Phosphorus versus Sulfur: Discovery of Benzenephosphonamidates as Versatile Sulfonamide-Mimic Chemotypes Acting as Carbonic Anhydrase Inhibitors

Article abstract of DOI:10.1002/chem.201805039

The first zinc-binding group (ZBG) to have been identified as inhibitor of the metallo-enzymes carbonic anhydrases (CA, EC 4.2.1.1) was the sulfonamide. From then on several classes of zinc-binders have been described. This work reports the benzenephospon

Full text of DOI:10.1002/chem.201805039

A Journal of
Accepted Article
Title: Phosphorus vs sulphur: discovery of benzenephosphonamidates
as new versatile sulfonamide-mimic chemotypes acting as
carbonic anhydrase inhibitors
Authors: Alessio Nocentini, Paola Gratteri, and Claudiu T. Supuran
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COMMUNICATION
Phosphorus vs sulphur: discovery of benzenephosphonamidates
as new versatile sulfonamide-mimic chemotypes acting as
carbonic anhydrase inhibitors
Alessio Nocentini,[a,b] Paola Gratteri,*[a] and Claudiu T. Supuran *[b]
Abstract: The first zinc binding group (ZBG) to have been identified
as inhibitor of the metallo-enzymes carbonic anhydrases (CA, EC
4.2.1.1) was the sulfonamide. From then on several classes of zinc-
binders have been described. Herein we propose the
benzenephosponamidates as a new chiral aromatic sulfonamide-
mimic ZBG able to meet the requirements for effectively binding the
enzyme active site. Several low micromolar CA I, II, VII, IX inhibitors
were thus detected. Kinetic studies, QM-polarized ligand docking
and MM-GBSA in silico methods were used to characterize this
newly identified CA inhibitor chemotype.
the coordinated nitrogen atom satisfying the hydrogen bond
acceptor character of Thr199 side chain (Figure 1).[3]
main drawback related to sulfonamides is a low membrane-
permeability and likely allergic reactions aroused in
patients,[2,3] as well as their non-selective inhibition of many
CA isoforms.
As result of a straightforward ligand-based drug design
process, sulfamides and sulfamates arose as sulfonamide
most related isosters.[9] An additional heteroatom confers to
the zinc-binding group a more extended H-bond network
forming ability. In the last period, some of us ventured out
from the sulfonamides shell presenting additional CA-ZBG,
among which carboxylates, hydroxamates, phosphonates
and lately crucial advances have been made in this field,
A
Searching for new chemotypes able to yield enzymatic
inhibition is a main feature of the ongoing research
regarding the metallo-enzymes carbonic anhydrases (CA,
EC 4.2.1.1).[1-4] Their role in cells as well as in complex
organisms, is primarily related to the ability to reversibly
catalyse the carbon dioxide hydration reaction, affording
bicarbonate and a proton.[5] Such an equilibrium is crucial
for a vast array of physio/pathological processes, with
ligands targeting both human (h) and pathogens isozymes
possessing pharmacologic applications in the management
of human diseases such as glaucoma, edema, obesity,
epilepsy, hypoxic tumors, neuropathic pain, or arthritis, and
with
mono-
and
dithiocarbammates,
xanthates,
thioxanthates and boroles identified as novel zinc-
binders.[10-16]
Most of these inhibitory chemotypes bind in deprotonated
form, as anions, straightly coordinating the Zn(II) ion from
the enzyme active site.[17] There is overwhelming X-ray
crystallographic evidence showing this type of binding for
sulfonamides, sulfamates, sulfamides, dithiocarbamates,
and their derivatives, hydroxamates, some carboxylates,
one phosphonate, and some boroles.[3,10-16]
for the development of anti-infectives with
a
new
mechanism of action.[2,3,6] Up to now, seven distinct genetic
families have been identified, namely the α-, β-, γ-, δ-, ζ-, η-
and θ-CAs.[2,7,8] All CAs known so far are metal ion-
dependent enzymes, with a metal-hydroxide species within
the active site cavity acting as a nucleophile in the catalytic
cycle. The metal ions identified in different CAs gather
Zn(II), Cd(II), Co(II) or Fe(II), with the first ion being the
cofactor present in α- and β-isozymes.[2,7,8] In humans, 15
α-CA isoforms are known, CA I−CA VA, CA VB, CA VI−CA
XIV.[2]
A recent comparison between carbon- and sulphur-based
ZBGs provided for mechanistic and structural insights over
a
pattern of chemotypes featuring rather diverse
hybridizations and electronic properties of the central
element.[17] Of note, phosphorus compounds did not enjoy
an analogue attention and investigation as that dedicated to
carbon and mainly sulphur compounds, thus being only
scarcely investigated as CAIs. However, among
pseudopeptides
containing
a
phosphorus
atom,
-
A crucial event mainly occurring in the enzyme inhibition
process is the inhibitor binding to the metal ion. Most CA
inhibitors owe their activity to zinc binding groups (ZBGs) of
the sulfonamide type, which displaces the zinc-bound
nucleophile (water molecule or hydroxide ion).[9] The
majority of the clinically used CAIs are sulfonamides.
Structural resolutions of ligand-CA adducts highlighted that
the sulfonamide group is an ideal ligand for the CA active
site owing to the combination of the coordination bond
between the negatively charged nitrogen with the positively
charged zinc(II) ion, and of the presence of one proton on
phosphonamidates of the RNHPO2 types are considered
the closest analogues of the high energy tetrahedral
transition state of the amide bond hydrolysis and such
compounds were mostly investigated as protease
inhibitors.[18,19] Phosphonamidates and phosphinamidates
have gained increasing interest not only for the unique
structures but also the distinguished properties in
pharmaceutical applications and material science.[20,21] In
the context of CAs, it should be stressed that only a few
phosphonates have been investigated as inhibitors, and just
one compound, foscarnet was crystallized bound to hCA I,
witnessing the zinc-binder character of such an acidic
function.[16]
[a]
[b]
Dr. A. Nocentini, Prof. P. Gratteri
Department NEUROFARBA
section; Laboratory of Molecular Modeling Cheminformatics
QSAR, University of Firenze, via Ugo Schiff 6, 50019 Sesto
Fiorentino (Italy). e-mail: paola.gratteri@unifi.it
Dr. A. Nocentini , Prof. C.T. Supuran
The electronic properties of phosphorus, that belongs to
group V, do elicit interesting different structural features for
a phosphonamidate compared to the lead sulfonamide,
though likewise in this latter, a tetrahedral geometry is
maintained for the central phosphorus atom. Conversely,
carbon-based ZBGs exhibit a trigonal planar geometry due
to the sp2 hybridization (Figure 1). Comparing
phosphonamidates and sulfonamides, one of the S=O
–
Pharmaceutical and nutraceutical
&
Department NEUROFARBA
– Pharmaceutical and nutraceutical
section, University of Firenze, via Ugo Schiff 6, 50019 Sesto
Fiorentino (Italy); e-mail: claudiu.supuran@unifi.it
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201805039
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Figure 1. Schematic representation of the binding mode of carbon, sulphur and phosphorus zinc-binders chemotypes.
double bonds of the sulfonamide is substituted by a single
P-X bond which can be exploited to incorporate an
additional amino function or alternative substitutions, such
as alkyl phosphoesters. This implies that an additional
functionalization can be appended to the ZBG maintaining
pivotal elements present in the lead, such as the NH2 and
one P=O (S=O in the lead), thus likely extending the
interaction network with the enzymatic counterpart (Figure
phenylphosphonic diamide 2 and alkyl phosphonamidates
3-10 to inhibit a pattern of hCAs (i.e. hCA I, II, IV, VII, and
IX) and studied in silico their binding mode within the
enzyme active site.
A straightforward strategy was used to synthesize the
compounds starting from phenylphosphonic dichloride
Phenylphosphonic diamide was obtained by reacting
with an aqueous solution of 35% ammonia. Derivative
1.
1
2
2
1). Indeed, it should be noted that the so-called “deep
was the common intermediate to easily obtain alkyl
phosphonamidates 3-10 by reaction with the proper alcohol,
as described in the literature.[23] Unlike the diamide
[3]
water” area
in the hydrophobic half of the hCAs active
site, is not reached by the sulfonamide moiety, thus leaving
an empty targetable-pocket that is defined by residues
Trp9, Val121, Val143 and Leu198 (taking CA II as
representative isoenzyme).[3] Moreover, as a result of the
electronic properties of the central atom and of the
geometrical features, the acid-base properties of
benzenephosphonamidates 2-10 considerably differ from
those of the sulfonamide lead. A remarkable difference
derivative 2, all alkyl phosphonamidates 3-10 were obtained
as racemic mixtures of both R and S optical isomers. All the
obtained derivatives were properly characterized by means
of 1H-NMR, 13C-NMR, 31P-NMR as well as MS (ESI).
Table 1: Inhibition data of human CA isoforms I, II, IV, VII and IX with
phenylphosphonic diamide
2 and alkyl phosphonamidates 3-10 and the
standard sulfonamide inhibitor acetazolamide (AAZ) by a stopped flow
CO2 hydrase assay.[26]
indeed
exists
between
benzenesulfonic
and
KI (µM)a
phenylphosphonic acid (pKa of -2.8 and 1.85, respectively),
that is even more evident when compared to benzoic acid
pKa (4.2)[17] Likewise, benzenesulfonamide (pKa of 10.2)
acts as stronger acid than benzamide (pKa of 14.5). In this
context, it has been long debated how the pKa of the ZBG
influences ligands CAI properties, with the conclusion being
that it is not the most influential factor, although it is a
relevant one.[17] Indeed, the sulfonic acid is a weaker CAI
than the corresponding sulfonamide.[17] It is well established
that a zinc-binder must be deprotonated to efficiently bind
the zinc ion, but a medium-range dissociation is preferable
over too strong or too weak ones.[17] In this context, a
brand-new crystallographic study outlined the binding mode
of weak acid to CA II, namely benzylcarbamate.[22]
Mimicking bicarbonate binding, the carbamate moiety
directly coordinates the catalytic zinc ion. Although the
difference between the pKa of carbonic acid and the
carbamate is huge, the deprotonation of the -NH2 group is
promoted into the CA active site.[22]
R
-
Cmp
CAI
CA II
CA IV
346.9±22
610.2±34
>1000
CA VII
39.1±3.0
51.9±3.6
98.0±5.3
CA IX
7.6±0.6
16.9±0.9
45.3±2.8
2
3
77.8±4.2
145.6±8.3
32.8±2.6
39.8±3.2
-CH3
4
-CH2CH3
-(CH2)2CH3
-CH(CH3)2
-(CH2)3CH3
-(CH2)2OCH3
-(CH2)2Cl
-CH2CCH
-
338.6±22 160.6±9.8
5
589.9±31
730.0±45
876.3±51
961.2±54
322.2±23
575.8±36
0.25
459.4±28
348.8±20
750.0±48
520.1±28
95.4±7.2
465.3±30
0.01
>1000
247.6±18 116.2±8.5
406.2±23 212.0±13
516.1±28 123.5±7.2
727.3±41 250.9±15
160.5±9.1 146.3±8.9
602.8±35 323.3±19
6
>1000
7
>1000
8
>1000
9
916.6±48
>1000
10
AAZ
0.07
0.01
0.03
a. Inhibition data are expressed as means ± SEM of 3 different assays.
Among the twelve catalytically active hCAs, the isoforms
chosen to work out our proof-of-concept were the cytosolic
hCA I and II (widespread house-keeping enzymes involved
in a host of physiologic processes), the membrane-bound
hCA IV (involved in glaucoma, retinitis pigmentosa, stroke
and rheumatoid arthritis), hCA VII (drug-target for epilepsy),
and the tumor-associated hCA IX (abundant in hypoxic
tumors and recently validated as antitumor target).[2,24,25]
Phosphonamidates have been shown to be fully stable up
to pH 7 with significant hydrolysis evidenced at pH below
6.20. A longer CA/inhibitor preincubation (1h) than that
Scheme 1. Synthesis of benzenephosphonamidate derivatives.
Considering what mentioned above and our interest in the
development of novel classes of CAIs, alternative to the
sulfonamides, we have explored the capability of
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Figure 2. QPLD/MM-GBSA predicted poses of the studied compounds with hCA II: a)
2
(pink), b)
3
-(R) (plum) and
3-(S) (violet), c) 4-(R) (yellow), 7-
(R) (magenta), 9-(R) (dark green) and d) 4-(S) (pink), 7-(S) (purple), 9-(S) (blue). e) docking of not dissociated 2 within hCA II active form (Zn-bound
hydroxide ion).
usually used for sulfonamide derivatives (15 min) was
necessary to observe the CAs inhibitory efficacy of
phosphonamidates derivatives 2-10. The data of Table 1
show that most screened derivatives inhibit hCAs in the
micromolar range depending on the substitution pattern on
the phosphorus atom. The simplest and less sterically
mode and the unexpected inhibitory trend of Table 1,
computational investigations were undertaken. Quantum-
polarized ligand dockings (QPLD) were performed on hCA
II preparing both enantiomers of phosphonamidates 3-10 in
the negatively-charged form and the selected poses were
submitted to MM-GBSA calculations (ΔG bind data, Table
2). The combination of QPLD and GBSA methods has been
recently shown to provide reliable docking/scoring results
with low deviations from ligand/target crystallographic
geometries.[27,28]
hindered compounds
2 and 3 arose as the best inhibitors
against all the evaluated isoforms. These compounds
showed target-promiscuity, comparably inhibiting hCA II, VII
and IX, which were the most affected isoforms, with
inhibition constants (KIs) in the range of 32.8-47.1 µM, 39.1-
51.9 µM and 7.6-20.7 µM, respectively. Phenylphosphonic
It is worth noting that phenylphosphonic diamide
2 assumed
a
sulfonamide-like binding mode with the negatively
diamide
2
exhibited a low micromolar efficacy against hCA
charged nitrogen coordinating the Zn ion and the NH
donating a H-bond to Thr199 side chain hydroxyl group.
Moreover, The P=O moiety accepted a H-bond from the
IX with a KI of 7.6 µM and a greater than four-fold selective
action for the tumor-associated isozymes over the
remaining considered ones. However, the introduction of
bulkier substituents of the phosphoester type on the
phosphorus atom leads to a noticeable change in the CA
inhibitory properties, with the further elongation of the
aliphatic chain being deleterious for the inhibition almost
unambiguously against all isozymes. Indeed, derivatives 4-
10 showed a feeble worsening of efficacy against isozyme
IX, with KIs settling in the range 45.3-323.3 µM. The
roomier active site of hCA IX likely better accommodates
the ligands rearrangement due to the presence of
increasingly bulkier motifs. Elongation of the R group elicits
a wider binding worsening to other isoforms, with the case
of hCA IV being noteworthy since 4-10 do not inhibit the
isozyme up to 10 mM. A diverse trend was observed for the
same residue backbone NH. The other NH2 of
3 slightly
protrudes into the internal pocket lined by Val143, Trp9,
Val121, Leu198. The aromatic ring is π-alkyl stacked by
Val121 and Leu198 side chains (Figure 2A).
Not surprisingly, two alternative and clearly distinct binding
modes were found for 3-10 according to the R/S
configuration of the ZBG central atom. With the exception of
the
less
sterically
hindered
methyl
P-
phenylphosphonamidate
3
(Figure 2B), the alkyl
phosphoester groups accommodate within two distinct
pockets of hCA II active site depending on the considered
configuration. The stabilization of a unique binding mode for
enantiomer was driven by the common necessity to bind
the Zn through the NH moiety and to establish a proper
network of H-bonds with the residues nearby. As a result,
the (R) enantiomers assumed an orientation whereby the
coordinating NH protrudes towards the target pocket and
the P=O is in H-bond distance with Thr199, thus exposing
the alkyl groups to the pocket defined by Ala65, Asn244,
His64 (Figure 2C). In a completely opposite manner, the (S)
enantiomers maintain mostly the same set of interactions,
except for the alkyl moieties that occupy the target “deep
water” area lined by the hydrophobic Val121, Trp9, Leu198
and Val143 side chains (Figure 2D). According to literature
reports, the aromatic ring positioning is deeply influenced
by the ZBG nature, namely by the metal coordination
pattern and by the network of H-bonds formed, with a 90°
rotation occurring between the (R) and (S) subsets. The
chloroethyl derivative
Table 1 not consistent with what mentioned above (KIs of
322.2, 95.4, 916.6, 160.5, 146.3, respectively). Although
9, being the inhibition data reported in
9
incorporates one of the unwieldy substituents on the central
ZBG atom, only a slight activity lowering is observed in
comparison to equally long motifs-bearing congeners, such
as 6-8. Plausible halogen-bond interactions could take
place within the binding site cavities and justify the
exhibited trend. A covalent bond involving the chlorine atom
could also occur, although it should be verified that this
hypothesis may take place.
The phosphonamidate was designed as ZBG to likely
increase the binding within CAs active site by additional
functionalization of the ZBG. The micromolar inhibitory
profiles of derivatives prove the capability of the newly
designed molecules to act as CAIs. To clarify the binding
small methyl group of derivative
3 allowed intermediate
binding modes for both enantiomers than those above
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depicted (Figure 2B), since the methyl groups do not point
to any precise pocket.
zinc-binding efficacy (as in the case of benzylcarbammate)
[22] or alternatively an anchoring binding mode as depicted in
Figure 2e rather than coordinating the Zn ion the anionic
form. In this latter case, the efficacy of binding might be
considerably reduced and should be re-considered because
of the lacking coordination to the metal ion.
Table 2: MM-GBSA ΔG bind data of derivatives 2-11
with hCA II
MM-GBSA
Cmpd
ΔG bind (kcal/mol)
In conclusion, altogether the data here reported provide
evidence that phosponamidates can be efficiently used as a
new class of CAIs, presenting interesting inhibition
properties and a new, chiral binding mode to the CAs active
site. It might be worth to evaluate such new chemotypes for
inhibition of different metallo-enzymes, since phosphonates
more effectively act against other enzymes, such as
peptidases, compared to sulfonamides.[18,19] Insights on the
experimental pKa and kinetic studies on single enantiomers
will be helpful to precisely work out the reported SAR as
well as crystallography studies to validate the proposed
binding mode.
2
-36.732
(R)
(S)
3
4
-49.611
-41.379
-47.993
-33.819
-46.702
-50.216
-49.410
-46.762
-41.460
-46.549
-54.298
-52.174
-54.590
-48.379
-55.858
-47.840
5
6
7
8
9
10
The binding free energy data (Table 2) clearly ascribed to
(S)-enantiomers the role of eutomers within the racemic
mixtures. It should be considered that, unlike the “deep
water” cleft, the pocket that fits the alkyl moieties of (R)
enantiomers could be occupied by water molecules that are
actually present in almost all X-ray solved hCAs/ligand
structures. The displacement of such water molecules could
be associated with unfavourable entropic contribution to the
binding free energy. The poses depicted in Figure 2 and the
data in Table 2 confirm that the stereochemistry undeniably
possesses a significant role in the ligand/target recognition,
but does not hinder the ZBG character of the studied
chemotype to the CAs.
Owing to the poor correlation between the data in Table 1
and the binding free energy estimations in Table 2, further
aspects need to be considered to properly typify such a
new binding chemotype.
In fact, both the enantiomer R and S of compounds 3-10
possess better free energy values than compound
Acknowledgements
Ente Cassa di Risparmio di Firenze, Italy, is gratefully
acknowledged for a grant to A.N (ECR 2016.0774).
Conflict of interest
The authors declare no conflict of interest.
Keywords: metallo-enzymes, carbonic anhydrase, zinc-binder,
phosphonamidate, inhibition, QPLD, MM-GBSA.
1
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contending their worse in vitro inhibitory efficacy. Moreover,
in vitro inhibition values of phosphonamidates are several
orders of magnitude lower than sulfonamides despite an
almost common binding mode which is additionally
strengthened by interaction with the “deep water” pocket.
To shed light on these issues, pKas of derivatives 2-10
were computed by QM techniques. To validate the found
7
8
9
S. Del Prete, D. Vullo, G.M. Fisher, K.T. Andrews, S. Poulsen, C.
Capasso, C. T. Supuran, Bioorg. Med. Chem. Lett. 2014, 18, 4389.
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the
experimentally
known
pKas
for
10 A. Di Fiore, A. Maresca, C. T. Supuran, G. De Simone. Chem.
Commun. (Camb). 2012, 48, 8838.
benzenesulfonamide
A
and benzamide
B were compared
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to those obtained applying the same QM procedure. The
comparison showed the almost 100-fold less acidic
character
of
2-10
(pKa
12.5±0.5)
than
lead
benzenesulfonamide
A
(pKa 10.2) thus suggesting the poor
deprotonation degree associated with these compounds
and, as a consequence, a not sufficiently strong Zn-binder
character. This is what the difference in inhibition efficacy of
sulfonamides vs phosphonamidates is probably due.
Indeed, it has been shown the importance of the ZBG
anionic form to effectively displace the Zn-bound
nucleophile. In other words, it is likely that
phosphonamidates predominantly exist in the not-
dissociated form within the site, exhibiting a diminished
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COMMUNICATION
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
There is
a lack of studies that
Alessio Nocentini, Paola Gratteri* and
Claudiu T. Supuran *
investigate phosphorus derivatives as
Carbonic Anhydrase inhibitors (CAIs).
In the present study, we started to fill
Page No. – Page No.
this
gap
demonstrating
that
phosphonamidates can effectively
inhibit human CAs as sulfonamide-
mimic chemotypes by using kinetic
studies and QPLD/MM-GBSA in silico
methods.
Phosphorus vs sulphur: discovery of
benzenephosphonamidates as new
versatile sulfonamide-mimic
chemotypes acting as carbonic
anhydrase inhibitors
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