Mono- and di-thiocarbamate inhibition studies of the δ-carbonic anhydrase TweCAδ from the marine diatom Thalassiosira weissflogii

Silvia Bua; Murat Bozdag; Sonia Del Prete; Fabrizio Carta; William A Donald; Clemente Capasso; Claudiu T Supuran

doi:10.1080/14756366.2018.1450400

. 2018 Mar 26;33(1):707–713. doi: 10.1080/14756366.2018.1450400

Mono- and di-thiocarbamate inhibition studies of the δ-carbonic anhydrase TweCAδ from the marine diatom Thalassiosira weissflogii

Silvia Bua ^a, Murat Bozdag ^b, Sonia Del Prete ^a,^c, Fabrizio Carta ^a, William A Donald ^d, Clemente Capasso ^c,^✉, Claudiu T Supuran ^a,^d,^✉

PMCID: PMC6010021 PMID: 29577755

Abstract

The inhibition of the δ-class carbonic anhydrase (CAs, EC 4.2.1.1) from the diatom Thalassiosira weissflogii, TweCAδ, was investigated using a panel of 36 mono- and di-thiocarbamates chemotypes that have recently been shown to inhibit mammalian and pathogenic CAs belonging to the α- and β-classes. TweCAδ was not significantly inhibited by most of such compounds (K_I values above 20 µM). However, some aliphatic, heterocyclic, and aromatic mono and di-thiocarbamates inhibited TweCAδ in the low micromolar range. For some compounds incorporating the piperazine ring, TweCAδ was effectively inhibited (K_Is from 129 to 791 nM). The most effective inhibitors identified in this study were 3,4-dimethoxyphenyl-ethyl-mono-thiocarbamate (K_I of 67.7 nM) and the R-enantiomer of the nipecotic acid di-thiocarbamate (K_I of 93.6 nM). Given that the activity and inhibition of this class of enzyme have received limited attention until now, this study provides new molecular probes and information for investigating the role of δ-CAs in the carbon fixation processes in diatoms, which are responsible for significant amounts of CO₂ taken from the atmosphere by these marine organisms.

Keywords: Carbonic anhydrase, metalloenzymes, mono-thiocarbamate, di-thiocarbamate, Thalassiosira weissflogii

Introduction

The di-thiocarbamates (DTCs) possessing the general formula RR¹NCS₂M (where R, R¹ may be H, alkyl, cycloalkyl, aryl, hetaryl, etc., and M is a cation) were recently reported as a new class of inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1)¹. Their inhibitory activity was investigated against α- and β-class CAs from various organisms¹^,² and they also led to the discovery of two new CA inhibitor (CAI) classes, the xanthates³ and the mono-thiocarbamates (MTCs)⁴. Representatives of MTCs and DTCs acting as CAIs are shown in Figures 1 and 2.

Figure 1. — Monothiocarbamates (MTCs) 1–15 investigated as CA inhibitors⁴.

Figure 2. — Dithiocarbamates (DTCs) 16–36 investigated as CA inhibitors¹^,².

Inhibition of CAs belonging to some of the seven genetically distinct families known to date^5–10 has various biomedical applications owing to the fact that these enzymes catalyse a simple but physiologically crucial reaction: the hydration of CO₂ to bicarbonate and hydronium ions^5–10. Interference with this process has important physiological and pathological consequences because CAs are involved in pH regulation, biosynthetic processes, metabolism, secretion of electrolytes, transport of CO₂/bicarbonate, etc.^5–10. Their dysregulated expression or activity leads to various pathologies, and as a consequence, their inhibitors are clinically used as diuretics, antiglaucoma, antiepileptic, anti obesity, and antitumour agents^5–9. Recently, the CAIs were also shown to be effective for the control of neuropathic pain, cerebral ischemia, and some forms of arthritis¹⁰. The primary sulphonamides and their isosteres (sulphamides and sulphamates) are the main class of CAIs, but in many cases, they indiscriminately inhibit most of the many CA isoforms known in an organism (e.g. 15 CA isoforms belonging to the α-class are known in humans⁵^,^11–16). This is the reason why alternative chemotypes, such as the DTCs and MTCs have recently been explored^1–4. However, this class of CAIs has only been investigated to date for their interaction with human (h), α-class enzymes, and with several CAs from pathogens or model organisms, belonging to the α- and β-CA classes^1–4. The δ-CAs were discovered in the diatom Thalassiosira weissflogii^6d, but orthologues of this enzyme have been identified in most diatoms from natural phytoplankton assemblages and are responsible (along with other CAs) for CO₂ fixation by marine organisms¹⁷. A related species of this diatom, Thalassiosira pseudonana, was shown to possess genes for three α-, five γ-, four δ-, and one ζ-CAs¹⁸. However, none of these enzymes have been cloned and characterised in detail to date, except TweCAδ¹¹. Diatoms can be considered to be the organisms with the most intricate and poorly understood distribution of CAs, but the roles of these enzymes seem to be crucial for CO₂ fixation and photosynthesis in many organisms and are estimated to be responsible for at least 25% of the inorganic carbon fixation in the oceans⁶^,¹⁷^,¹⁸. However, few studies are available for the interaction of δ-CAs with modulators of activity, inhibitors, and activators. TweCAδ was the only representative of the δ-class for which anion and sulphonamide inhibition studies have been reported to date^6d^,¹¹. Here we report the first CA inhibition study with MTCs and DTCs of a δ-CA class enzyme, TweCAδ, which was cloned and characterised from the marine diatom T. weissflogii^6d^,^6e.

Materials and methods

Materials

MTCs 1–15⁴ and DTCs 16–36¹^,² were reported earlier by our group. Reagents/buffers of the highest available purity were obtained from Sigma-Aldrich, Milan, Italy. TweCAδ was a recombinant protein produced as reported earlier by our group^6e^,¹¹.

CA enzyme inhibition 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 reaction¹². Phenol red (at a concentration 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, and 0.1 M Na₂SO₄ (for maintaining constant ionic strength, which is not inhibitory against TweCAδ¹¹), following the CA-catalysed 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 inhibitor at least six traces of the initial 5–10% of the reaction have been used for determining the initial rate. The uncatalysed rates were determined in the same manner and subtracted from the total observed rates. Stock solutions of inhibitors (10 mM) were prepared in distilled-deionised diluted to 1 nM using the assay buffer. Inhibitor 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 enzyme inhibitor complex. The inhibition constant (K_I), was obtained by considering the classical Michaelis–Menten equation and the Cheng-Prusoff algorithm by using non-linear least squares fitting as reported earlier^13–16.

Results and discussion

TweCAδ is the only CA belonging to the δ-class for which anion and sulphonamide inhibition studies were reported so far^6d^,¹¹. Here, we investigated the inhibition of this enzyme with the panel of MTCs and DTCs of the types 1–36 shown in Figures 1 and 2. The results are shown in Table 1, where for comparison reasons, the inhibition of the human dominant isoforms hCA I and II with the same compounds are reported¹^,²^,⁴.

Table 1.

TweCAδ, hCA I, and hCA II Inhibition Data with MTCs 1–15, DTCs 16–36, and acetazolamide (AAZ, 5-acetamido-1,3,4-thiadiazole-2-sulphonamide) as standard drug, by a stopped-flow CO₂ hydrase assay.

	RR¹NCOS⁻ Na⁺ (1–15)		RR¹NCS₂M (16–36)
			K_I (nM)^a
No.	R	R¹	TweCAδ	hCA I	hCA II
1	n-Pr	n-Pr	806.7	>2000	46.7
2	Et	n-Bu	783.3	700	>2000
3	n-Bu	n-Bu	1142	909	>2000
4	i-Bu	i-Bu	>20,000	681	43.0
5	Me	CH₂COOEt	>20,000	827	44.5
6		–(CH₂CH₂)–O–(CH₂CH₂)–	>20,000	569	>2000
7	H	–N(CH₂CH₂)N(CH₃)CH₂CH₂–	487	>2000	35.0
8		– (CH₂CH₂)–NH-(CH₂CH₂)–	483	876	22.4
9		–(CH₂CH₂)-N(CH₂CONHC₆H₁₁)–(CH₂CH₂)–	129	949	45.9
10	Me	CH₂Ph	>20,000	>2000	>2000
11	H	CH₂CH₂Ph	997	>2000	43.7
12		HCH₂CH₂(3,4-di-MeO-C₆H₄)	67.7	891	26.7
13		– (CH₂CH₂)–N(3-Cl-C₆H₄)– (CH₂CH₂)–	1505	686	>2000
14		–(CH₂CH₂)–N(4-F-C₆H₄)–(CH₂CH₂)–	1498	895	46.8
15		–(CH₂CH₂)-N(4-CF₃-C₆H₄)– (CH₂CH₂)–	1152	>2000	43.6
16	Me₂N(CH₂)₂	H	8406	85.9	35.8
17	HO(CH₂)₃	H	8691	706	41.7
18	HO(CH₂)₄	H	7168	295	24.3
19	HO(CH₂)₅	H	8597	66.5	17.3
20		H	>20,000	494	48.7
21	(R)	H	>20,000	240	18.9
22	(S)	H	7995	615	65.9
23	–(CH₂)₅–	–	>20,000	252	30.1
24	–(CH₂)₃–CH(OH)CH₂–	–	>20,000	428	60.7
25	–(CH₂)₄–CH(COONa)–	–	>20,000	485	80.1
26	–(CH₂)₃–CH(COONa)CH₂–	–	8429	290	45.4
27	(R)–(CH₂)₃–CH(COONa)CH₂–	–	93.6	496	80.5
28	(S) -(CH₂)₃–CH(COONa)CH₂–	–	556	109	8.9
29	–(CH₂)₂–CH(COONa)(CH₂)₂–	–	8980	337	78.7
30	–(CH₂)₃-CH(NHAc)CH₂–	–	783	910	47.9
31	–(CH₂)₃-CH(NHBoc)CH₂–	–	9239	683	13.2
32	–CH(Me)CH₂-O-(CH₂)₂–	–	>20,000	434	60.2
33	–CH(COONa)CH₂-O– (CH₂)₂–	–	>20,000	84.7	78.5
34	–	–(CH₂)₂N(CH₂CONHC₆H₁₁)(CH₂)₂–	791	415	67.2
35	Ph(CH₂)₂	H	897	425	107
36	–	H₂NO₂SC₆H₄(CH₂)₂H	704	97.5	48.1
AAZ	–	–	83	250	12.1

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Mean ± standard error (from three different assays), by a stopped-flow technique (errors were in the range of ±5–10% of the reported values).

The following structure-activity relationship (SAR) can be obtained from the data of Table 1:

(i) A number of MTCs, including 4–6, 10 and the DTCs 20, 21, 23–25, 32, and 33, did not inhibit TweCAδ up to 20 µM, although many of these compounds were rather effective inhibitors of hCA I and/or hCA II (Table 1). Such MTCs/DTCs inhibitors are classified as aliphatic, heterocyclic, aromatic, or polycyclic types. Given the structural diversity of such compounds and high inhibition constants, it is challenging to delineate the SAR.

(ii) The MTCs/DTCs 3, 13–19, 22, 26, 29, and 31 were relatively ineffective inhibitors of TweCAδ with inhibition constants in the micromolar range (K_Is ranged between 1142 and 9239 nM; Table 1). These compounds are also highly heterogeneous. The main observation of these data is that the identity of the zinc-binding group, ZBG (MTC or DTC), does not significantly impact the activity of TweCAδ.

(iii) The MTC/DTCs 1, 2, 7–9, 28, 30, and 34–36 were relatively effective inhibitors of TweCAδ, with inhibition constants in the range of 129–997 nM (Table 1). Some of the MTC and DTCs incorporate the piperazine ring (7–9, 34). In addition, MTC 9 and DTC 34 have the same scaffold but a different ZBG. In this particular case, MTC 9 inhibited TweCAδ 6.1-times more efficiently than DTC 34. Interestingly, for the β-CAs, the MTCs were usually much weaker inhibitors compared to the structurally similar DTCs⁴. In addition, the sulphonamide-containing DTC 36 (which contains two potential ZBGs, the sulphonamide and the DTC), there are no net differences of TweCAδ inhibitory activity compared to the structurally similar derivatives (e.g. 35) which probably is due to the fact that the DTC in 36 is primarily binding to the metal ion in the enzyme active site, and not the sulphonamide moiety. However, the heterocyclic sulphonamide acetazolamide (AAZ, 5-acetamido-1,3,4-thiadiazole-2-sulphonamide), a clinically used drug⁵, is a much more potent inhibitor (K_I of 83 nM) of TweCAδ compared to 36 (Table 1).

(iv) The most effective TweCAδ inhibitors identified in this MTC/DTC panel were the MTC 12 (K_I of 67.7 nM) and the DTC 27 (K_I of 93.6 nM). These compounds incorporate scaffolds rather similar to those present in other investigated compounds, which were, however, much less effective as inhibitors of this enzyme. For example, 12 has two methoxy moieties on the scaffold of 11, but there is a difference of activity of 14.7-fold between the two MTCs. The R-enantiomer 27 was on the other hand 5.9 times a more effective inhibitor compared to the S-enantiomer 28. All these data show that small changes in the structure or the stereochemistry of a DTC/MTC lead too dramatic changes of affinity for the target enzyme.

(v) With a few exceptions, TweCAδ was less sensitive to this class of CAIs compared to the α-CAs hCA I and II (Table 1). There are several X-ray crystal structures that demonstrate that the DTCs (and presumably also the MTCs) bind to the metal ion in the CA active site by substituting the hydroxide nucleophile that is responsible for the catalytic activity of the enzyme¹^,². Most probably, this is also the inhibition mechanism by which DTCs and MTCs interact with δ-CAs. However, this enzyme class is the least studied of the 7 CA genetic families, and there are no X-ray crystal structures or even homology models available for any δ-CAs.

We try to rationalise the obtained inhibition data based on the amino acid sequence of TweCAδ, which has been aligned with that of α-CAs for which the X-ray crystal structure is known, of bacterial (HpylCA, α-CA from Helicobacter pylori, SspCA, α-CA from Sulfurihydrogenibium yellowstonensis) or human origin (hCA I and II) (Figure 3). Data of Figure 3 show that for the α-CAs, the zinc ligands are three His residues (His94, 96, and119, hCA I numbering system), which align well for the bacterial and human enzymes, whereas the putative zinc ligands of TweCAδ do not align at all with those of the α-class enzyme. The same is true for other amino acid residues from the α-CAs, such as the proton shuttle (His64) which is an Asp residue in TweCAδ, or residues 106 (a conserved Asp residue in all α-CAs), which is a Thr in TweCAδ. Based on these data it is obvious that it is not possible to rationalise the observed SAR with mono- and di-thiocarbamates based only on the sequence of the enzyme, without a homology model or better, an X-ray crystal structure of the diatom enzyme.

Figure 3. — Multialignment of the TweCAδ amino acid sequence with those of bacterial (HpylCA, α-CA from *Helicobacter pylori*, SspCA, α-CA from *Sulfurihydrogenibium yellowstonensis*) and human (hCA I and II) α-class enzymes. The zinc ligands of the α-CAs and the putative zinc ligands of TweCAδ are evidenced in red, whereas amino acid residues involved in the catalytic inhibition/mechanism (e.g. His64 and Asp106, hCA I numbering) are shown in green and blue, respectively.

Conclusions

The first inhibition study of a δ-CA with mono- and di-thiocarbamates, classes of CAIs recently discovered, was reported. TweCAδ from the marine diatom T. weissflogii was not particularly sensitive to inhibition by these classes of compounds. Many of the mono- and di-thiocarbamates did not show inhibitory action up to 20 µM, whereas some aliphatic, heterocyclic, and aromatic inhibited this enzyme in the low micromolar range. Several MTCs/DTCs incorporating the piperazine ring effectively inhibited TweCAδ with K_Is in the range of 129–791 nM. The most effective inhibitors identified were 3,4-dimethoxyphenyl-ethyl-mono-thiocarbamate (K_I of 67.7 nM) and the R-enantiomer of the nipecotic acid DTC (K_I of 93.6 nM). Such inhibitors can now be used as molecular probes to investigate the role of this enzyme in the carbon fixation processes in diatom marine organisms that are responsible for removing large amounts of CO₂ from the atmosphere.

Funding Statement

This research was financed in part by the Australian Research Council [DP160102681].

Disclosure statement

The authors do not declare any conflict of interest.

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[CIT0014] 14.a) Krall N, Pretto F, Decurtins W, et al. . A small‐molecule drug conjugate for the treatment of carbonic anhydrase IX expressing tumors. Angew Chem Int Ed Engl 2014;53:4231–5. b) Rehman SU, Chohan ZH, Gulnaz F, Supuran CT.. In-vitro antibacterial, antifungal and cytotoxic activities of some coumarins and their metal complexes. J Enzyme Inhib Med Chem 2005;20: 333,–40. c) Clare BW, Supuran CT.. Carbonic anhydrase activators. 3: structure‐activity correlations for a series of isozyme II activators. J Pharm Sci 1994;83: 768,–73. d) Dubois L, Peeters S, Lieuwes NG, et al. . Specific inhibition of carbonic anhydrase IX activity enhances the in vivo therapeutic effect of tumor irradiation. Radiother Oncol 2011;99: 424,–31. e) Chohan ZH, Munawar A, Supuran CT.. Transition metal ion complexes of Schiff-bases. Synthesis, characterization and antibacterial properties. Met Based Drugs 2001;8: 137,–43. f) Zimmerman SA, Ferry JG, Supuran CT.. Inhibition of the archaeal β-class (Cab) and γ-class (Cam) carbonic anhydrases. Curr Top Med Chem 2007;7: 901,–8. g) De Simone G, Supuran CT.. (In)organic anions as carbonic anhydrase inhibitors. J Inorg Biochem 2012;111: 117–29. [Google Scholar]

[CIT0015] 15.a) Supuran CT, Nicolae A, Popescu A.. Carbonic anhydrase inhibitors. Part 35. Synthesis of Schiff bases derived from sulfanilamide and aromatic aldehydes: the first inhibitors with equally high affinity towards cytosolic and membrane-bound isozymes. Eur J Med Chem 1996;31:431–8. b) Pacchiano F, Aggarwal M, Avvaru BS, et al. . Selective hydrophobic pocket binding observed within the carbonic anhydrase II active site accommodate different 4-substituted-ureido-benzenesulfonamides and correlate to inhibitor potency. Chem Commun (Camb) 2010;46: 8371,–3. c) Ozensoy Guler O, Capasso C, Supuran CT.. A magnificent enzyme superfamily: carbonic anhydrases, their purification and characterization. J Enzyme Inhib Med Chem 2016;31: 689,–94. d) De Simone G, Langella E, Esposito D, et al. . Insights into the binding mode of sulphamates and sulphamides to hCA II: crystallographic studies and binding free energy calculations. J Enzyme Inhib Med Chem 2017;32: 1002,–11. e) Di Fiore A, De Simone G, Alterio V, et al. . The anticonvulsant sulfamide JNJ-26990990 and its S,S-dioxide analog strongly inhibit carbonic anhydrases: solution and X-ray crystallographic studies. Org Biomol Chem 2016;14: 4853,–8. f) Supuran CT, Scozzafava A, Mastrolorenzo A.. Bacterial proteases: current therapeutic use and future prospects for the development of new antibiotics. Expert Opin Ther Pat 2001;11: 221–59. [Google Scholar]

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[CIT0017] 17.McGinn PJ, Morel FM.. Expression and regulation of carbonic anhydrases in the marine diatom Thalassiosira pseudonana and in natural phytoplankton assemblages from Great Bay, New Jersey. Physiol Plant 2008;133:78–91. [DOI] [PubMed] [Google Scholar]

[CIT0018] 18.Tachibana M, Allen AE, Kikutani S, et al. . Localization of putative carbonic anhydrases in two marine diatoms, Phaeodactylum tricornutum and Thalassiosira pseudonana. Photosynth Res 2011;109:205–21. [DOI] [PubMed] [Google Scholar]

PERMALINK

Mono- and di-thiocarbamate inhibition studies of the δ-carbonic anhydrase TweCAδ from the marine diatom Thalassiosira weissflogii

Silvia Bua

Murat Bozdag

Sonia Del Prete

Fabrizio Carta

William A Donald

Clemente Capasso

Claudiu T Supuran

Abstract

Introduction

Figure 1.

Figure 2.