and p-bromothio-
phenol (1b-d) were smoothly converted into the corresponding β-
aminosulfides 3b-d upon reaction with 2a under the same conditions.
Interestingly, the yield proved to be strongly influenced by the position
of the bromine on the aromatic ring, increasing from 44% (for the more
hindered o-Br-C6H4 substituent) to 63% (for the less hindered p-Br-
C6H4). Furthermore, the reaction of 2-mercaptopyrimidine 1e with 2-
methylaziridine resulted in the formation of the heteroaromatic
In order to continue our studies in this less investigated field, we
synthetized, for the first time, organic chalcogenides structurally re-
lated to the psychoactive drug Amphetamine. We sought to use NeH
⁎ Corresponding authors.
E-mail addresses: claudiu.supuran@unfi.it (C.T. Supuran), andrea.angeli@unifi.it (A. Angeli).
https://doi.org/10.1016/j.bioorg.2019.03.062
Received 1 March 2019; Received in revised form 22 March 2019; Accepted 23 March 2019
Availableonline25March2019
0045-2068/©2019ElsevierInc.Allrightsreserved.

D. Tanini, et al.
BioorganicChemistry87(2019)516–522
Fig. 1. Examples of CAAs: Histamine, Histidine,
Amphetamine and Methamphetamine.
Scheme 1. Synthesis of β-amino sulfides 3a-g and β-amino selenides 5a-i from NeH aziridines, Yields refer to isolated products.
aminosulfide 3e. In order to evaluate the effect of the substituent on the
stereogenic centre and to further enlarge the scope of the reaction, we
also synthesized enantioenriched aminosulfides 3f,g from thiophenol
and (S)eNeH aziridines 2b,c. Having obtained different novel sulfur-
containing hCA activator candidates, we next evaluated the reactivity
of selenols [31,32] with 2-methylaziridine, in order to access new β-
aminoselenides with potential activity as hCA activators. Therefore, a
series of differently substituted aryl selenols (4a-g) were treated with
aziridines 2a in the presence of KOH to afford the corresponding β-
aminoselenides 5a-g. Furthermore, chiral enantioenriched β-phenylse-
leno amines 5h,i were successfully achieved from the corresponding
(S)-aziridines 2b,c and benzeneselenol 4a. These findings describe the
first example of ring opening reaction of N-unactivated aziridines with
stable aryl selenols (See Scheme 1).
aziridine, respectively (See Scheme 2).
2.2. Carbonic anhydrase activation
To the best of our knowledge, this is the first study which evaluates
the activation profile of different β-aminochalcogenides. For this
reason, we investigated the CA activating properties of amines 3a-g, 5a-
I and 7a-g against 4 catalytically active and physiologically relevant
hCA isoforms, the hCA I, II, VA and VII. Amphetamine (AMP) and
histamine (HIST) were used as standard activators and shown in
Table 1.
The following SAR can be observed regarding the activation data of
Table 1:
Having synthesised a wide variety of arylthio- and arylseleno-
amines, we also investigated the reactivity of unprotected aziridines
with tellurium-containing nucleophiles. Owing to the instability of
tellurols, we sought to exploit the reactivity of in situ generated ar-
yltellurolate anions. Thus, differently substituted diaryl ditellurides 6a-
e were treated with NaBH4 and, then, reacted with NeH aziridine 2a,
affording the corresponding β-amino aryltellurides 7a-e, bearing dif-
ferent substituted phenyl rings (7a-d) or the naphthyl group (7e).
Furthermore, enantioenriched β-phenyltelluro amines 7e,f were
achieved from ditelluride 6a and (S)-2-benzyl- or (S)-2-isopropyl-
(i) The cytosolic, widespread isoform hCA II was not activated by
these amines except for compound 5g which showed an activation
constant of 45.1 µM.
(ii) The widely abundant cytosolic isozyme hCA I was moderately
activated by most of the compounds here studied. β-Aminosulfides
3a-g showed KAs spanning between 7.7 and 13.5 µM. The presence
of the bromine atom on aromatic ring plays a crucial role in
modulation of activity. Indeed, bromine in position 3 decreased the
potency almost 2 times for compound 3d and 1.5 time when Br is
placed in position 4 (3d). The replacement of the sulfur with
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D. Tanini, et al.
BioorganicChemistry87(2019)516–522
Scheme 2. Synthesis of β-amino tellurides 7a-g from NeH aziridines. Yields refer to isolated products.
selenium or tellurium in compounds 3a, 5a and 7a did not influ-
neoglucogenesis, [34] was also activated by β-aminochalcogenides
3a-g, 5a-I and 7a-g with KAs ranging between 3.3 and 43.7 µM
(Table 1). The best activators against this isoform were compounds
with para substitution 7b and 7c with KAs of 4.0 and 3.3 µM, re-
spectively. Additional substitution (7d) or replacement with a
more bulky scaffold (7e) decreases the activity. Additional sub-
stitution (7d) or replacement with a more bulky scaffold (7e) de-
crease the activity (KA 9.4 and 20.2 µM respectively). On the other
hand, β-aminosulfides 3a-g showed a flat SAR against hCA VA with
KAs ranging in a narrow interval of 10.2 to 13.3 µM except for
compound 3e with KA of 43.7 µM. It should be noted that, also for
this isoform, replacing the chalcogen atom within the homologous
series of compounds 3f, 5h and 7f results in increased potency
moving from sulfur- to tellurium-containing derivatives (KAs
10.2–4.7 µM). These compounds remained, in any case, less ef-
fective on mitochondrial hCA compared to the psychotropic amine
AMP.
ence significantly the activity (KAs of 11.8–9.9 µM). On the other
hand, this replacement from sulfur to tellurium influenced the
potency for the analogous compounds 3f, 5h and 7f. Indeed, such
structures showed an increased activity moving within the chal-
cogen series, from sulfur to tellurium (KAs 8.8 to 5.1 µM). A dif-
ferent trend was observed for β-aminochalcogenides with iso-
propyl moiety (3g, 5i and 7g). Compound 3g showed a KA of
7.9 µM and the activity increased with the passage of selenium
analog 5i (KA 5.9 µM), but this time, organo-tellurium compound
7g showed less activating effects near two time than 3g (KA
13.3 µM).
(iii) The mitochondrial isoform hCA VA, involved in different meta-
bolic pathway such as ureagenesis, lipogenesis and
Table 1
Activation data of human CA isoforms I, II, VA and VII with compounds 3a-g,
5a-i, 7a-g, AMP and HIST by a stopped flow CO2 hydrase assay [33].
(iv) The brain-associated cytosolic CA isoform, hCA VII, [35] is mod-
erately activated by compounds here reported, with activation
constants in the range of 8.9–44.9 µM. The less active compounds
(7a, 7c and 7e) contain a tellurium atom. Contrarily, all other
analog compounds such as 3a, 5a and 5e showed near two time
more efficacy than them (KAs 20.4–23.4 versus 41.2–44.9 µM). It is
interesting to note there were not differences between the acti-
vating effects of β-aminosulfides 3a-g and β-aminoselenides 5a-i.
KA (µM)*
Cmp
hCA I
hCA II
hCA VA
hCA VII
3a
3b
3c
11.8
9.5
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
45.1
12.4
13.3
12.9
12.4
43.7
10.2
11.6
14.7
9.1
23.4
23.2
11.4
14.8
21.8
14.8
14.3
20.6
10.4
14.2
21.4
23.3
13.4
12.1
10.1
11.4
41.2
21.9
44.9
14.3
44.7
8.9
13.5
7.7
3d
3e
9.7
3f
8.8
3g
5a
5b
5c
7.9
2.3. Antioxidant assays
9.9
5.2
In order to develop novel hCA activators with antioxidant proper-
ties, we also evaluated the thiol peroxidase-like properties of selected β-
arylchalcogeno amines. Therefore, the activity of sulfides 3a,c, sele-
nides 5a,e,l and tellurides 7a-c,f as mimics of Glutathione peroxidase
(GPx) was assessed by using the dithiothreitol (DTT) oxidation test
[36–39] and the GSH/GR coupled assay [39,40]. Results of this in-
vestigation are reported in Table 2.
12.1
6.0
20.0
20.9
20.3
13.1
14.0
6.6
5d
5e
21.4
19.6
22.1
6.3
5f
5g
5h
5i
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
5.9
8.3
7a
7b
7c
9.9
14.2
4.0
8.2
Whilst aminosulfides did not show significant catalytic properties
(T50 ≫ 24 h for DTT assay), according both tests, all tested organose-
lenides and organo-tellurides exhibited remarkable catalytic anti-
oxidant activity. Particularly, as expected, β-aryltelluro amines 7a-c,f
proved to behave as excellent catalysts, being able to promote DTT and
GSH oxidation in 2 min and in 15 s, respectively [39]. As previously
reported, aminoselenides and aminotellurides bearing a free amino
function behave as better catalysts with respect to their N-Ts protected
analogues (Table 2, entries 3, 7 vs entries 8, 9); [39] this suggests im-
portant criteria in order to maintain both the hCA activator and the
4.6
3.3
7d
7e
9.5
9.4
12.6
5.1
20.2
4.7
7f
7g
AMPa
HISTa
13.3
> 100
2.1
13.7
0.81
0.01
11.0
0.91
37.5
* Mean from 3 different assays, by a stopped flow technique (errors were in
the range of 5–10% of the reported values).
a
Data from Ref. [21].
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D. Tanini, et al.
BioorganicChemistry87(2019)516–522
Table 2
MPD350.BM3.5 apparatus and are uncorrected. The solvents used in
MS measures were acetone, acetonitrile (Chromasolv grade), purchased
from Sigma-Aldrich (Milan - Italy), and mQ water 18 MΩ, obtained
from Millipore's Simplicity system (Milan-Italy). The mass spectra were
obtained using a Varian 1200L triple quadrupole system (Palo Alto, CA,
USA) equipped by Electrospray Source (ESI) operating in both positive
and negative ions. Stock solutions of analytes were prepared in acetone
at 1.0 mg mL−1 and stored at 4 °C. Working solutions of each analyte
were freshly prepared by diluting stock solutions in a mixture of mQ
H2O/ACN 1/1 (v/v) up to a concentration of 1.0 µg mL−1 The mass
spectra of each analyte were acquired by introducing, via syringe pump
at 10 µL min−1, of the its working solution. Raw-data were collected
and processed by Varian Workstation Vers. 6.8 software. The HPLC was
performed by using a Waters 2690 separation module coupled with a
photodiode array detector (PDA Waters 996) using a Nova-Pak C18
4 μm 3.9 mm × 150 mm (Waters) silica-based reverse phase column.
The sample was dissolved in 10% acetonitrile/H2O and an injection
volume of 45 μL. The mobile phase (flow rate 1.0 mL/min) was a gra-
dient of H2O + trifluoroacetic acid (TFA) 0.1% (A) and
acetonitrile + TFA 0.1% (B), with steps as follows: (A%/B%), 0–10 min
90:10, 10–25 min gradient to 60:40, 26:28 min isocratic 20:80,
29–35 min isocratic 90:10. TFA 0.1% in water as well in acetonitrile
was used as counterion. All compounds reported here were ≥ 95%
HPLC pure.
Thiol peroxidase-like activity of β -arylchalcogeno amines according to dif-
ferent methods.
a,b,c
a,d
Entry
Compound
DTT(T50
)
GSH(T50)
1
2
5a
442( 42)
434( 38)
398( 54)
402( 48)
< 60
24( 7)
21( 6)
28( 6)
32( 9)
< 5
5e
3
5i
4
5h
5
7a
6
7b
< 60
< 5
7
7c
< 60
< 5
8
7f
< 60
< 5
9
N-Ts-5i
N-Ts-7f
3186( 198)
600( 61)
129( 16)
14( 3)
10
a
T50 is the time required, in seconds, to reduce the initial thiol concentration
with 50% after the addition of H2O2; data in parenthesis are the experimental
error.
b
DTT oxidation was monitored by the mean of 1H NMR spectroscopy;
10 mol % of organoselenide and 1 mol % of organotelluride with respect to the
thiol were used.
c
T50 for PhSeSePh (commonly used reference compound) was found to be
796 ( 84) seconds, according to DTT oxidation test.
d
NADPH consumption was monitored by UV spectroscopy (340 nm); 10 mol
% of organoselenide and 1 mol % of organotelluride with respect to GSH were
used.
GPx-like properties.
4.2. General procedure for the synthesis of β-arylthio- and β -arylseleno-
amines
3. Conclusions
Potassium hydroxide (1.1 eq.) was added to a solution of thiol 1a-e
or selenol 4a-g (1.0 eq.) in DMF (2 mL) under inert atmosphere (N2) at
0 °C. Then NeH aziridine 2a-c (1.2 eq.) was slowly added and the
mixture was stirred at 0 °C for 3 h. Afterwards the reaction was diluted
with EtOAc (5 mL) and saturated aq. NH4Cl (2 mL) was added. The
organic phase was collected and the aqueous phase was extracted with
EtOAc (2 × 5 mL). The combined organic phases were dried over
Na2SO4 and concentrated under reduced pressure. The residue was
purified by flash column chromatography to yield the desired β -ar-
ylthioamine 3 or β-arylselenoamine 5.
We have used a fast and easy synthetic strategy to obtain ring
opening reactions of strained heterocycles with chalcogen-containing
nucleophiles to afford novel CA activators. Many of them showed an
interesting pattern of activation against four of the most important
physiologic carbonic anhydrase isoforms such as the cytosolic enzymes
hCA I, II and VII, but also, against the mitochondrial isoform hCA VA.
Compounds with selenium and in particular tellurium atoms are also
able to prevent the generation of ROS metabolites that cause oxidative
stress and cellular damage. In this context, CAAs may be used in the
memory therapy and cognitive neurodegenerative disorders where the
levels of ROS are particular high, but also in the metabolic pathologies
where is present a decreased function of hCA VA without increased ROS
levels.
1-(Phenylthio)propan-2-amine (3a):
Following the general procedure, thiophenol 1a (22 mg, 0.2 mmol)
and 2-methylaziridine 2a (14 mg, 0.24 mmol) gave, after purification
by flash column chromatography (petroleum ether:EtOAc 1:2), 1-
(phenylthio)propan-2-amine 3a (17 mg, 51%).
4. Experimental part
1H NMR (400 MHz, CDCl3): δ (ppm) 1.23 (3H, d, J = 6.3 Hz), 2.49
(2H, bs, NH2), 2.84 (1H, dd, J = 7.9,13.1 Hz, CHaHbS), 3.07 (1H, dd,
J = 4.7, 13.1 Hz, CHaHbS), 3.09–3.17 (1H, m, CHNH2), 7.19–7.23 (1H,
m), 7.28–7.32 (2H, m), 7.38–7.41 (2H, m). 13C NMR (100 MHz, CDCl3):
δ (ppm) 22.4, 43.6, 46.2, 126.3, 129.0, 129.8, 135.9. All recorded
spectroscopic data matched those reported in the literature [41].
1-((2-Bromophenyl)thio)propan-2-amine (3b)
4.1. General
Anhydrous solvents and all reagents were purchased from Sigma-
Aldrich, Alfa Aesar and TCI. All reactions involving air- or moisture-
sensitive compounds were performed under a nitrogen atmosphere
using dried glassware and syringes techniques to transfer solutions.
Nuclear magnetic resonance (1H NMR, 13C NMR, 19F NMR, 77Se-NMR
and 125Te-NMR) spectra were recorded using a Bruker Advance III
400 MHz spectrometer in DMSO-d6. (PhSe)2 was used as an external
reference for 77Se NMR (δ = 461 ppm). Diphenyl ditelluride (PhTe)2
was used as an external reference for 125Te NMR (δ = 420 ppm).
Chemical shifts are reported in parts per million (ppm) and the coupling
constants (J) are expressed in Hertz (Hz). Splitting patterns are desig-
nated as follows: s, singlet; d, doublet; t, triplet; q, quadruplet; m,
multiplet; brs, broad singlet; dd, double of doublets. The assignment of
exchangeable protons (OH and NH) was confirmed by the addition of
D2O. Analytical thin-layer chromatography (TLC) was carried out on
Merck silica gel F-254 plates. Flash chromatography purifications were
performed on Merck Silica gel 60 (230–400 mesh ASTM) as the sta-
tionary phase and ethyl acetate/n-hexane were used as eluents. Melting
points (mp) were measured in open capillary tubes with a Gallenkamp
Following the general procedure, 2-bromobenzenethiol 1b (38 mg,
0.2 mmol) and 2-methylaziridine 2a (14 mg, 0.24 mmol) gave, after
purification by flash column chromatography (petroleum ether:EtOAc
1:2), 1-((2-bromophenyl)thio)propan-2-amine 3b (21 mg, 43%).
1H NMR (400 MHz, CDCl3): δ (ppm) 1.23 (3H, d, J = 6.3 Hz), 2.23
(2H, bs, NH2), 2.83 (1H, dd, J = 7.9,12.9 Hz, CHaHbS), 3.05 (1H, dd,
J = 4.7, 12.9 Hz, CHaHbS), 3.11–3.19 (1H, m, CHNH2), 7.04 (1H, td,
J = 1.6, 7.9 Hz), 7.23–7.28 (1H, m), 7.28, 7.33 (1H, m), 7.55 (1H, dd,
J = 1.0, 7.9 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 22.8, 43.0, 45.9,
124.1, 126.9, 127.7, 128.9, 133.0, 137.4. MS (ESI, positive): 246.2
[M + H]+
.
1-((3-Bromophenyl)thio)propan-2-amine (3c)
Following the general procedure, 3-bromobenzenethiol 1c (47 mg,
0.25 mmol) and 2-methylaziridine 2a (17 mg, 0.30 mmol) gave, after
purification by flash column chromatography (petroleum ether:EtOAc
1:2), 1-((3-bromophenyl)thio)propan-2-amine 3c (33 mg, 54%).
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1HMR (400 MHz, CDCl3): δ (ppm) 1.18 (3H, d, J = 6.3 Hz), 1.86
(34 mg, 0.20 mmol) and 2-methylaziridine 2a (14 mg, 0.24 mmol) gave,
after purification by flash column chromatography (petroleum
ether:EtOAc 1:2), 1-(o-tolylselanyl)propan-2-amine 5c (31 mg, 67%).
1H NMR (400 MHz, CDCl3): δ (ppm) 1.20 (3H, d, J = 6.3 Hz), 2.08
(2H, bs, NH2), 2.42 (3H, s), 2.80 (1H, dd, J = 7.9, 12.2 Hz, CHaHbSe),
3.01 (1H, dd, J = 4.8, 12.2 Hz, CHaHbSe), 3.07–3.15 (1H, m, CHNH2),
7.09 (1H, td, J = 1.7, 7.4 Hz), 7.14 (1H, td, J = 1.3, 7.4 Hz), 7.14–7.19
(1H, m), 7.44 (1H, apd, J = 7.6 Hz). 13C NMR (100 MHz, CDCl3): δ
(ppm) 22.4, 23.3, 37.6, 46.7, 126.5, 126.8, 130.0, 131.0, 131.8, 139.5.
77Se NMR (76 MHz, CDCl3): δ (ppm) 206.7. MS (ESI, positive): 229.8
(2H, bs, NH2), 2.78 (1H, dd, J = 7.9, 13.0 Hz, CHaHbS), 3.02 (1H, dd,
J = 4.7, 13.0, CHaHbS), 3.06–3.14 (1H, m, CHNH2), 7.13 (1H, t,
J = 7.9 Hz), 7.25–7.31 (2H, m), 7.48 (1H, apt, J = 1.8 Hz). 13C NMR
(100 MHz, CDCl3): δ (ppm) 22.8, 43.6, 46.0, 122.7, 127.5, 128.9,
130.1, 131.4, 138.7. MS (ESI, positive): 246.6 [M + H]+
.
1-((4-Bromophenyl)thio)propan-2-amine (3d)
Following the general procedure, 4-bromobenzenethiol 1d (38 mg,
0.2 mmol) and 2-methylaziridine 2a (14 mg, 0.24 mmol) gave, after
purification by flash column chromatography (petroleum ether:EtOAc
1:2), 1-((4-bromophenyl)thio)propan-2-amine 3d (30 mg, 61%).
1H NMR (400 MHz, CDCl3): δ (ppm) 1.13 (3H, d, J = 6.3 Hz), 1.78
(2H, bs, NH2), 2.72 (1H, dd, J = 8.0, 13.1, CHaHbS), 2.96 (1H, dd,
J = 4.6, 13.1, CHaHbS), 2.99–3.08 (1H, m, CHNH2), 7.18 (2H, apd,
J = 8.5 Hz), 7.35 (2H, apd, J = 8.5 Hz). 13C NMR (100 MHz, CDCl3): δ
(ppm) 22.8, 43.9, 45.9, 119.8, 130.89, 131.84, 135.7. MS (ESI, posi-
[M + H]+
.
1-((2,6-Dimethylphenyl)selanyl)propan-2-amine (5d)
Following the general procedure, 2,6-dimethylbenzeneselenol 4d
(37 mg, 0.20 mmol) and 2-methylaziridine 2a (14 mg, 0.24 mmol) gave,
after purification by flash column chromatography (petroleum
ether:EtOAc 1:2), 1-((2,6-dimethylphenyl)selanyl)propan-2-amine 5d
(20 mg, 42%).
tive): 246.3 [M + H]+
.
1-(Pyrimidin-2-ylthio)propan-2-amine (3e)
1H NMR (400 MHz, CDCl3): δ (ppm) 1.21 (3H, d, J = 6.4 Hz), 2.58
(6H, s), 2.70 (1H, dd, J = 7.3, 12.0 Hz, CHaHbSe), 2.79 (1H, dd,
J = 5.5, 12.0 Hz, CHaHbSe) 2.92–3.08 (3H, m, CHNH2 partially over-
lapped con NH2), 7.07–7.14 (3H, m). 13C NMR (100 MHz, CDCl3): δ
(ppm) 22.4, 24.7, 47.6, 127.7, 128. 4, 136.5, 143.0. MS (ESI, positive):
Following the general procedure, pyrimidine-2-thiol 1e (23 mg,
0.2 mmol) and 2-methylaziridine 2a (14 mg, 0.24 mmol) gave, after
purification by flash column chromatography (petroleum ether:EtOAc
1:2), 1-(pyrimidin-2-ylthio)propan-2-amine 3e (14 mg, 41%).
1H NMR (400 MHz, CDCl3): δ (ppm) 1.25 (3H, d, J = 6.3 Hz), 2.09
(2H, bs, NH2), 3.09 (1H, dd, J = 6.7, 12.9 Hz, CHaHbS), 3.33 (1H, dd,
J = 4.9, 12.9 Hz, CHaHbS), 3.25–3.32 (1H, m, CHNH2), 6.96 (1H, t,
J = 4.8 Hz), 8.50 (2H, d, J = 4.8 Hz). 13C NMR (100 MHz, CDCl3): δ
(ppm) 22.5, 40.1, 46.8, 116.6, 157.2, 127.2. MS (ESI, positive): 169.9
244.1 [M + H]+
.
1-((4-Methoxyphenyl)selanyl)propan-2-amine (5e)
Following the general procedure, 4-methoxybenzeneselenol 4e
(56 mg, 0.30 mmol) and 2-methylaziridine 2a (21 mg, 0.36 mmol) gave,
after purification by flash column chromatography (petroleum
ether:EtOAc 1:2), 1-((4-methoxyphenyl)selanyl)propan-2-amine 5e
(40 mg, 55%).
[M + H]+
.
(S)-1-Phenyl-3-(phenylthio)propan-2-amine (3f)
Following the general procedure, thiophenol 1a (22 mg, 0.2 mmol)
and (S)-2-benzylaziridine 2b (32 mg, 0.24 mmol) gave, after purifica-
tion by flash column chromatography (petroleum ether:EtOAc 1:1), (S)-
1-phenyl-3-(phenylthio)propan-2-amine 3f (27 mg, 55%). All recorded
spectroscopic data matched those reported in the literature [42].
(S)-3-Methyl-1-(phenylthio)butan-2-amine (3 g)
1H NMR (400 MHz, CDCl3): δ (ppm) 1.17 (3H, d, J = 6.3 Hz), 2.40
(2H, bs, NH2), 2.73 (1H, dd, J = 8.0, 12.3 Hz, CHaHbSe), 2.93 (1H, dd,
J = 4.7,12.3 Hz, CHaHbSe), 3.0–3.08 (1H, m, CHNH2), 3.78 (3H, s,
CH3O), 6.80 (2H, apd, J = 8.6 Hz), 7.48 (2H, apd, J = 8.6 Hz). 13C
NMR (100 MHz, CDCl3): δ (ppm) 22.9, 39.6, 46.6, 55.3, 114.8, 119.6,
135.7, 159.3. MS (ESI, positive): 245.8 [M + H]+
.
Following the general procedure, thiophenol 1a (28 mg, 0.25 mmol)
and (S)-2-isopropylaziridine 2c (26 mg, 0.30 mmol) gave, after pur-
ification by flash column chromatography (petroleum ether:EtOAc 1:1),
(S)-3-methyl-1-(phenylthio)butan-2-amine 3 g (28 mg, 57%). All re-
corded spectroscopic data matched those reported in the literature
[41].
1-((4-Fluorophenyl)selanyl)propan-2-amine (5f)
Following the general procedure, 4-fluorobenzeneselenol 4f (35 mg,
0.20 mmol) and 2-methylaziridine 2a (14 mg, 0.24 mmol) gave, after
purification by flash column chromatography (petroleum ether:EtOAc
1:2), 1-((4-fluorophenyl)selanyl)propan-2-amine 5f (33 mg, 71%).
1H NMR (400 MHz, CDCl3): δ (ppm) 1.17 (3H, d, J = 6.3 Hz), 2.24
(2H, bs, NH2), 2.78 (1H, dd, J = 7.9, 12.3 Hz, CHaHbSe), 2.97 (1H, dd,
J = 4.8, 12.3 Hz, CHaHbSe), 3.01–3.1 (1H, m, CHNH2), 6.95 (2H, apt,
J = 8.7 Hz), 7.50 (2H, apdd, J = 8.7 Hz). 13C NMR (100 MHz, CDCl3): δ
1-(Phenylselanyl)propan-2-amine (5a)
Following the general procedure, benzeneselenol 4a (31 mg,
0.2 mmol) and 2-methylaziridine 2a (14 mg, 0.24 mmol) gave, after
purification by flash column chromatography (petroleum ether:EtOAc
1:2), 1-(phenylselanyl)propan-2-amine 5a (21 mg, 48%).
2
(ppm) 23.1, 39.5, 46.6, 116.3 (d, JC-F = 21.5 Hz), 124.2 (4JC-
F = 3.4 Hz), 135.4 (3JC-F = 7.9 Hz), 162.4 (1JC-F = 247.1 Hz). 77Se NMR
1H NMR (400 MHz, CDCl3): δ (ppm) 1.19 (3H, dd, J = 6.3, 12.4 Hz),
2.45 (2H, bs, NH2), 2.84 (1H, dd, J = 7.7, 12.2 Hz, CHaHbSe), 3.05 (1H,
dd, J = 4.8, 12.2 Hz, CHaHbSe), 3.08–3.16 (1H, m, CHNH2), 2.24–2.30
(3H, m), 7.52–7.56 (2H, m). 13C NMR (100 MHz, CDCl3): δ (ppm) 23.1,
38.7, 46.7, 127.0, 129.1, 130.0, 132.8. 77Se NMR(76 MHz, CDCl3): δ
(76 MHz, CDCl3): δ (ppm) 251.0. 19F NMR (376 MHz, CDCl3): δ (ppm)
−114.6 (tt, J = 5.4, 8.7 Hz). MS (ESI, positive): 234.4 [M + H]+
4-((2-Aminopropyl)selanyl)-N,N-dimethylaniline (5g)
.
Following the general procedure, 4-(dimethylamino)benzeneselenol
4g (40 mg, 0.20 mmol) and 2-methylaziridine 2a (14 mg, 0.24 mmol)
gave, after purification by flash column chromatography (petroleum
ether:EtOAc 1:2), 4-((2-aminopropyl)selanyl)-N,N-dimethylaniline 5g
(32 mg, 62%).
(ppm) 254.1. MS (ESI, positive): 216.5 [M + H]+
1-(p-Tolylselanyl)propan-2-amine (5b)
.
Following the general procedure, 4-methylbenzeneselenol 4b
(43 mg, 0.25 mmol) and 2-methylaziridine 2a (17 mg, 0.30 mmol) gave,
after purification by flash column chromatography (petroleum
ether:EtOAc 1:2), 1-(p-tolylselanyl)propan-2-amine 5b (30 mg, 53%).
1H NMR (400 MHz, CDCl3): δ (ppm) 1.18 (3H, d, J = 6.3 Hz), 2.31
(3H, s), 2.48 (2H, bs, NH2), 2.79 (1H, dd, J = 7.9, 12.4 Hz, CHaHbSe),
2.99 (1H, dd, J = 4.8, 12.4 Hz, CHaHbSe), 3.04–3.12 (1H, m, CHNH2),
7.07 (2H, apd, J = 8.0 Hz), 7.42 (2H, apd, J = 8.0 Hz). 13C NMR
(100 MHz, CDCl3): δ (ppm) 21.1, 23.0, 38.8, 46.7, 125.9, 133.4, 137.2.
77Se NMR (76 MHz, CDCl3): δ (ppm) 246.7. MS (ESI, positive): 230.2
1H NMR (400 MHz, CDCl3): δ (ppm) 1.18 (3H, d, J = 6.4 Hz), 2.64
(2H, bs, NH2), 2.69 (1H, dd, J = 8.2, 12.4 Hz, CHaHbSe), 2.90 (1H, dd,
J = 4.7, 12.4 Hz, CHaHbSe), 2.94 (6H, s, (CH3)2N), 3.01–3.09 (1H, m,
CHNH2), 6.61 (2H, apd, J = 8.8 Hz), 7.43 (2H, apd, J = 8.8 Hz). 13C
NMR (100 MHz, CDCl3): δ (ppm) 22.6, 39.4, 40.3, 46.7, 133.1, 113.9,
136.0, 150.2. MS (ESI, positive): 258.8 [M + H]+
.
(S)-1-Phenyl-3-(phenylselanyl)propan-2-amine (5h)
Following the general procedure, benzeneselenol 4a (31 mg,
0.2 mmol) and (S)-2-benzylaziridine 2b (32 mg, 0.24 mmol) gave, after
purification by flash column chromatography (petroleum ether:EtOAc
1:1), (S)-1-phenyl-3-(phenylselanyl)propan-2-amine 5h (37 mg, 64%).
All recorded spectroscopic data matched those reported in the literature
[M + H]+
.
1-(o-Tolylselanyl)propan-2-amine (5c)
Following the general procedure, 2-methylbenzeneselenol 4c
520

D. Tanini, et al.
BioorganicChemistry87(2019)516–522
[42].
3.85 (6H, s) 6.97 (2H, s). 13C NMR (100 MHz, CDCl3): δ (ppm) 22.5,
(S)-3-Methyl-1-(phenylselanyl)butan-2-amine (5i)
24.5, 47.8, 56.3, 60.9, 104.2, 116.4, 138.4, 153.4. 125Te NMR
Following the general procedure, benzeneselenol 4a (39 mg,
0.25 mmol) and (S)-2-isopropylaziridine 2c (26 mg, 0.30 mmol) gave,
after purification by flash column chromatography (petroleum
ether:EtOAc 1:1), (S)-3-methyl-1-(phenylselanyl)butan-2-amine 5i
(37 mg, 61%). All recorded spectroscopic data matched those reported
in the literature [43].
(126 MHz, CDCl3) δ (ppm): 434.6. MS (ESI, positive): 356.4 [M + H]+
(S)-1-Phenyl-3-(phenyltellanyl)propan-2-amine (7f)
.
Following the general procedure, 1,2-diphenylditellane 6a (41 mg,
0.1 mmol) and (S)-2-benzylaziridine 2b (32 mg, 0.24 mmol) gave, after
purification by flash column chromatography (petroleum ether:EtOAc
1:1), (S)-1-phenyl-3-(phenyltellanyl)propan-2-amine 7f (39 mg, 57%).
All recorded spectroscopic data matched those reported in the literature
[26].
4.3. General procedure for the synthesis of β-aryltelluro amines
(S)-3-Methyl-1-(phenyltellanyl)butan-2-amine (7g)
Sodium borohydride (3.0 eq.) was added to a suspension of diaryl
ditelluride 6a-e (1.0 eq.) in dry EtOH (2 mL) under inert atmosphere
(N2) at 0 °C. Then NeH aziridine 2a-c (2.4 eq.) was slowly added and
the mixture was allowed to warm to room temperature and then stirred
2 h. Afterwards the reaction was diluted with EtOAc (5 mL) and satu-
rated aq. NH4Cl (2 mL) was added. The organic phase was collected and
the aqueous phase was extracted with EtOAc (2 × 5 mL). The combined
organic phases were dried over Na2SO4 and concentrated under re-
duced pressure. The residue was purified by flash column chromato-
graphy to yield the desired β -aryltelluroamine 7.
Following the general procedure, benzeneselenol 4a (41 mg,
0.1 mmol) and (S)-2-isopropylaziridine 2c (26 mg, 0.30 mmol) gave,
after purification by flash column chromatography (petroleum
ether:EtOAc 1:1), (S)-3-methyl-1-(phenyltellanyl)butan-2-amine 7g
(35 mg, 60%). All recorded spectroscopic data matched those reported
in the literature [39].
4.4. Carbonic anhydrase enzyme activation assay
An Sx.18Mv-R Applied Photophysics (Oxford, UK) stopped-flow
instrument has been used to assay the catalytic activity of various CA
isozymes for CO2 hydration reaction [33]. Phenol red (at a concentra-
tion of 0.2 mM) was used as indicator, working at the absorbance
maximum of 557 nm, with 10 mM Hepes (pH 7.5) as buffer 0.1 M
Na2SO4 (for maintaining constant ionic strength), following the CA-
catalyzed CO2 hydration reaction for a period of 10 s at 25 °C. The CO2
concentrations ranged from 1.7 to 17 mM for the determination of the
kinetic parameters and activation constants. For each activator at least
six traces of the initial 5–10% of the reaction have been used for de-
termining the initial velocity. The uncatalyzed rates were determined in
the same manner and subtracted from the total observed rates. Stock
solutions of activators (10 mM) were prepared in distilled-deionized
water and dilutions up to 1 nM were done thereafter with the assay
buffer. Activator and enzyme solutions were pre-incubated together for
15 min (standard assay at room temperature) prior to assay, in order to
allow for the formation of the E–A complex. The activation constant
(KA), defined similarly with the inhibition constant KI, can be obtained
by considering the classical Michaelis–Menten equation (Eq. (1)), which
has been fitted by non-linear least squares by using
1-(Phenyltellanyl)propan-2-amine (7a)
Following the general procedure, 1,2-diphenylditellane 6a (41 mg,
0.1 mmol) and 2-methylaziridine 2a (14 mg, 0.24 mmol) gave, after
purification by flash column chromatography (petroleum ether:EtOAc
1:2), 1-(phenyltellanyl)propan-2-amine 7a (28 mg, 53%).
1H NMR (400 MHz, CDCl3): δ (ppm) 1.23 (3H, d, J = 6.2 Hz), 2.31
(2H, bs, NH2), 2.95 (1H, dd, J = 7.0, 11.8 Hz, CHaHbTe), 3.11 (1H, dd,
J = 5.2, 11.8 Hz, CHaHbTe), 3.14–3.21 (1H, m, CHNH2), 7.2–7.24 (2H,
m), 7.28–7.32 (1H, m), 7.75–7.78 (2H, m). 13C NMR (100 MHz, CDCl3):
δ (ppm) 21.7, 24.3, 47.8, 111.6, 127.7, 129.2, 138.4. 125Te NMR
(126 MHz, CDCl3): δ (ppm) 390.5. MS (ESI, positive): 266.1 [M + H]+
1-(p-Tolyltellanyl)propan-2-amine (7b)
.
Following the general procedure, 1,2-di-p-tolylditellane 6b (44 mg,
0.1 mmol) and 2-methylaziridine 2a (14 mg, 0.24 mmol) gave, after
purification by flash column chromatography (petroleum ether:EtOAc
1:2), 1-(p-tolyltellanyl)propan-2-amine 7b (36 mg, 65%).
1H NMR (400 MHz, CDCl3): δ (ppm) 1.19 (3H, d, J = 6.2 Hz), 2.15
(2H, bs, NH2), 2.33 (3H, s), 2.87 (1H, dd, J = 7.1, 11.9 Hz, CHaHbTe),
3.04 (1H, dd, J = 5.1, 11.9 Hz, CHaHbTe), 3.08–3.15 (1H, m, CHNH2),
7.01 (2H, apd, J = 7.9 Hz), 7.64 (2H, apd, J = 7.09 Hz). 13C NMR
(400 MHz, CDCl3): δ (ppm) 21.2, 22.0, 24.4, 47.7, 107.3, 130.2, 137.7,
138.8. 125Te NMR (126 MHz, CDCl3): δ (ppm) 377.1. MS (ESI, positive):
PRISM 3:
Vmax
V =
{1 + KM/[S](1 + [A]f /KA)}
(1)
280.4 [M + H]+
.
where [A]f is the free concentration of activator. Working at substrate
concentrations considerably lower than KM ([S] ≪ KM), and considering
that [A]f can be represented in the form of the total concentration of the
enzyme ([E]t) and activator ([A]t), the obtained competitive steady-
state equation for determining the activation constant is given by Eq.
(2):
1-((4-Methoxyphenyl)tellanyl)propan-2-amine (7c)
Following the general procedure, 1,2-bis(4-methoxyphenyl)di-
tellane 6c (47 mg, 0.1 mmol) and 2-methylaziridine 2a (14 mg,
0.24 mmol) gave, after purification by flash column chromatography
(petroleum ether:EtOAc 1:2), 1-((4-methoxyphenyl)tellanyl)propan-2-
amine 7c (41 mg, 70%).
1H NMR (400 MHz, CDCl3): δ (ppm) 1.21 (3H, d, J = 6.3 Hz), 2.86
(1H, dd, J = 7.1, 12.0 Hz, CHaHbTe), 2.92 (2H, bs, NH2), 2.99 (1H, dd,
J = 5.5, 12.0 Hz, CHaHbTe), 3.08–3.16 (1H, m, CHNH2), 3.78 (3H, s,
CH3O), 6.75 (2H, apd, J = 8.7 Hz), 7.69 (2H, apd, J = 8.7 Hz). 13C
NMR (100 MHz, CDCl3): δ (ppm) 21.3, 23.9, 47.9, 55.1, 100.3, 115.2,
141.0, 159.8. 125Te NMR (126 MHz, CDCl3): δ (ppm) 379.8. MS (ESI,
V KA
0
V =
{KA + ([A]t 0.5{([A]t + [E]t + KA) ([A]t + [E]t + KA)2 4[A]t [E]t })1/2
}
(2)
where V0 represents the initial velocity of the enzyme-catalyzed reac-
tion in the absence of activator. The enzymes were recombinant ones,
prepared in-house as reported earlier [28–31].
positive): 295.9 [M + H]+
.
1-((3,4,5-Trimethoxyphenyl)tellanyl)propan-2-amine (7d)
Following the general procedure, 1,2-bis(3,4,5-trimethoxyphenyl)
ditellane 6d (59 mg, 0.1 mmol) and 2-methylaziridine 2a (14 mg,
0.24 mmol) gave, after purification by flash column chromatography
(petroleum ether:EtOAc 1:2), 1-((3,4,5-trimethoxyphenyl)tellanyl)
propan-2-amine 7d (43 mg, 61%).
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