Cyclic tertiary sulfamates: Selective inhibition of the tumor-associated carbonic anhydrases IX and XII by N- and O-substituted acesulfame derivatives

Monte, Celeste De; Carradori, Simone; Secci, Daniela; D’Ascenzio, Melissa; Vullo, Daniela; Ceruso, Mariangela; Supuran, Claudiu T.

doi:10.1016/j.ejmech.2014.07.014

Cited by 40 publications

(36 citation statements)

References 28 publications

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“…By using saccharin 11 as lead 46 , Carradori's group reported a range of N-substituted saccharins, among which 74-77 (and some of their congeners) showed CA XII selective inhibitory action 149 . Acesulfame 150 or probenecid 78 derivatives of type 79, incorporating a variety of aliphatic, aromatic, or amino acid Figure 11. Some of the investigated coumarins 33-51 as CAIs which showed highly isoform-selective inhibition profile against various human CA isoforms 124,125 .…”

Section: Compounds Acting As Cais With An Unknown Mechanism Of Actionmentioning

confidence: 99%

How many carbonic anhydrase inhibition mechanisms exist?

Supuran

2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Six genetic families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) were described to date. Inhibition of CAs has pharmacologic applications in the field of antiglaucoma, anticonvulsant, anticancer, and anti-infective agents. New classes of CA inhibitors (CAIs) were described in the last decade with enzyme inhibition mechanisms differing considerably from the classical inhibitors of the sulfonamide or anion type. Five different CA inhibition mechanisms are known: (i) the zinc binders coordinate to the catalytically crucial Zn(II) ion from the enzyme active site, with the metal in tetrahedral or trigonal bipyramidal geometries. Sulfonamides and their isosters, most anions, dithiocarbamates and their isosters, carboxylates, and hydroxamates bind in this way; (ii) inhibitors that anchor to the zinc-coordinated water molecule/hydroxide ion (phenols, carboxylates, polyamines, 2-thioxocoumarins, sulfocoumarins); (iii) inhibitors which occlude the entrance to the active site cavity (coumarins and their isosters), this binding site coinciding with that where CA activators bind; (iv) compounds which bind out of the active site cavity (a carboxylic acid derivative was seen to inhibit CA in this manner), and (v) compounds for which the inhibition mechanism is not known, among which the secondary/tertiary sulfonamides as well as imatinib/nilotinib are the most investigated examples. As CAIs are used clinically in many pathologies, with a sulfonamide inhibitor (SLC-0111) in Phase I clinical trials for the management of metastatic solid tumors, this review updates the recent findings in the field which may be useful for a structure-based drug design approach of more selective/potent modulators of the activity of these enzymes. KeywordsAnchoring to zinc-coordinated water, carbonic anhydrase, inhibition mechanism, inhibitors, occlusion of the active site entrance, out of the active site binding, zinc binder History

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Section: Compounds Acting As Cais With An Unknown Mechanism Of Actionmentioning

confidence: 99%

How many carbonic anhydrase inhibition mechanisms exist?

Supuran

2015

Journal of Enzyme Inhibition and Medicinal Chemistry

Self Cite

628

519

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“…As observed for sulphonamides, also sulphamates and sulphamides exert their inhibitory action through coordination to zinc ion and consequent substitution of the water molecule/ hydroxide ion 1 . Plenty of studies has been reported showing that many sulphamates possess effective inhibitory properties against all known human isoforms 1,11,[16][17][18][19] , with some derivatives, such as the sugar sulphamate topiramate (compound 1 in Figure 1), successfully used for the treatment of a variety of diseases such as epilepsy, migraine, and obesity 20,21 . Although the sulphamide group was initially considered not particularly suitable for obtaining potent CAIs 22 , several compounds containing a primary sulphamide moiety have also been proved to possess a high CA inhibition activity 1,11,19,23 .…”

Section: Introductionmentioning

confidence: 99%

Insights into the binding mode of sulphamates and sulphamides to hCA II: crystallographic studies and binding free energy calculations

Simone

Langella

Esposito

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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Sulphamate and sulphamide derivatives have been largely investigated as carbonic anhydrase inhibitors (CAIs) by means of different experimental techniques. However, the structural determinants responsible for their different binding mode to the enzyme active site were not clearly defined so far. In this paper, we report the X-ray crystal structure of hCA II in complex with a sulphamate inhibitor incorporating a nitroimidazole moiety. The comparison with the structure of hCA II in complex with its sulphamide analogue revealed that the two inhibitors adopt a completely different binding mode within the hCA II active site. Starting from these results, we performed a theoretical study on sulphamate and sulphamide derivatives, demonstrating that electrostatic interactions with residues within the enzyme active site play a key role in determining their binding conformation. These findings open new perspectives in the design of effective CAIs using the sulphamate and sulphamide zinc binding groups as lead compounds. ARTICLE HISTORY

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“…However, more recently it has been shown that saccharin ( SAC ), the main additive in the artificial sweetener, “Sweet N′ Low”, selectively binds to CA IX with nanomolar affinity 17 , and SAC-based compounds were highly selective for CA IX (with >1000-fold selectivity over other CA isoforms) 18,19 (Figure 1). However until this study, structural information on specific interactions of either SAC or SAC-based compounds to the active site of CA IX were not known.…”

Section: Introductionmentioning

confidence: 99%

Saccharin: A lead compound for structure-based drug design of carbonic anhydrase IX inhibitors

Mahon

Hendon

Driscoll

et al. 2015

Bioorganic & Medicinal Chemistry

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Carbonic anhydrase IX (CA IX) is a key modulator of aggressive tumor behavior and a prognostic marker and target for several cancers. Saccharin (SAC) based compounds may provide an avenue to overcome CA isoform specificity, as they display both nanomolar affinity and preferential binding, for CA IX compared to CA II (>50-fold for SAC and >1000-fold when SAC is conjugated to a carbohydrate moiety). The X-ray crystal structures of SAC and a SAC-carbohydrate conjugate bound to a CA IX-mimic are presented and compared to CA II. The structures provide substantial new insight into the mechanism of SAC selective CA isoform inhibition.

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Cyclic tertiary sulfamates: Selective inhibition of the tumor-associated carbonic anhydrases IX and XII by N- and O-substituted acesulfame derivatives

Cited by 40 publications

References 28 publications

How many carbonic anhydrase inhibition mechanisms exist?

How many carbonic anhydrase inhibition mechanisms exist?

Insights into the binding mode of sulphamates and sulphamides to hCA II: crystallographic studies and binding free energy calculations

Saccharin: A lead compound for structure-based drug design of carbonic anhydrase IX inhibitors

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