Future

Review

For reprint orders, please contact [email protected]

Medicinal Chemistry

Sulfonamides and their isosters as carbonic anhydrase inhibitors

Molecules containing the sulfonamide group (R-SO2NH2) as well as its structurally related isosters, sulfamido (R-NH-SO2NH2) and sulfamato (R-O-SO2NH2), constitute the most important class of inhibitors acting on the metalloenzyme carbonic anhydrase (EC 4.2.1.1). Despite their presence in the literature, in general the reports lack of a clear and organic overview linking the main structural features of the clinically used inhibitors with the therapeutic aspects. The current review is intended to highlight the structural basis of the interactions of sulfonamide-like groups within the active site of the carbonic anhydrases and will summarize the clinical use of the most interesting molecules for the treatment of relevant pathologies, such as glaucoma, obesity, cancer and CNS-affecting diseases.

The carbonic anhydrases (CA; EC 4.2.1.1) are metalloenzymes expressed in a wide range of organisms belonging both to the prokaryotic and the eukaryotic families [1,2] . From the genetic viewpoint such enzymes are classified into five unrelated families (α, β, γ, δ and ξ-CAs) and are responsible for the catalysis of the carbon dioxide hydration reaction (Equation 1) . CO2 + H2 O

CAs

H5 + HCO36 Equation 1

The dynamic control of such reaction is fundamental for the cellular life cycle as it presents several peculiar characteristics, which are exploited for different purposes: • Drastic volume reduction of a freely and diffusible gas, the carbon dioxide, into bicarbonate and viceversa; • The ionic species in Equation 1 are actively involved in the control of pH, osmosis, electric and ionic potentials in the cells, as well as in specific cellular compartments; • The biosynthetic pathways, such as the gluconeogenesis, lipogenesis, ureagenesis

10.4155/FMC.14.68 © 2014 Future Science Ltd

and de novo synthesis of pyrimidines, which all need bicarbonate as reagent [3,4,5,6,7,8,9,10] .

Fabrizio Carta1, Claudiu T Supuran1,2 & Andrea Scozzafava*,1 1 Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy 2 Università degli Studi di Firenze, NEUROFARBA Department, Section of Pharmaceutical Chemistry, Via Ugo Schiff 6, Sesto Fiorentino, Florence 50019, Italy *Author for correspondence: [email protected]

The structural differences among the CA classes have been deeply investigated also by means of x ray crystallography as reported by De Simone et al. in a recent review [11,12,13,14,15] . The α-CAs, which represents the main subject of this review, are expressed in all the vertebrates and up to now 16 different isoforms have been reported in humans. As depicted in Table 1, they all differ for catalytic activities, cell and tissue distributions [1,2,11,16] . Variations of the CAs expressions in humans are strictly associated with important pathologies, such as edema, glaucoma, cancer, obesity, osteoporosis and CNSaffecting diseases, [17,18] , and this makes the CAs valuable and validated pharmaceutical targets for the treatment of such dysfunctions [1,2,16,17,18,19,20,21,22,23,24] . Many x ray structures of α-CAs are now available [16,25,26] , and all of them show the zinc (II) ion located at the bottom of a 15 Å deep cavity, tetra-coordinated by three hystidines residues (His94, His96 and His119)

Future Med. Chem. (2014) 6(10), 1149–1165

part of

ISSN 1756-8919

1149

Review  Carta, Supuran & Scozzafava

Table 1. Classification, catalytic activities and distributions of the human carbonic anhydrases in the healthy organism [1,2,11,16] . Isozyme

Catalytic activity Sub-cellular localization

Tissue/organ localization

CA I

Moderate

Cytosol

Erythrocytes, GI tract

CA II

High

Cytosol

Erythrocytes, eye, GI tract, bone osteoclasts, kidney, lung, testis, brain

CA III

Very low

Cytosol

Skeletal muscle, adipocytes

CA IV

High

Membrane bound

Kidney, lung, pancreas, brain capillaries, colon, heart muscle

CA VA

Low-moderate

Mitochondria

Liver

CA VB

High

Mitochondria

Heart and skeletal muscle, pancreas, kidney, spinal cord GI tract

CA VI

Moderate

Secreted in saliva/milk

Salivary and mammary glands

CA VII

High

Cytosol

 

CA VIII

Acatalytic

Cytosol

 

CA IX

Moderate-high

Transmembrane

Tumors, GI mucosa

CA X

Acatalytic

Secreted

 

CA XI

Acatalytic

Secreted

 

CA XII

Low

Transmembrane

Renal, intestinal reproductive epithelia, eye, tumors

CA XIII

Moderate

Cytosol

Kidney, brain, lung, gut, reproductive tract

CA XIV

Moderate

Transmembrane

Kidney, brain, liver

CA XV

Low

Membrane bound

Kidney

CA: Carbonic anhydrase.

and a water/hydroxide. The metal coordinated water/ hydroxide ion interacts through hydrogen bonds with the hydroxyl moiety of the closed Thr199, which in turn is engaged with the pendant Glu106 carboxylate residue (Figure 1A) . Such a cluster appears highly conserved among all the α-CA isoforms and represents the enzymatic catalytic core. The metal ion exerts its essential role by significantly lowering the coordinated water pKa (∼7), therefore generating the nucleophilic hydroxide species (ii), which triggers the catalytic cycle as reported below in Figure 1B [27] . The main class of CA inhibitors (CAIs) is constituted by molecules containing the primary sulfonamide group (R-SO2NH2) [28] . Acetazolamide 1, the earliest in the series, was introduced for clinical use in the late 1950s as the first non-mercurial diuretic [29] . However, the evidence that the sulfonamides act as CAIs was reported nearly 20 years before with the simple sulfanilamide 2 [30] . As showed in Figure 2, the typical binding mode consists of the sulfonamidic ionized NH- coordinating the enzymatic zinc (II) ion to form a tetrahedral adduct. Such a complex is further stabilized through a hydrogen bond network formed by the

1150

Future Med. Chem. (2014) 6(10)

same nitrogen atom and the OH functionality of the Thr199, which in turn interacts through its peptidic NH to one of the oxygens of the sulfonamide group. It is worth mentioning that the sulfonamide binding mode is very close to the coordination pattern of the native zinc bound hydroxide ion, and is therefore consistent with the high stability of the CA/sulfonamide adducts [1,2,11] . The structurally related sulfonamide derivatives, such as the sulfamates (R-O-SO2NH2) and the sulfamides (R-NH-SO2NH2), represent a valid approach for the synthesis of new CAIs with high binding affinities [16,17,21,23] . As for the sulfonamides, a wide range of kinetic as well as crystallographic data have been obtained on the sulfamates and sulfamides with various CA isozymes [16,17,21,23] . As prototypes of the two series herein we refer to the binding modes of the simple sulfamic acid 3 [31] and sulfamide 4 [31] in adduct with the human CA (hCA) II (Supplementary Figure 1) . Such compounds bind within the enzymatic cavity as ionic species through their –SO2-NH- moieties to form the corresponding tetrahedral adducts [31] . The high stability of such complexes are ensured by an intricate network of favorable hydrogen bond interactions

future science group

Sulfonamides & their isosters as carbonic anhydrase inhibitors 

occurring with 3 and 4 with both the aminoacidic and water residues placed nearby the enzymatic cavity [31] . The common side effects associated with the systemic use of CAIs include metabolic acidosis, depression, fatigue, general malaise, weight loss, gastrointestinal irritations, formation of renal calculi and some cases of decreased libido were reported [1,2,17,18,25,32,33,34,35] . Nevertheless the safety profile of the CAIs remains high as none of the adverse affects is permanent and can be adequately treated [32,33,34,35] . Despite the differences among the CAs, the sulfonamide group di per se do not contain any particular structural feature that can lead to selective enzyme inhibition. Therefore, alternative approaches have been explored for the design and synthesis of scaffolds bearing the zinc-binding groups (ZBGs) with the aim to selectively inhibit the CA isoforms strictly associated with the disease intended to treat (Figure 3) [1,16] . As typical examples herein we report the development of the antiglaucoma agents dorzolamide 5 and brinzolamide 6 for topical eye administration [36,37]

Review

and the introduction of positively charged groups, as in CA IX selective compounds of the type 7, for the ring and the tail approach, respectively [38,39,40,41,42,43] (Figure 4) . The current review is intended to highlight the structural basis of the interactions of sulfonamidelike groups within the active site of the CAs and will summarize the most interesting molecules for the treatment of relevant pathologies, such as glaucoma, obesity, cancer, CNS-affecting diseases. Clinical uses of sulfonamides The current section of the review is dedicated to the use of sulfonamides and their corresponding isosters as CAIs. The main aspects of the pathologies as well as the role of the CA enzymes will be considered. Diuretics

Traditionally the use of diuretics in therapy was mainly intended for the modification of the body fluid volumes as well as of their ionic compositions [1,28,33] . Therefore their employment, alone or in association with specific

O Thr199

H O

N H O

H



O– Zn2+

His94

O Glu106

His119 His96

OH



Zn2+

His119 His96

His94

i

Hydrophobic pocket Val 121 Val 143 Leu 198

- BH+ + CO2

Rate limiting-step

O OH2 Zn2+ His94

O

OH



His119 His96

His94

iv

Zn2+

His119 His96

ii + H2O

O

H O

- HCO 3 -

Zn2+ His94

O–

His119 His96

iii

Figure 1. Structural and mechanistic insights of carbonic anhydrases. (A) Coordination of the zinc (II) ion within the human carbonic anhydrase II [16,25,26] . (B) Catalytic cycle of human carbonic anhydrase [27] .

future science group

www.future-science.com

1151

Review  Carta, Supuran & Scozzafava

SO2NH2 O

N N N H

SO2NH2

S

NH2 1, Acetazolamide

2, Sulfanilamide

Hydrophobic side

Hydrophilic side R

NH

O

O S O

Thr199

HN-

O O

H O-

Zn2+ HN

N

N

N

NH

NH

Glu106 His96

His119

His94

Figure 2. Acetazolamide 1, the first non-mercurial diuretic [29] , and sulfanilamide 2, the first sulfonamidebased carbonic anhydrase inhibitor [30] , as well as the binding mode of the sulfonamide group within the catalytic site of the α-carbonic anhydrases [11] .

therapeutic protocols, is highly beneficial for the treatment of hypertensive patients and for subjects affected by cardiovascular diseases or more in general for the management of the edema [28,33] . Recently diuretics are also indicated in pathologies such as Type II diabetes, obesity and for the treatment of metabolic dysfunctions [28,45] . From a chemical viewpoint, the diuretic classes include a wide variety of molecules acting with

different mechanisms [46,47] . This current review, focusing only on the sulfonamide-based diuretics, will principally refer to the latest developments in the field since a more comprehensive review has already been recently published by our group [33] . The rationale behind the use of sulfonamide-containing molecules as diuretics mainly relies on the high expression of the CAs in the kidneys [48,49,50,51,52] . The total estimated concentration of CAs in such organs is up to 10 μM, with the CA II, IV, VB, IX, XII and XIV as the most representative isoforms [48,49] . The distribution of such enzymes within the nephron unit was deeply investigated and accounts for the hCA II as the most abundant isoform [48,49,50,51,52,53] . Thus the CAs, through the carbon dioxide hydration reaction listed in Equation 1, play a fundamental role in the kidneys, which include the acid–base homeostasis control, the bicarbonate re-absorption process and the ammonium excretion [47,48,54,55] . All these processes are precisely located along the nephron unit [48,49,50,51,52,53] . Acetazolamide 1 was the first sulfonamide-based diuretic for systemic administration introduced in the clinic, and since 1956 still is widely adopted [29,33] . The physiological effects of of the acetazolamide 1 in the kidneys are typical for the first generation sulfonamidic diuretics (structures are reported in Table 2) and include rapid increase of the urine volume which turned from been slightly acidic (∼6) to basic (∼8) [1,33,47] . The urine pH shift determines the retention of the tritatable acid and ammonia, and hence it creates metabolic acidosis as the main side effect [29,33,56] . Moreover the inhibition of the CAs in the kidneys results in enhancement of the bicarbonate ion excre-

His 94

His 96

Zn2+

ZBG

Main scaffold

Tail

His 119

Classical ZBGs include: • The sulfonamides (-SO2NH2) • Sulfamides (-NRSO2NH2) • Sulfamates (-OSO2NH2) Recently introduced: • DTCs (-NRCSS-) • Xantates (-OCSS-)

Usually consists of aromatic/ heteroaromatic ring moieties. Modifications at this level greatly influence the binding modes of the CAIs into the CAs enzymatic cavity

Usually modifications at this level account for the physicochemical properties of the CAIs

Figure 3. The ring and the tail approaches used for the specific inhibition of the carbonic anhydrases. CA: Carbonic anhydrase; CAI: Carbonic anhydrase inhibitor; DTC: Dithiocarbammate; ZBG: Zinc-binding groups.

1152

Future Med. Chem. (2014) 6(10)

future science group

Sulfonamides & their isosters as carbonic anhydrase inhibitors 

NH

NH

S

S O

Review

SO2NH2

O O

O 5

SO2NH2

S

S O 6

SO2NH2 SO2NH2

i O +

_

_ BF4

ClO4 R

n = 0,1

ii

HClO4

n = 0,1

N +

R1 R2

NH2 R3

R, R1, R2, R3 = H, alkyl, phenyl 7

Figure 4. Towards the selective carbonic anhydrase inhibition. (A) Structures of the antiglaucoma agents dorzolamide 5 and brinzolamide 6 [36,37,44] . (B) Structural tail modifications for the specific inhibition of the tumor associated carbonic anhydrase IX [38,39,40,41,42,43] .

tion, with values up to 120-fold times higher than the physiological ones, and having sodium and potassium as the counter ions [29] . The elimination of important amounts of sodium bicarbonate is a self-limiting process as it activates CA-independent re-absorption mechanisms [29,49] . Moreover, the inhibition of the CAs in the kidneys has important effects for the Na-H antiporters expressed at the baso-lateral membrane of the nephrons, as the amount of available proton ions are reduced [29,47,57,58,59,60] . The overall effect is an increased excretion of sodium bicarbonate in the interstitial area of the nephronic cells, thus an osmotic potential is created, which drains water out of the organism [29,47,57,58,59,60] . The diuretic effect is mainly due to the inhibition of the CAs expressed at the proximal tube section of the nephron [48,49,50,51,52,53] . As previously mentioned, metabolic acidosis is the main side effect associated to the inhibition of the renal CAs. Other effects observed include the formation of kidney stones or encephalopathy and in all cases their incidence is quite low and will occur in patients with a compromised clinical scenario [47] . Fatigue, general malaise, weight loss and gastrointestinal irritations are the general effects arising from the indiscriminate inhibition of the CA isoforms expressed in the other organs and tissues [1,33,47] . The K I values of the firstgeneration sulfonamide-based diuretics are reported in Table 2, and they clearly show to be effective inhibitors of the human CAs [33] .

future science group

A step forward to reducing the number the side effects, derived from indiscriminate inhibition of the CA isoforms present in humans, was accomplished with the benzolamide 11 (Table 3) [33] . Such a molecule has an in vitro kinetic profile not too dissimilar from the first-generation diuretics previously discussed; however, it shows a 10-times fold increase in the excretion of bicarbonate and therefore of the diuretic effect [33,61] , and most importantly a selective renal accumulation was observed [33,61] . However the benzolamide 11 showed unsuccessful pharmacokinetic profiles, which prevented its further development for clinical use [33,61] . The first-generation diuretics, despite their lack of organ selectivity, are still widely employed in the clinic. More importantly, the prototype acetazolamide 1 has been the lead compound that triggered the development of the second-generation sulfonamide-based diuretics 12–22 (Supplementary Figure 2) [33] . The kinetic data referred to the second-generation diuretics clearly demonstrated that such compounds are weaker inhibitors of the CA I/II isoforms when compared with the previous series, with the only exception being furosemide 21. On the contrary, they showed good potencies for all the other isoforms [33] . For a detailed structure–activity relationship discussion of the single compounds, please refer to the literature [33,56,57,58,59,60] . Since their introduction in the clinical use, all sulfonamide-based compounds were considered as diuretics merely for the physiological

www.future-science.com

1153

Review  Carta, Supuran & Scozzafava

Table 2. Structures of the first-generation diuretics acetazolamide 1, methazolamide 8, ethoxzolamide 9, dichlorphenamide 10 and their carbonic anhydrase inhibition constants [33] . N N

O N H

N N

O SO2NH2

S

SO2NH2

S

N 8

1

SO2NH2

N SO2NH2

S

O

Cl

SO2NH2 Cl

9

10

Isozyme

KI (nM) 1

8

9

10

hCA I

250

50

25

1200

hCA II

12

14

8

38

hCA III

2 x 105

7 x 105

1 x 10 6

6.8x105

hCA IV

74

6200

93

15,000

hCA VA

65

65

25

630

hCA VB

54

62

19

21

hCA VI

11

10

43

79

hCA VII

2.5

2.1

0.8

26

hCA IX

25

27

34

50

hCA XII

5.7

3.4

22

50

mCA XIII

17

19

50

23

hCA XIV

41

43

25

345

mCA XV

72

65

58

95

hCA: Human carbonic anhydrase; mCA: Murine carbonic anhydrase.

effects exerted as consequence of the CA II isoform inhibition in the nephron. Nowadays, the state-of-theart research on sulfonamide-based diuretics is involved in a deep re-examination of such compounds. For instance, the property of the first-generation diuretics, to induce vasodilatation in a variety of organs, was recently explained by the control of NO/nitrite homeostasis by the CAs [62,63,64] . Systemic administration of the promiscuous CAI acetazolamide 1 induced an increased of the nitrite excretion at the renal proximal tubes proving for the first time a relationship between the CAs and the adsorption of the nitrite at the kidneys level [62,63,64] . More interestingly, it has been hypothesized that a direct involvement of the CAs takes place in nitrite homeostasis due to the catalysis of the reaction between carbon dioxide and nitrite producing the labile species nitritocarbonate as in Equation 2 [65] . CO2 + NO26

CAs

ONOCO26 Equation 2

The final proof of such mechanism has not yet been reported; however, it is clear that the sulfonamide-

1154

Future Med. Chem. (2014) 6(10)

based molecules exert their pharmacological effects through several mechanisms, which are still to be clarified. Despite no new sulfonamide-based diuretics appearing in last 40 years, the recent developments in the field account for a wide range of associations of the first- and second-generation diuretics with β-adrenergic receptor antagonists [66] , cholesterol-lowering agents [67] , cardiac glycosides [68] , inhibitors of neutral peptidase [69] or inhibitors of the organic acid transporter isoform 4 [70] . Antiglaucoma

The sulfonamide-based molecules having antiglaucoma and diuretic effects were developed almost at the same time as the same compounds, such as the acetazolamide 1, methazolamide 4, ethoxzolamide 5 and dichlorphenamide 6, demonstrated to be effective for the treatment of such pathologies [32] . Glaucoma is a progressive ophthalmic neurodegenerative disease, which affects large amounts of the population worldwide [32,71] and, if not treated, is responsible for permanent damage of the optical nerves and permanent blindness [32,71] . Among the symptoms associated to the glaucoma, the elevated

future science group

Sulfonamides & their isosters as carbonic anhydrase inhibitors 

intraocular pressure (IOP) is the most common one, and is created by the unbalance between secretion and drain of the aqueous humor within the eyes [32,71] . The aqueous humor is secreted in the ciliary bodies, which are particularly rich in CA II, IV and XII, and its production is strictly dependent from the bicarbonate production, which in turn is regulated by the physiological reaction catalyzed from the CAs [32,71] . Thus, the inhibition of the CAs in the eyes represented a valid approach for the treatment of such pathology [1,32] . The systemic administration of CAI-based sulfonamides, such as the acetazolamide 1 and its derivatives, was the first and efficient line of intervention for the treatment of such pathology. Actually, the acetazolamide 1 and dichlorphenamide 10 are used for the systemic treatment of the glaucoma associated with elevated IOPs [32] . However, the side effects derived from the inhibition of all the other CA isoforms distributed within different tissues and organs represent a serious hurdle for the chronic treatment of glaucoma [1,72] . The introduction for the clinical use of the topically active CAIs, such as the dorzolamide 5 and brinzolamide 6 in 1995 and 1999, respectively, represented a major advance in the pharmacological treatment of glaucoma [1,32] . Such molecules were the result of an intense applied ring approach research on the concept first elaborated by Maren et al. almost 10 years earlier [73] . Dorzolamide 5 and brinzolamide 6 were effective CA II and XII inhibitors [1] and they possessed the right physicochemical properties that allowed them to penetrate the cornea once applied in loco [1,32,73] . The overall pharmacological effects are a sensible reduction of the IOP up to 30% when compared with the basal values and a drastic reduction of side effects due to the systemic administration [74] . Blurred vision, pruritus and bitter taste [1,74] are the common disturbs associated with their use, which are given by the acidic pH of the preparations or by the drain of the drugs into the oropharynx and inhibition of the CAs expressed therein [1,32,74] . However, some serious cases of side effects were also reported for dorzolamide 5 and brinzolamide 6 [32] and alternative ways to generate CAI-sulfonamide based drugs for topical administration were found. Such efforts are mainly represented by the insertion of hydrophilic moieties into a sulfonamide-bearing scaffold to give a large amount of derivatives [32] , which in general exert their IOP-lowering effect for longer times when compared with 5 and 6 [32] . A patent review on CA inhibitors as antiglaucoma agents has been recently published by our group [32] and the interested reader can find more details there. Herein, we want to recall explicitly the sulfonamide– NO donor conjugates recently developed by Nicox

future science group

Review

Table 3. Structure of the benzolamide 11 and its inhibition constants towards the different carbonic anhydrase isozymes [33] . O S O

N H

SO2NH2

S

11

Isozyme

11 (KI ; nM)

hCA I

15

hCA II

9

hCA III

1.4 x 105

hCA IV

n.t.

hCA VA

37

hCA VB

34

hCA VI

93

hCA VII

0.45

hCA IX

49

hCA XII

3.5

mCA XIII

n.t.

hCA XIV

33

mCA XV

70

hCA: Human carbonic anhydrase; mCA: Murine carbonic anhydrase; n.t.: Not tested.

(Valbonne, France)

[75,76,77,78]

and Pfizer (NY, USA)

[79,80] (Figure 5A & B) .

The idea to develop such molecules originated from the observation that glaucomatous patients with high IOPs have low amounts of NO/cGMP in their aqueous humor. The consequent vascular hypertension at the optic nerve is therefore responsible for a lower oxygen perfusion of the neuronal tissues [82,83] . Tests of such compounds in a glaucoma animal model were successful in lowering the IOPs as well as ensuring the efficacy in comparison with the dorzolamide 5 and brinzolamide 6 [84] . In analogy to the sulfonamide–NO donor conjugates the latest pharmacological approach for the treatment of glaucoma is enriched by the sulfonamide–prostaglandine receptor antagonists of the type reported in Figure 5C [81] . The rationale behind such molecules was to reduce the production of aqueous humor through the inhibition of CAs and to promote its outflow via the inhibition of PG2α receptors. The latest effect was achieved from the observation that latanoprost resulted as an effective IOP lowering agent [32,71] . Recent updates in the literature account for the development of small molecules bearing the sulfonamide moiety of the type 34 and 35, sulfamates 36

www.future-science.com

1155

Review  Carta, Supuran & Scozzafava

R

N

O

SO2NH2

S

S

23 24 25 26 27

O

R = CO(CH2)5ONO2 (NCX 274) R = CO-p-(C6H4)-CH2ONO2 (NCX 265) R = COO(CH2)3ONO2 (NCX 278) R = COO(CH2)4ONO2 (NCX 245) R = COOCH2CH(ONO2)CH2ONO2 (NCX 201)

23–27

R NH

X

O2NO

S

S

O

SO2NH2

O

HO

O OR

HO

28 X = N, R = H 29 X = CH, R = H, C1–C10 alkyl; C5–C10 aryl

HN

O

HO

S

OR

30 R = i-Pr 31 R = H HO

N N N H

O

SO2NH2

N

N N

32 R = Me 33 R = H

SO2NH2

Figure 5. Sulfonamide-NO donor conjugates that have been recently developed. (A) Nicox 23–27 [75,76,77,78] and (B) Pfizer 28 & 29 [32,79,80] . (C) Sulfonamide–prostaglandine receptor antagonists conjugates 30-33 [32,81] .

and sulfamides 37, which structures are reported in Supplementary Figure 3 [85,86,87,88,89,90] . However, the patents claiming the antiglaucoma properties of such compounds lack complete data [85,86,87,88,89,90] . Antiobesity

According to the latest health worldwide surveys, obesity is a fast spreading pathology that affects large parts of the population [91] . Besides the intimate physiopathological mechanisms, obesity is the result of a serious impairment between energy intake and expenditure [45,92,93] , as well as being the cause of serious pathologies affecting both the cardiovascular and the CNS [45,92,93] . The pharmacological treatment of obesity uses mainly a few compounds, and a detailed discussion of their mechanism of action is reported the latest review published by our group [45] . The idea to use CAIs for the treatment of obesity, or obesity-related disorders, originated from the observation that patients under anticonvulsant therapeutic protocols, based on the sulfamate derivative topiramate (TPM) 38, had a sensible weight reduction [94,95] . Such effect was also experimentally replicated in rats [96] .

1156

Future Med. Chem. (2014) 6(10)

Among the various biological effects, which account for the anticonvulsant, analgesic and mood-stabilizing properties of the TPM, the inhibition of the CAs must also be taken into account since TPM is an effective inhibitor [94] . Crystallographic studies of TPM/CA II adduct revealed the classical tetrahedral coordination of the ZBG to the zinc ion, and the scaffold of the molecule was engaged into a net of hydrogen bonds and van der Waals interactions within the enzymatic cavity (Supplementary Figure 4A) [5] . However, the proof-of-concept that CAs play a key role in the metabolism regulation was only recently reported by means of an electrochemical method of wiring mitochondria [97] . The use of specific inhibitors of the mitochondrial CAs (CA VA and VB) determined a disruption of the pyruvate, acetate or succinate metabolisms (Figure 6) [97,98] . Thus, it became reasonable that TPM exerts its weight-loss effect by inhibiting the mitochondrial CAs and therefore affecting the dependent biosynthetic routes of the de novo lipogenesis [1,45] . For a more detailed discussion of the mechanisms the authors refer to the recent review on the obesity treatment recently published [45] .

future science group

Sulfonamides & their isosters as carbonic anhydrase inhibitors 

A molecular dynamic/docking investigation on the TPM/CA VA adduct, using the TPM-CA II crystallographic data as a template, revealed that similar binding modes of the sulfamate TPM within the enzymatic clefts occurred [5,99] giving more strength to the link between CAs and metabolism regulation (Supplementary Figure 4B) . Since the appearance of the patent of Najarian in 2000, which claims the use of TPM in association with a sympathomimetic agent for the treatment or prevention of obesity [100] , a series of related patents were reported with the same scope, and all of them consider the TPM in association with a second agent [101,102,103,104,105] or included in time-controlled devices [106,107,108] . In 2000, the combination of TPM with a sympathomometic agent was approved by US FDA for the treatment of obesity and obesity-related pathologies under the tradename Qnexa® [109] . The development of the zonisamide 39 (Supplementary Figure 5A) for the treatment of obesity went in parallel with TPM. Recent advances in the use of these molecules include patents that consider its association with a sympathomimetic agent, CB1 antagonist or 5HT2c-selective antagonist [103,110,111,112,113] . Anticonvulsants/antiepileptics

A complete overview on the CAI-based treatment of epilepsy is recently given by Mckenna’s group [34] and in this chapter only a resume of the most interesting aspects are reported. The uncontrolled generation of partial or generalized seizures within the brain are the main symptoms associated to the epilepsy. The sources of seizures are various and individual, thus any appropriate stimulus might trigger an abnormal and uncontrolled electric neuronal activity. Among the causes of the epileptic events the concentration of the carbon dioxide within the brain is also taken into account. Experimental data on rats showed that the increase of the carbon dioxide tension into the brain is correlated with the seizures threshold [114] . Moreover animals models showed that inhibition of the CAs expressed in the brain through the use of acetazolamide 1, [115] methazolamide 8, [116] and sulthiame 45, [117] determined an increase of the carbon dioxide concentration and therefore resulted into an increase of the cerebral blood flow [114] , which in turn might be responsible for lowering the brain excitability and increasing the seizures threshold [114] . Nowadays the use of CAIs, such as the acetazolamide 1 and methazolamide 8, as antiepileptics are limited. The latest report accounting the use of acetazolamide 1 appeared in 2001 for the treatment of the catamenial epilepsy in women [118] , whereas the use of the methazolamide 8 as antiepileptic was abandoned. Currently

future science group

Review

X

O N H

40 n = 0; X = H 41 n = 0; X = Cl 42 n = 1; X = H 43 n = 2; X = H

n

SO2NH2

S

SO2NH2 O

S N H

N N

44

Figure 6. Sulfonamide type CAVA/VB specific inhibitors [45,97,98] .

the aromatic sulfonamide derivative sulthiame 45 is largely prescribed for the treatment of epilepsy in Europe and Australia [119] . In particular, sulthiame 45 was reported to be effective for the treatment of partial epilepsy in children even if it affects important mental abilities [120] . The sulfamate derivative TPM and the sulfonamide zonizamide (ZNS) are more effective for the treatment of epilepsy. TPM showed good pharmacological profile as well as appropriate bioavailability and since it is administered orally its tolerance is high [121,122,123] . TPM used in monotherapy regimen showed to be effective in the treatment of both partial and generalized epilepsy [121] . It was previously described that TPM is and effective CAI [94] and therefore might exert its antiepileptic effect by increasing the concentration of the carbon dioxide in the blood and the brain. Moreover, the therapeutic result is also due to the interference with the ionic and electric neuronal potentials created from Na and Ca channels, AMPA/kainate and GABA receptors [124,125,126,127] . Despite the large use and the effectiveness of TPM for the treatment of epilepsy, serious side effects are associated with its use such as impairment of recognition and coordination and paresthesia [128] . The sulfonamide derivative ZNS has a mechanism of action and a clinical use similar to TPM. The main side effect associated with ZNS is the tolerance in analogy with the acetazolamide 1 and methazolamide 8 when used for the same purposes [45] . (Supplementary Figure 5B)

Anticancer

One of the main achievements in the anticancer research field in the latter years has been represented by the discovery that in many solid tumors an over-expression of hCA IX and XII isoforms is observed as a consequence

www.future-science.com

1157

Review  Carta, Supuran & Scozzafava of the reduced oxygen tension in the inner tumoral areas [1,2,9,129] . hCA IX isoform is the most investigated one, as its expression is closely related to the development of malignances (Supplemetary Figure 6A & B) [129] . The authors of the present review gave significant contributions regarding the expression, regulations mechanisms, structural and functional characterization of the CA IX, and for detailed discussions of all these aspects the reader can consult the latest updates in the literature [35] . Here we simply remind the most significative aspects of CAIX: • The expression of the CA IX is closely related to the transformation of normal cell into the cancerogenic ones. In particular, the solid hypoxic tumors are particularly rich in CA IX; • The expression of the CA IX in the cells has to be considered as part of a complex machinery, which is intended to guarantee the cell survival in nonphysiological conditions; • CA IX (also CA XII) has the catalytic site orientated towards the extracellular environment – a unique structural feature among all the CAs; • Inhibitors can bind the catalytic site of CAIX only in hypoxic conditions. The expression of the CA XII on its turn, seems to be related to specific tumors such as the RCC [130,131] , astrocytoma [132] , breast [133] , ovarian [134] , pancreatic [135] , colorectal [136] and gastrointestinal [136] carcinoma as well as in non-small-cell lung cancer [136] . In addiction, the regulation mechanism of the CA XII appears different from those of the CA IX [1,2] . In consideration of the relevance of CA IX within the malignant cells, many efforts have been made to

develop molecules useful for the treatment, as well as for the detection, of hypoxic cancers [1,2,35] . An update patent review on anticancer CAIs covering work until 2013 has been published by some authors of the current review [35] . Herein, a summary of the more promising small molecules containing the sulfonamide ZBG or its structural isosters as CA IX/XII-targeting agents is reported. One of the more successful approaches for the selective inhibition of the tumor-related CA isoforms was previously mentioned in the beginning section. For instance, sulfonamide-based compounds of type 7, which bear a permanent positively charged moiety, are able to selectively inhibit the CA IX and XII at low nanomolar concentration [38,39,40,41,42,43] . The charged moiety confers to the molecules physicochemical properties that hamper their ability to cross the cellular membranes, and thus, preventing the inhibition of the CA pool expressed within the cells environment [38,39,40,41,42,43] . For diagnostic purposes fluorescent-tagged compounds of type 46 (Figure 7) have been developed. In analogy to 7, the introduction of a fluorescent tag afforded a series of compounds with interesting properties. For instance, such molecules proved to be effective inhibitors of the CA IX isoform only under hypoxic condition, which are proper of the solid tumors [137] . Moreover, their ability to inhibit the CA IX determined a restoration of the pH values from acidic, typical of the tumor cells, to the physiological ones [137] . Such properties clearly validated compounds of type 46 as valid tools both for the selective treatment of hypoxic tumors and for the development of probes for imaging purposes [1,2,137] . Recently the ureido benzenesulfonamide compound derivatives of the type 47 were reported as effective

SO2NH2

SO2NH2

SO2NH2

n = 0, 1

NH

HN

O HN

S HO2C

45

O

OH

O

HN

46

R

O

HN HN

47

NO2

Figure 7. Sulfonamide-based fluorescent tagged compounds 45 [137] and ureido benzenesulfonamide derivatives 46 for the treatment of cancer [35,138,139,140] .

1158

Future Med. Chem. (2014) 6(10)

future science group

Sulfonamides & their isosters as carbonic anhydrase inhibitors 

Review

Table 4. Most promising carbonic anhydrase IX inhibitors for the treatment of cancer [2] . Compound Generic/Trade name

Category

Imatinib

Gleevec

Nilotinib

Indications

Highest phase

Organization

PTK and/or CA GISTs, CML inhibitor

Clinical

Novartis

Tasigna

PTK and/or CA GISTs, CML inhibitor

Clinical

Novartis

U-104

Not available

Sulfonamide CA inhibitor

Solid Tumors and/or metastases

Preclinical

Signalchem Lifesciences Corp.

GC-205

Not available

Coumarin CA inhibitor

Solid Tumors and/or metastases

Preclinical

Signalchem Lifesciences Corp.

CA: Carbonic anhydrase.

inhibitors of the tumor associated CA isoforms IX and XII [138] . Moreover such compounds demonstrated to reduce the amount of cancer stem cells in hypoxic conditions [139] . Among the ureido series, the compound bearing the m-nitrophenyl moiety 47 showed quite interestingly properties when tested in breast cancer models, as they demonstrated to able to significantly reduce both the primary tumor as well as the formation of metastases  [140] . The introduction of a nitroimidazole moiety in a series of compounds of type 48–57, reported in Supplementary Figure 7, were claimed in a recent patent [141] . All compounds demonstrated to be effective inhibitors of the tumor-associated CA IX/XII isoforms. Moreover, the nitroimidazoyl tail generated radical species upon irradiation and thus giving the opportunity for a more effective treatment of the tumors [141] . Anti-infectives

The carbon dioxide hydration reaction catalyzed by the CAs is also implicated in bacteria, fungi and protozoa in fundamental physiological processes, such as the photosynthesis, respiration, pH control and metabolism of xenobiotics [1,2] . Moreover, such a simple reaction plays an important role in ensuring the survival of the pathogenic species within their hosts [142] . Thus, targeting the pathogenic CAs represents an attractive approach for the development of new anti-infective drugs to be used alone or in association with known antibiotics [142] . Sulfonamide-based CAIs clinically used have been tested in vitro and in vivo on different bacterial species including those particularly pathogenic for the humans such as Brucella Suis and Mycobacterium Tuberculosis. A comprehensive overview covering the latest patent and literature aspects on the ongoing researches aiming to develop effective inhibitors of the bacterial and fungal CAs recently appeared [143] and it can be observed that:

future science group

• Bacterial species express multiple CA isoforms, in some case belonging to different classes, thus expanding the possibility to target them; • The inhibition data clearly demonstrated that the bacterial CAs are effectively inhibited by the sulfonamide-based CAIs currently used for the treatment of pathologies previously discussed; • CAI targeting of fungal CAs is less advanced if compared with the bacterial status (Supplementary Tables 1, 2 & 3) . Still, however, remains the need to develop specific inhibitors of CAs expressed by the pathogenic species without interfering with those expressed in the host organisms [143] . Among the protozoan parasites, only the Plasmodium falciparum and the Trypanosoma cruzi have been investigated for their CA inhibition profiles [144,145] . The first is the causative agent of malaria and encodes for several CAs. However, a complete inhibition profile was accomplished on the P. falciparum CA isoform with sulfonamides derivatives [144] . In particular, the benzenesulfonamide derivative 58 showed particularly efficient in the treatment of a malarial model (Supplementary Figure 8) [144] . In summary, the expression of the various CA isoforms in parasites gives the opportunity to identify selective inhibitors that might be used as lead molecules for the development of new tools for the treatment of infection diseases. Future perspective The CA metalloenzymes are widely distributed among the eukaryotic and prokaryotic organisms and are responsible for the catalysis of the carbon dioxide hydration. Such a simple transformation plays a fundamental role in a plethora of physiological transformations, which include control of pH, osmosis, electric and ionic potentials in the cells as well as in specific

www.future-science.com

1159

Review  Carta, Supuran & Scozzafava

Table 5. Structure and inhibition data of pazopanib 59 in comparison with acetazolamide 1 [146] .

N N

N N N

N H

SO2NH2

59

Isozyme

KI (nM) 59

1

hCA I

12.1

250

hCA II

32.4

12

hCA III

4570

2 x 105

hCA IV

78

74

hCA VA

6.1

63

hCA VB

6.4

54

hCA VI

24.3

11

hCA VII

76.5

2.5

hCA IX

9.1

25

hCA XII

0.88

5.7

hCA XIII

35.2

17

hCA XIV

26.5

41

hCA: Human carbonic anhydrase.

cellular compartments, and modulation of biosynthetic pathways, such as the gluconeogenesis, lipogenesis, ureagenesis and de novo synthesis of pyrimidines. To date, five unrelated families of CAs are reported and characterized and among each family are distinct subtypes also present. Validation of the CAs as pharmaceutical targets is based on the fundamental role played from such enzymes in the control of physio/pathological status. Thus, the development of selective inhibitors of such enzymes indeed represents an important approach for the identification of new lead compounds for future clinical applications. The role of sulfonamide-based CAIs as diuretics, antiglaucoma and antiobesity is well established. Recent advances on the role of the CAs in the renal as well in the ocular physiologies are leading to more effective drugs. Today, the research field on CAIs is particularly focused in the anticancer area through the development of CA IX specific inhibitors (Table 4) . As listed in Table 4, several CA IX specific inhibitors are in advanced stages of evaluation and among

1160

Future Med. Chem. (2014) 6(10)

them is the sulfonamide-based derivative U-104 in preclinical phase for the treatment of solid tumors as well as their metastases [2] . Another challenging area could be represented by the anti-infectives. To date, very few are known and reported on the expression of bacterial, fungal and protozoan CAs, and only a limited number of sulfonamide-based compounds were screened for their ability to inhibit the prokaryotic CAs. Such a result, however, indicates the intriguing possibility to look for specific compounds against the metalloenzymes expressed from the pathogens [143] . A recent example of sulfonamide-bearing compound is represented from the pazopanib 59. Such a molecule was recently approved by the US FDA for the treatment of RCC, lung cancers, breast cancers, ovarian cancers, gliomas and soft tissue sarcomas [146] . Pazopanib is a tyrosine kinase inhibitor, however the presence of the typical ZBG for the CAs as well as the high expression of CA IX in the tumors previous mentioned, prompted us to perform a screening of the molecule towards the humans CAs (Table 5) . The kinetic profile of 59 on the catalytic hCAs in comparison with the promiscuous CA inhibitor acetazolamide 1, revealed that such a molecule is an effective inhibitor of all the CA isoforms. All the data are in the low nanomolar range, with the only exception of CA III, IV and VII. More importantly are the inhibition data of the tumor-associated isoforms IX and XII (9.1 and 0.88 nM, respectively). Although little is known about the role of the CA XII within such tumors, it is reasonable to assume that some of the therapeutic effect of the pazopanib 59 might be exerted also from the inhibition of the tumor-associated CA isoforms [146] . Supplementary data To view the supplementary data that accompany this paper please visit the journal website at: www.future-science.com/ doi/10.4155/FMC.14.68

Financial & competing interests disclosure This work was financed in part by by several grants of the 6th and 7th Framework Programs of the European Union (DeZnIT, Metoxia and Dynano projects). The authors declare conflict of interest being authors on many patents dealing with various classes of CA inhibitors (most of which cited in the review). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

future science group

Sulfonamides & their isosters as carbonic anhydrase inhibitors 

Review

Executive Summary Background • The carbonic anhydrases (CA, EC 4.2.1.1) are metalloenzymes responsible for the catalysis of the carbon dioxide hydration reaction, which is fundamental in many physiological events. • The main class of CA inhibitors (CAIs) is constituted by molecules containing the primary sulfonamide group (R-SO2NH2).

Diuretics

• State-of-the-art research on the sulfonamide-based diuretics is involved in a deep reexamination of such compounds.

Antiglaucoma • Sulfonamide–NO donor conjugates for the treatment of glaucoma were recently developed by Nicox and Pfizer. • The observation that latanoprost resulted as an effective intraocular pressure-lowering agent drove for the development of the sulfonamide–prostaglandine receptor antagonists conjugates.

Antiobesity • The proof that CAs play a key role in the metabolism regulation was only recently reported. • Topiramate exerts its weight-loss effect by inhibiting the mitochondrial CAs and therefore affecting the dependent biosynthetic routes of the de novo lipogenesis.

Anticonvulsants/antiepileptics • Sulthiame is largely prescribed for the treatment of partial epilepsy in children epilepsy in the Europe and Australia. • The sulfamate derivative topiramate and the sulfonamide zonizamide are more effective for the treatment of epilepsy.

Anticancer • Ureido-benzenesulfonamide and nitroimidazole derivatives were reported as effective inhibitors of the tumor associated CA isoforms IX and XII.

Anti-infectives • The expression of the various CA isoforms in parasites gives the opportunity to identify selective inhibitors that might be used as lead molecules for the development of new tools for the treatment of infection diseases.

Future perspective • Validation of the CAs as pharmaceutical targets is based on the fundamental role played from such enzymes in the control of physio/pathological status. Thus, the development of selective inhibitors of such enzymes indeed represents an important approach for the identification of new lead compounds for future clinical applications.

References

5

Vitale RM, Pedone C, Amodeo P et al. Molecular modeling study for the binding of zonisamide and topiramate to the human mitochondrial carbonic anhydrase isoform VA. Bioorg. Med. Chem. 15, 4152–4158 (2007).

6

Nishimori I, Minakuchi T, Onishi S, Vullo D, Scozzafava A, Supuran CT. Carbonic anhydrase inhibitors. DNA cloning, characterization and inhibition studies of the human secretory isoform VI, a new target for sulfonamide and sulfamate inhibitors. J. Med. Chem. 50, 381–388 (2007).

7

Vullo D, Voipio J, Innocenti A et al. Carbonic anhydrase inhibitors. Inhibition of the human cytosolic isozyme VII with aromatic and heterocyclic sulfonamides. Bioorg. Med. Chem. Lett. 15, 971–976 (2005).

8

Nishimori I. Carbonic Anhydrase – Its Inhibitors and Activators. Supuran CT, Scozzafava A, Conway J (Eds). CRC, FL, USA, 25–43 (2004).

9

Vullo D, Franchi M, Gallori E et al. Carbonic anhydrase inhibitors. Inhibition of the tumor-associated isozyme IX with aromatic and heterocyclic sulfonamides. Bioorg. Med. Chem. Lett. 13, 1005–1009 (2003).

Papers of special note have been highlighted as: • of interest; •• of considerable interest 1

Supuran CT. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nature Rev. Drug Discov. 7, 168–181 (2008).

••

Excellent review on carbonic anhydrase (CA) inhibitors (CAIs) and activators.

2

Neri D, Supuran C T. Interfering with pH regulation in tumors as a therapeutic strategy. Nat. Rev. Drug Discov. 10, 767–778 (2011).

••

Excellent review on the use of CAIs as antitumor agents.

3

Nishimori I, Minakuchi T, Onishi S et al. Carbonic anhydrase inhibitors. Cloning, characterization and inhibition studies of the cytosolic isozyme III with sulfonamides. Bioorg. Med. Chem. 15, 7229–7236 (2007).

4

Vullo D, Franchi M, Gallori E et al. Carbonic anhydrase inhibitors. Inhibition of mitochondrial isozyme V with aromatic and heterocyclic sulfonamides. J. Med. Chem. 47, 1272–1279 (2004).

future science group

www.future-science.com

1161

Review  Carta, Supuran & Scozzafava 10

11

27

Supuran CT. Structure-based drug discovery of carbonic anhydrase inhibitors. J. Enzyme Inhib. Med. Chem. 27, 759–772 (2012).

28

Carta F, Scozzafava A, Supuran CT. Sulfonamides: a patent review (2008–2012). Expert Opin. Ther. Pat. 22, 747–758 (2012).

29

Maren TH. Carbonic anhydrase: chemistry, physiology and inhibition. Physiol. Rev. 47, 595–781 (1967).

30

Mann T, Keilin T. Sulphanilamide as specific carbonic anhydrase inhibitor. Nature 146, 164–165 (1940).

31

Abbate F, Supuran CT, Scozzafava A, Orioli P, Stubbs MT, Klebe G. Nonaromatic sulfonamide group as an ideal anchor for potent human carbonic anhydrase inhibitors: role of hydrogen-bonding networks in ligand binding and drug design. J. Med. Chem. 45(17), 3583–3587 (2002).

32

Alterio V, Langella E, Viparelli F et al. Structural and inhibition insights into carbonic anhydrase CDCA1 from the marine diatom Thalassiosira weissflogii. Biochimie 94, 1232–1241 (2012).

Masini E, Carta F, Scozzafava A, Supuran CT. Antiglaucoma carbonic anhydrase inhibitors: a patent review. Expert Opin. Ther. Pat. 23, 705–716 (2013).



Recent review on CAIs as antiglaucomas.

33

Pen~a KL, Castel SE, de Araujo C et al. Structural basis of the oxidative activation of the carboxysomal γ -carbonic anhydrase, CcmM. Proc. Natl Acad. Sci. USA 107, 2455– 2460 (2010).

Carta F, Supuran CT. Diuretics with carbonic anhydrase inhibitory action: a patent and literature review (2005– 2013). Expert Opin. Ther. Pat. 23, 681–691 (2013).



Recent review on CAIs as diuretics.

34

Aggarwal M, Kondeti B, McKenna R. Anticonvulsant/ antiepileptic carbonic anhydrase inhibitors: a patent review. Expert Opin. Ther. Pat. 23, 717–724 (2013).



Recent review on CAIs as anticonvulsants/antiepileptics.

35

Monti SM, Supuran CT, Simone G. Anticancer carbonic anhydrase inhibitors: a patent review (2008–2013). Expert Opin. Ther. Pat. 23, 737–749 (2013).

De Simone G, Alterio V, Supuran CT. Exploiting the hydrophobic and hydrophilic binding sites for designing carbonic anhydrase inhibitors. Expert Opin. Drug Discov. 8, 793–810. (2013).



Recent review on CA structures.

12

Eriksson AE, Jones TA, Liljas A. Refined structure of human carbonic anhydrase II at 2.0 A resolution. Proteins 4, 274–282 (1988).

13

Schlicker C, Hall RA, Vullo D et al. Structure and inhibition of the CO2- sensing carbonic anhydrase Can2 from the pathogenic fungus Cryptococcus neoformans. J. Mol. Biol. 385, 1207–1220 (2009).

14

15

16

Supuran CT. Carbonic anhydrases as drug targets: general presentation. In: Drug Design of Zinc-Enzyme Inhibitors: Functional, Structural, and Disease Applications. Supuran CT, Winum JY (Eds). Wiley, NJ, USA, 473–486 (2009).

17

Supuran CT, Scozzafava A. Carbonic anhydrase inhibitors and their therapeutic potential. Expert Opin. Ther. Pat. 10, 575–600 (2000).

36

18

Supuran CT. Structure-based drug discovery of carbonic anhydrase inhibitors. J. Enzyme Inhib. Med. Chem. 27, 759–772 (2012).

Sugrue MF. Pharmacological and ocular hypotensive properties of topical carbonic anhydrase inhibitors. Progr. Ret. Eye. Res. 19, 87–112 (2000).

37

19

Liao SY, Ivanov S, Ivanova A et al. Expression of cell surface transmembrane carbonic anhydrase genes CA9 and CA12 in the human eye: overexpression of CA12 (CAXII) in glaucoma. J. Med. Genet. 40, 257–261 (2003).

Silver LH. Dose-response evaluation of the ocular hypotensive effect of brinzolamide ophthalmic suspension (Azopt). Brinzolamide dose-response study group. Surv. Ophthalmol. 44, 147–153 (2000).

38

20

Supuran CT, Parkkila S: WO139678 (2010).

21

Ebbesen P, Supuran CT, Scozzafava A et al.: WO098610 (2011).

Casey JR, Morgan PE, Vullo D et al. Carbonic anhydrase inhibitors. Design of selective, membrane-impermeant inhibitors targeting the human tumor-associated isozyme IX. J. Med. Chem. 47, 2337–2347 (2004).

22

Supuran CT, Dedhar S, McDonald P et al.: WO022012 (1963).

39

Scozzafava A, Briganti F, Ilies MA, Supuran CT. Carbonic anhydrase inhibitors: synthesis of membrane-impermeant low molecular weight sulfonamides possessing in vivo selectivity for the membrane-bound versus cytosolic isozymes. J. Med. Chem. 43, 292–300 (2000).

40

Institute of Virology of the Slovak Academy of Sciences: US095707 (2008).

41

Scozzafava A. Institute of Virology, Supuran CT: AU211499 (2012).

42

Institute of Virology, Supuran CT, Scozzafava A: AU200368 (2010).

43

Institute of Virology of the Slovak Academy of Sciences: US220001 (2008).

44

Maus TL, Larsson LI, McLaren JW, Brubaker RF. Comparison of dorzolamide and acetazolamide as

23

Supuran CT, Dedhar S, Carta F et al.: WO070024 (2012).

24

Masereel B, Frederick R, Supuran CT: WO175654 (2012).

25

Alterio V, Di Fiore A, D’Ambrosio K, Supuran CT, De Simone G. Multiple binding modes of inhibitors to carbonic anhydrases: how to design specific drugs targeting 15 different isoforms? Chem. Rev. 112, 4421–4468 (2012).

26

1162

Vullo D, Innocenti A, Nishimori I et al. Carbonic anhydrase inhibitors. Inhibition of the transmembrane isozyme XII with sulfonamides – a new target for the design of antitumor and antiglaucoma drugs? Bioorg. Med. Chem. Lett. 15, 963–969 (2005).

Alterio V, Di Fiore A, D’Ambrosio K, Supuran CT, De Simone G. X-ray christallography of carbonic anhydrase inhibitors and its importance in drug design Inhibitors. In: Drug Design of Zinc-Enzyme Inhibitors: Functional, Structural, and Disease Applications. Supuran CT, Winum JY (Eds) Wiley, NJ, USA, 155–170 (2009).

Future Med. Chem. (2014) 6(10)

future science group

Sulfonamides & their isosters as carbonic anhydrase inhibitors 

crystallographic studies for the indapamide-isozyme II adduct. Bioorg. Med. Chem. Lett. 18, 2567–2573 (2008).

suppressors of aqueous humor flow in humans. Arch Ophthalmol. 115, 45–49 (1997). 45

Scozzafava A, Supuran CT, Carta F. Antiobesity carbonic anhydrase inhibitors: a literature and patent review. Expert Opin. Ther. Pat. 23, 725–735 (2013).

46

Vullo D, Innocenti A, Supuran CT. Diuretics with carbonic anhydrase inhibitory activity: towards novel application for sulfonamide drugs. In: Drug Design of Zinc-Enzyme Inhibitors: Functional, Structural, and Disease Applications. Supuran CT, Winum JY (Eds). Wiley, NJ, USA, 473–486 (2009).

47

Jackson EK. Diuretics. In: Goodman and Gilman’s the pharmacological basis of therapeutics. 9th Edition. Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG (Eds). McGraw-Hill, NY, USA, 685–713 (1996).

48

Lonnerholm G, Wistrand PJ, Barany E. Carbonic anhydrases isoenzymes in the rat kidney. Effects of chronic acetazolamide treatment. Acta Physiol. Scand. 126, 51–60 (1986).

49

Parkkila S, Parkkila AK, Kivela J. Role ofcarbonic anhydrase and its inhibitors inbiological science related togastroenterology, neurology andnephrology. In: Carbonic anhydrase – its inhibitors and activators. Supuran CT, Scozzafava A, Conway J (Eds). CRC Press, FL, USA, 281–303 (2004).

59

Temperini C, Cecchi A, Scozzafava A et al. Carbonic anhydrase inhibitors. Comparison of chlorthalidone and indapamide X-ray crystal structures in adducts with isozyme II: when three water molecules and the ketoenol tautomerism make the difference. J. Med. Chem. 52, 322–328 (2009).

60

Temperini C, Cecchi A, Scozzafava A et al. Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide and furosemide x-ray crystal structures in adducts with isozyme II, when several water molecules make the difference. Bioorg. Med. Chem. 17, 1214–1221 (2009).

61

Supuran CT, Scozzafava A. Benzolamide is not a membraneimpermeant carbonic anhydrase inhibitor. J. Enzyme Inhib. Med. Chem. 19, 269–273 (2004).

62

Taki K, Hirahara K, Tomita S et al. Acetazolamide-induced increase in blood flow to rabbit organs is confirmed using colored microspheres. Heart Vessels 13, 63–67 (1998).

63

Taki K, Kato H, Endo S et al. Cascade of acetazolamideinduced vasodilatation. Res. Commun. Mol. Pathol. Pharmacol. 103, 240–248 (1999).

64

Taki K, Oogushi K, Hirahara K et al. Preferential acetazolamide-induced vasodilation based on vessel size andorgan: confirmation of peripheralvasodilation with use of colored microspheres. Angiology 52, 483–488 (2001).

50

Lonnerholm G. Histochemical demonstration of carbonic anhydrase in the human kidney. Acta Physiol. Scand. 88, 455–469 (1973).

65

51

Lonnerholm G, Ridderstrale Y. Distribution of carbonic anhydrase in the frog nephron. Acta Physiol. Scand. 90, 764–778 (1974).

Chobanyan-Jurgens K, Schwarz A, Bohmer A et al. Renal carbonicanhydrases are involved in the reabsorption of endogenous nitrite. Nitric Oxide 26, 126–131 (2012).

66

Kharwade P, Bhushan I: US0107726 (2008).

52

Lonnerholm G, Ridderstrale Y. Intracellular distribution of carbonic anhydrase in the rat kidney. Kidney Int. 17, 162–174 (1980).

67

Sasmal BK, Reddy BP, Nasare VD et al.: US0068269 (2010).

68

Hartley CE: US0137232 (2010).

69

Straub M, Witte K, Ziegler D et al.: US0323012 (2010).

70

Sedmak G, Vrecer F: WO161123 (2012).

71

Zhang K, Zhang L, Weinreb RN. Ophthalmic drug discovery: novel targets and mechanisms for retinal disease and glaucoma. Nature Rev Drug Discov. 11, 541–559 (2012).

72

Miller WH, Dessert AM, Roblin RO Jr. Heterocyclic sulfonamides as carbonic anhydrase inhibitors. J. Am. Chem. Soc. 72, 4893–4896 (1950).

73

Maren TH, Jankowska L, Sanyal G et al. The transcorneal permeability of sulfonamide carbonic anhydrase inhibitors and their effect on aqueous humor secretion. Exp. Eye Res. 36, 457–480 (1983).

74

Carta F, Supuran CT, Scozzafava A. Novel therapies for glaucoma: a patent review 2007–2011. Expert Opin. Ther. Patents 22, 79–88 (2012).

75

Supuran CT, Benedini F, Biondi S et al.: WO071421 (2008).

76

Mincione F, Benedini F, Biondi S et al. Synthesis and crystallographic analysis of new sulfonamides incorporating NO-donating moieties with potent antiglaucoma action. Bioorg. Med. Chem. Lett. 21, 3216–3221 (2011).

77

Fabrizi F, Mincione F, Somma T et al. A new approach to antiglaucoma drugs: carbonic anhydrase inhibitors with or without NO donating moieties. Mechanism of action and

53

Sly WS, Hewett-Emmett D, Whyte MP et al. Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. Proc. Natl Acad. Sci. USA 80, 2752–2756 (1983).

54

Nawata CM, Hung CC, Tsui TK et al. Ammonia excretion in rainbow trout (Oncorhynchus mykiss): evidence for Rh glycoprotein and H+−ATPase involvement. Physiol. Genomics 31, 463–474 (2007).

55

Weiner ID, Verlander JW. Renal and hepatic expression of the ammonium transporter proteins, Rh B Glycoprotein and Rh C Glycoprotein. Acta Physiol. Scand. 179, 331–338 (2003).

56

Supuran CT. Diuretics: from classical carbonic anhydrase inhibitors to novel applications of the sulfonamides. Curr. Pharm. Des. 14, 641–648 (2008).

57

Temperini C, Cecchi A, Scozzafava A et al. Carbonic anhydrase inhibitors. Sulfonamide diuretics revisited – old leads for new applications? Org. Biomol. Chem. 6, 2499–2506 (2008).

58

Temperini C, Cecchi A, Scozzafava A et al. Carbonic anhydrase inhibitors. Interaction of indapamide and related diuretics with twelve mammalian isozymes and X-ray

future science group

Review

www.future-science.com

1163

Review  Carta, Supuran & Scozzafava preliminary pharmacology. J. Enzyme Inhib. Med. Chem. 27, 138–147 (2012). 78

Benedini F, Biondi S, Ongini E: WO075155 (2008).

79

Patterson B, Rui E: WO120099 (2008).

80

Huang Q, Rui E: WO007814 (2009).

81

Long DD, Frieman B, Hegde SS et al. A multivalent approach towards linkeddual-pharmacology prostaglandin Freceptor agonist/carbonic anhydrase-II inhibitors for the treatment of glaucoma. Bioorg. Med. Chem. Lett. 23, 939–943 (2013).

82

Chiroli V, Batugo MR, Biondi S et al. Synthesis of novel nitric oxide (NO) – releasing esters of timolol. Bioorg. Med. Chem. Lett. 19, 2785–2788 (2009).

83

Steele RM, Batugo MR, Benedini F et al. Nitric oxidedonating carbonic anhydrase inhibitors for the treatment of open-angle glaucoma. Bioorg. Med. Chem. Lett. 19, 6565–6570 (2009).

84

Guzel O, Innocenti A, Scozzafava A, Salman A, Supuran CT. Carbonic anhydrase inhibitors. Aromatic/heterocyclic sulfonamides incorporating phenacetyl, pyridylacetyl and thienylacetyl tails act as potent inhibitors of human mitochondrial isoforms VA and VB. Bioorg. Med. Chem. 17, 4894–4899 (2009).

99

Dodgson SJ, Shank RP, Maryanoff BE. Topiramate as an inhibitor of carbonic anhydrase isoenzymes. Epilepsia 41, S35–9 (2000).

100 Najarian T: WO76493 (2000). 101 Najarian T: US0234950 (2006). 102 Najarian T: US0234951 (2006). 103 Najarian T, Tam PY, Wilson LF: WO153632 (2008). 104 Najarian T, Tam PY, Wilson LF: US0304785 (2009). 105 Najarian T, Tam PY, Wilson LF: US0262535 (2011). 106 Aronne LJ: WO045416 (2010). 107 Aronne LJ: WO009115 (2011). 108 Aronne LJ: WO041632 (2011). 109 Heal DJ, Gosden J, Smith SL. What is the prognosis for new

centrally-acting anti-obesity drugs? Neuropharmacology 63, 132–146 (2012).

85

Nair SK, Rui EY: WO075148 (2008).

110 Jenning JE: US0026977 (2005).

86

Schoen U, Waldeck H, Reinecker U et al.: WO050252 (2009).

111 Gadde MK, Krishnan KR: US0319036 (2008).

87

Antel J, Waldeck H, Schoen U et al.: US0117823 (2007).

88

Antel J, Waldeck H, Schoen U et al.: WO054580 (2007).

89

Matulis D, Dudutiene V, Matuliene J et al.: WO016288 (2008).

90

Baranauskiene L, Hilvo M, Matuliene J et al. Inhibition and binding studies of carbonic anhydrase isozymes I, II and IX with benzimidazo[1,2-c] [1,2,3] thiadiazole-7sulphonamides. J. Enzyme Inhib. Med. Chem. 25, 863–870 (2010).

112 Gadde MK, Krishnan KR: US0098289 (2011). 113 Hauske JR: WO017755 (2009). 114 Woodbury DM, Rollins LT, Gardner MD et al. Effects of

carbon dioxide on brain excitability and electrolytes. Am. J. Physiol. 192, 79–90 (1958). 115 Brzezinski J, Kjallquist A, Siesjo BK. Mean carbon dioxide

tension in the brain after carbonic anhydrase inhibition. J. Physiol. 188, 13–23 (1967). 116 Gray WD, Rauh CE. The anticonvulsant action of carbon

dioxide: interaction with reserpine and inhibitors of carbonic anhydrase. J. Pharmacol. Exp. Ther. 163, 431–438 (1968).

91

National Center for Health Statistics. www.cdc.gov/nchs/ products/hestats.htm

92

Kelner K, Helmuth L. Obesity – what is to be done? Science 299, 845 (2003).

93

Hill OJ, Wyatt HR, Reed GW, Peters JC. Obesity and the environment: where do we go from here? Science 299, 853–855 (2003).

118 Lim LL, Foldvary N, Mascha E, Lee J. Acetazolamide in

Supuran CT. Carbonic anhydrase inhibitors in the treatment and prophylaxis of obesity. Expert Opin. Ther. Pat. 13, 1545–1550 (2003).

119 Ben-Zeev B, Watemberg N, Lerman P, Barash I, Brand N,

94

95

Gordon A, Price LH. Mood stabilization and weight loss with topiramate. Am. J. Psychiatry. 156, 968 (1999).

96

Picard F, Deshaies Y, Lalonde J et al. Topiramate reduces energy and fat gains in lean (Fa/?) and obese (fa/fa) Zucker rats. Obes. Res. 8, 656–663 (2000).

97

Arechederra RL, Waheed A, Sly WS, Supuran CT, Minteer SD. Effect of sulfonamides as selective carbonic anhydrase VA and VB inhibitors on mitochondrial metabolic energy conversion. Bioorg. Med. Chem. 21, 1544–1548 (2013).

••

1164

Fabrizi F, Mincione F, Somma T et al. A new approach to antiglaucoma drugs: carbonic anhydrase inhibitors with or without NO donating moieties. Mechanism of action and preliminary pharmacology. J. Enzyme Inhib. Med. Chem. 27, 138–147 (2012).

98

Proof-of-concept for the use of sulfonamides as antiobesity agents.

Future Med. Chem. (2014) 6(10)

117 Leniger T, Wiemann M, Bingmann D, Widman G,

Hufnagel A, Bonnet U. Carbonic anhydrase inhibitor sulthiame reduces intracellular pH and epileptiform activity of hippocampal CA3 neurons. Epilepsia 43, 469–474 (2002). women with catamenial epilepsy. Epilepsia 42, 746–749 (2001). Lerman-Sagie T. Sulthiame in childhood epilepsy. Pediatr. Int. 46, 521–524 (2004). 120 Wirrell E, Sherman EMS, Vanmastrigt R et al. Deterioration

in cognitive function in children with benign epilepsy of childhood with central temporal spikes treated with sulthiame. J. Child Neurol. 23, 14–21 (2008). 121 Lyseng-Williamson KA, Yang LPH. Topiramate: a review

of its use in the treatment of epilepsy. Drugs 67, 2231–2256 (2007). 122 Guerrini R, Carpay J, Groselj J et al. Topiramate

monotherapy as broad-spectrum antiepileptic drug in a naturalistic clinical setting. Seizure 14, 371–380 (2005).

future science group

Sulfonamides & their isosters as carbonic anhydrase inhibitors 

123 Arroyo S, Dodson WE, Privitera MD et al. Randomized

136 Ilie MI, Hofman V, Ortholan C et al. Overexpression of

dose-controlled study of topiramate as first-line therapy in epilepsy. Acta Neurol. Scand. 112, 214–222 (2005).

carbonic anhydrase XII in tissues from resectable non-small cell lung cancers is a biomarker of good prognosis. Int. J. Cancer 128, 1614–1623 (2011).

124 Taverna S, Sancini G, Mantegazza M, Franceschetti S,

Avanzini G. Inhibition of transient and persistent Na+ current fractions by thenew anticonvulsant topiramate. J. Pharmacol. Exp. Ther. 288, 960–968 (1999).

137 Svastova´ E, Hulı´kova´ A, Rafajova´ M et al. Hypoxia

activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett. 577, 439–445 (2004).

125 McLean MJ, Bukhari AA, Wamil AW. Effects of topiramate

on sodium-dependent action-potential firing by mouse spinal cord neurons in cell culture. Epilepsia 41, S21–24 (2000).

138 Pacchiano F, Carta F, McDonald PC et al. Ureido-

substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J. Med. Chem. 54, 1896–1902 (2011).

126 Zhang X, Velumian AA, Jones OT, Carlen PL. Modulation

of high-voltage-activated calcium channels in dentate granule cells by topiramate. Epilepsia 41, S52–S60 (2000). 127 Skradski S, White HS. Topiramate blocks kainate-evoked

139 Lock FE, McDonald PC, Lou Y et al. Targeting carbonic

anhydrase IX depletes breast cancer stem cells within the hypoxic niche. Oncogene 32, 5210–5219 (2012).

cobalt influx into cultured neurons. Epilepsia 41, S45–S47 (2000). 128 Lyseng-Williamson KA, Yang LPH. Topiramate: a review

140 Pacchiano F, Carta F, McDonald PC et al. Ureido-

substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J. Med. Chem. 54, 1896–1902 (2011).

of its use in the treatment of epilepsy. Drugs 67, 2231–2256 (2007). 129 Pastorekova S, Zava J. Carbonic anhydrase IX (CA IX) as a

potential target for cancer therapy. Cancer Ther. 2, 245–262 (2004). 130 Tu¨reci O, Sahin U, Vollmar E et al. Human carbonic

anhydrase XII: cDNA cloning, expression, and chromosomal localization of a carbonic anhydrase gene that is overexpressed in some renal cell cancers. Proc. Natl Acad. Sci. USA 95, 7608–7613 (1998).

141 Stichting Maastricht Radiation Oncology Maastro Clinic;

Dubois LJ, Lambin P et al.: WO087115 (2012). 142 Supuran CT. Bacterial carbonic anhydrases as drug targets:

toward novel antibiotics? Front. Pharmacol. 2, 34 (2011). 143 Capasso C, Supuran CT. Anti-infective carbonic anhydrase

inhibitors: a patent and literature review. Expert Opin. Ther. Pat. 23, 693–704 (2013).

131 Haapasalo J, Hilvo M, Nordfors K et al. Identification of

an alternatively spliced isoform of carbonic anhydrase XII in diffusely infiltrating astrocytic gliomas. Neuro Oncol. 10, 131–138 (2008). 132 Wykoff CC, Beasley N, Watson PH et al. Expression of the

hypoxia-inducible and tumor-associated carbonic anhydrases in ductal carcinoma in situ of the breast. Am. J. Pathol. 158, 1011–1019 (2001). 133 Hynninen P, Vaskivuo L, Saarnio J et al. Expression of

transmembrane carbonic anhydrases IX and XII in ovarian tumours. Histopathology. 49, 594–602 (2006). 134 Kivela AJ, Parkkila S, Saarnio J et al. Expression of

transmembrane carbonic anhydrase isoenzymes IX and XII in normal human pancreas and pancreatic tumours. Histochem. Cell Biol. 114, 197–204 (2000). 135 Kivela A, Parkkila S, Saarnio J et al. Expression of a novel

transmembrane carbonic anhydrase isozyme XII in normal human gut and colorectal tumors. Am. J. Pathol. 156, 577–584 (2000).

future science group

Review



Recent review on CAIs as anti-infectives.

144 Krungkrai J, Krungkrai SR, Supuran CT. Carbonic

anhydrase inhibitors. Inhibition of Plasmodium falciparum carbonic anhydrase with aromatic/heterocyclic sulfonamides: in vitro and in vivo studies. Bioorg. Med. Chem. Lett. 18, 5466–5471 (2008). 145 Pan P, Vermelho AB, Capaci Rodrigues G et al. Cloning,

characterization, sulfonamide and thiol inhibition studies of an alpha-carbonic anhydrase from Trypanosoma cruzi, the causative agent of Chagas disease. J. Med. Chem. 56, 1761–1771 (2013). 146 Winum JY, Maresca A, Carta F, Scozzafava A, Supuran

CT. Polypharmacology of sulfonamides: pazopanib, a multitargeted receptor tyrosine kinase inhibitor in clinical use, potently inhibits several mammalian carbonic anhydrases. Chem. Commun. 48, 8177–8179 (2012).

www.future-science.com

1165

Sulfonamides and their isosters as carbonic anhydrase inhibitors.

Molecules containing the sulfonamide group (R-SO2NH2) as well as its structurally related isosters, sulfamido (R-NH-SO2NH2) and sulfamato (R-O-SO2NH2)...
1MB Sizes 6 Downloads 7 Views