Discovery of 4-sulfamoyl-phenyl-β-lactams as a new class of potent carbonic anhydrase isoforms I, II, IV and VII inhibitors: The first example of subnanomolar CA IV inhibitors
Graphical abstract
Introduction
Carbonic anhydrases (CAs, also known as carbonate dehydratase, EC 4.2.1.1) are ubiquitous metallo-enzymes, acting as quite efficient catalysts in promoting the hydration of carbon dioxide to produce bicarbonate and protons, a crucial reaction in all living organisms.1 Although the reaction also occurs without a catalyst, the hydration of CO2 is particularly slow at pH of 7.5 or lower but very effective at higher pH values, being instantaneous at pH > 12.2 CAs are involved in many physiological processes such as cell differentiation and proliferation, pH and CO2 homeostasis, transport of CO2 and bicarbonate in respiration, electrolyte secretion, neurotransmission and various biosynthetic pathways (bone resorption, calcification, gluconeogenesis and lipogenesis) and other physiologic or pathologic processes.3, 4, 5, 6 Indeed, seven (α-, β-, γ-, δ-, ζ-, η- and θ) genetically distinct families are known to date, which contain different metal ions at their active site which includes, Zn(II) (in all classes), Cd(II) (in ζ-CAs), Fe(II) (for γ-CAs, in anaerobic conditions) and Co(II) (in the δ class).7, 8 So far, in humans, 15 different α-CAs were described and these are inhibited by various classes of compounds. Currently known CA inhibitors (CAIs) can be divided into several groups: those that coordinate to the active site metal ion9 and those that do not interact with it.10 Sulfonamides/sulfamates, mercaptophenols, ureates/hydroxamates and metal complexing anion inhibitors are coordinating to the Zn+2 metal ion from the active site to elicit their inhibitory activity.9, 10
The sulfonamides and their bioisosters such as sulfamates and sulfamides are well known CAIs and are in clinical use for the treatment of various diseases such as glaucoma, epilepsy, obesity and as diuretics. The wide use of CAIs relies on the structural diversity and subcellular localization of the 15 human (h) CA isoforms as well as on their implication in many physiological/pathological conditions. The diuretic11 CAI drugs mainly target CA II, IV, XII, and XIV Antiglaucoma12 CA II, IV, and XII; the antiepileptics13 CA VII and XIV. The inhibition of the hCA IX and XII isoforms selectively, results in antitumor and antimetastatic effects.14 However, the main drawback associated with the use of carbonic anhydrase inhibitors (CAIs) is represented by the lack of selectivity in inhibiting the various isoforms, thus resulting in a plethora of unfavourable side effects. In the last decade, many efforts have been made mainly by using structure-based drug design approach (mostly the “tail approach”) to develop isoform-selective CA inhibitors.15, 16 In the “tail approach”, the attached tails (moieties) interact with the active site cavity preferably, middle and the rim part, which is more variable among the 15 human (h) CA isoforms. Consequently, their abnormal activity and/or dysregulated expression may have important pathological consequences. For this reason, in the past years there has been an ever increasing interest in the design of new isoform-selective CAIs belonging to several chemical entities. Some of the structures of CAIs in clinical use/preclinical development are shown in Fig. 1.
Owing to the development of new carbonic anhydrase inhibitors (CAI), we hypothesized that the unexplored 4-sulfamoylbenzene-β-lactam scaffold, extending the chemospace of the benzensulfonamides, could allow for the development of novel inhibitors that are able to interact with the active site region of carbonic anhydrase. On the basis of this hypothesis, the present study was designed to investigate new 4-sulfamoylbenzene-β-lactam derivatives as CAIs. Herein, we describe the synthesis, biological evaluation of a series of 4-sulfamoyl benzene-β-lactam derivatives (3a–n).
Section snippets
Chemistry
The rationale behind the drug design presented in this work is based on a recent report by Krasavin et al.,17 who showed that benzene sulfonamides incorporating 1,3-oxazol-5-yl moieties act as picomolar inhibitors of several CA isoforms, among which CA I and II. Such compounds were obtained from sulfanilamide 1, by building a 5-membered heterocyclic ring which also incorporates the nitrogen atom from the 4-amino moiety of 1. Thus, we decided to apply the same procedure by incorporating the
Conclusion
In conclusion, a nw series of benzenesulfonamides is reported in this paper. Ghey were prepared from sulfanilamide Schiff’s bases and in situ obtained ketenes, by using the Staudinger cycloaddition reaction and incorporate a never before investigated for CA inhibition 1,3,4-trisubstituted-β-lactam scaffold. The new sulfonamides were assayed as inhibitors of four such isoforms, i.e., hCA I, II, IV and VII. Excellent inhibitory activity was observed against all these isoforms, as follows: hCA I,
Chemistry
All chemicals and solvents were of analytical grade and used without further purification as received from the suppliers. The reactions were monitored by TLC on silica gel. The TLC analysis was performed using Polygram® precoated silica gel TLC sheets SIL G/UV254. Melting points were obtained on Stuart digital melting-point apparatus/SMP 30 and were uncorrected. 1H NMR spectra were recorded on an Avance NMR instrument operated at 500 MHz. 13C NMR spectra was recorded on an Avance NMR instrument
Acknowledgments
SA and PVSR are thankful to Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India, New Delhi for the award of NIPER fellowship. This research was financed in part by grants of the European Union (Dynano and METOXIA projects to CTS).
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Continued exploration and tail approach synthesis of benzenesulfonamides containing triazole and dual triazole moieties as carbonic anhydrase I, II, IV and IX inhibitors
2019, European Journal of Medicinal ChemistryFrom random to rational: A discovery approach to selective subnanomolar inhibitors of human carbonic anhydrase IV based on the Castagnoli-Cushman multicomponent reaction
2019, European Journal of Medicinal ChemistryCitation Excerpt :These, however, are not easy to come by. Besides compound 1 (Fig. 2), only a limited number of compounds with pronounced inhibitory selectivity and/or potency toward hCA IV have been reported to-date [25–28]. The goal of designing isoform-specific carbonic anhydrase inhibitors (CAIs) is particularly difficult in light of significant similarity of amino acid composition and active site architecture of hCA isoforms [29].
Novel sulfonamides incorporating 1,3,5-triazine and amino acid structural motifs as inhibitors of the physiological carbonic anhydrase isozymes I, II and IV and tumor-associated isozyme IX
2018, Bioorganic ChemistryCitation Excerpt :It is present under physiological conditions in almost every human tissue and organ [16]. Other physiologically relevant human carbonic anhydrase isoforms include e.g. cytosolic hCA I, that is found at the highest level in erythrocytes and is also expressed in normal colorectal mucosa [17,18], or membrane-bound hCA IV, that is present in the eye [19]. In order to eliminate the hypoxia-induced tumor cells with a minimum impact on the healthy cells, a big effort is put on the selectivity enhancement of newly developed potential hCA inhibitors.
Design and synthesis of novel benzenesulfonamide containing 1,2,3-triazoles as potent human carbonic anhydrase isoforms I, II, IV and IX inhibitors
2018, European Journal of Medicinal ChemistryCitation Excerpt :In addition, primary sulfonamides constitute an important pharmacophore in many leading classes of drugs with several types of pharmacological activities [8–12]. Acetazolamide (AAZ), methazolamide (MZA), ethoxzolamide (EZA), celecoxib (CLX) etc. (Fig. 1) are well known clinically used drugs bearing sulfonamide groups cutting across different therapeutic areas [13,14]. These are also established as strong carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, but may have many side effects.
Synthesis of novel 4-functionalized 1,5-diaryl-1,2,3-triazoles containing benzenesulfonamide moiety as carbonic anhydrase I, II, IV and IX inhibitors
2018, European Journal of Medicinal ChemistryCitation Excerpt :Many sulfonamide-based drugs, such as acetazolamide (AAZ), methazolamide (MZA), ethoxzolamide (EZA), dorzolamide (DZA), brinzolamide (BRZ), celecoxib (CLX) are known. Some of them are in clinical use as diuretics (targeting hCA II, IV, XII and XIV), antiepileptics (targeting hCA VII and XIV), antiglaucoma (targeting hCA II, IV and XII), or in clinical trials as antitumor/antimetastatic agents (targeting hCA IX and XII) [33,34]. Furthermore, compounds containing 1,2,3-triazole ring system has been studied extensively for the synthesis of novel derivatives, such as 1–3 with pharmacologic applications (Fig. 1) [35–37].
Four-Membered Ring Systems
2018, Progress in Heterocyclic ChemistryCitation Excerpt :Benzenesulfonamides incorporating 1,3,4-trisubstituted-β-lactam moieties were prepared from sulfanilamide Schiff bases and in situ obtained ketenes. The new compounds were assayed as inhibitors of four human isoforms of the metalloenzyme carbonic anhydrase (17BMC539). Compounds 67 exhibited good anticancer activity.