Design, synthesis and evaluation of N-substituted saccharin derivatives as selective inhibitors of tumor-associated carbonic anhydrase XII

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

doi:10.1016/j.bmc.2014.01.056

Cited by 74 publications

(59 citation statements)

References 71 publications

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“…[71][72][73], some of which showed selective inhibitory action against the tumor-associated isoforms hCA IX/ XII, without significant inhibition of hCA I and II [145][146][147][148] . 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.…”

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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628

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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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“…In addition, a range of secondary and tertiary sulfonamides has been investigated as CAIs recently, some of them showing effective and selective inhibition of several important isoforms [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] . However, the inhibition mechanism with secondary and tertiary sulfonamides is unknown, as no X-ray crystal structures of such derivatives bound to the CA are available to date.…”

Section: Chemistrymentioning

confidence: 99%

“…However, the inhibition mechanism with secondary and tertiary sulfonamides is unknown, as no X-ray crystal structures of such derivatives bound to the CA are available to date. Thus, the sulfonamides reported here incorporate in their molecule the urea fragment found in SLC-0111 and the secondary sulfonamide moiety present in sulfa drugs and several recently investigated CAIs [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] .…”

Section: Chemistrymentioning

confidence: 99%

Design, synthesis and biological evaluation ofN-(5-methyl-isoxazol-3-yl/1,3,4-thiadiazol-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamides as human carbonic anhydrase isoenzymes I, II, VII and XII inhibitors

Mishra

Kumari

Angeli

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of N-(5-methyl-isoxazol-3-yl/1,3,4-thiadiazol-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamide derivatives has been designed, synthesized and screened for their in vitro human carbonic anhydrase (hCA; EC 4.2.1.1) inhibition potential. These newly synthesized sulfonamide compounds were assessed against isoforms hCA I, II, VII and XII, with acetazolamide (AAZ) as a reference compound. The majority of these compounds were found quite weak inhibitor against all tested isoforms. Compound 15 showed a modest inhibition potency against hCA I (K i ¼ 73.7 mM) and hCA VII (K i ¼ 85.8 mM). Compounds 19 and 25 exhibited hCA II inhibition with K i values of 96.0 mM and 87.8 mM, respectively. The results of the present study suggest that, although the synthesized derivatives have weak inhibitory potential towards all investigated isoforms, some of them may serve as lead molecules for the further development of selective inhibitors incorporating secondary sulfonamide functionalities, a class of inhibitors for which the inhibition mechanism is poorly understood.

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“…This comes from data that have shown saccharin's ability to inhibit the carbonic anhydrase (CA) family of enzymes, and especially the cancer-related isoforms IX and XII [8][9][10][11]. CAs are zinc metalloproteins that catalyze the interconversion of CO 2 to bicarbonate and a proton, a reaction that is important for many physiological processes including respiration, fluid secretion and pH regulation [12].…”

mentioning

confidence: 98%