X-ray crystallography-promoted drug design of carbonic anhydrase inhibitors

Ivanova, Jekaterīna; Leitans, Janis; Tanç, Muhammet; Kazāks, Andris; Žalubovskis, Raivis; Supuran, Claudiu T.; Tars, K.

doi:10.1039/c5cc01854d

Cited by 73 publications

(47 citation statements)

References 24 publications

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“…Isoform-selective inhibitors. 1-N-Alkylated-6-sulfamoyl saccharin derivative that was unintentionally hydrolyzed during X-ray experiment was further developed into the inhibitor showing selectivity between CA isoforms (Ivanova et al, 2015).…”

Section: Para-meta-benzenesulfonamidesmentioning

confidence: 99%

Thermodynamic, kinetic, and structural parameterization of human carbonic anhydrase interactions toward enhanced inhibitor design

Linkuvienė

Zubrienė

Manakova

et al. 2018

Quart. Rev. Biophys.

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Section: Para-meta-benzenesulfonamidesmentioning

confidence: 99%

Thermodynamic, kinetic, and structural parameterization of human carbonic anhydrase interactions toward enhanced inhibitor design

Linkuvienė

Zubrienė

Manakova

et al. 2018

Quart. Rev. Biophys.

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“…Common variations include the length of the tail and class or characteristics of the chemical substituents used to derivatize the inhibitor [ 5 , 29 ]. Recently, the success of the tail method to produce isoform specific inhibitors was highlighted by the design of SLC-0111, a CA IX-specific inhibitor currently being tested in clinical trials for the treatment of breast cancer [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Non-Classical Inhibition of Carbonic Anhydrase

Lomelino

Supuran

McKenna

2016

IJMS

109

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Specific isoforms from the carbonic anhydrase (CA) family of zinc metalloenzymes have been associated with a variety of diseases. Isoform-specific carbonic anhydrase inhibitors (CAIs) are therefore a major focus of attention for specific disease treatments. Classical CAIs, primarily sulfonamide-based compounds and their bioisosteres, are examined as antiglaucoma, antiepileptic, antiobesity, antineuropathic pain and anticancer compounds. However, many sulfonamide compounds inhibit all CA isoforms nonspecifically, diluting drug effectiveness and causing undesired side effects due to off-target inhibition. In addition, a small but significant percentage of the general population cannot be treated with sulfonamide-based compounds due to a sulfa allergy. Therefore, CAIs must be developed that are not only isoform specific, but also non-classical, i.e. not based on sulfonamides, sulfamates, or sulfamides. This review covers the classes of non-classical CAIs and the recent advances in the development of isoform-specific inhibitors based on phenols, polyamines, coumarins and their derivatives.

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“…In a recent publication, Ivanova et al. reported on the spontaneous ring opening of cyclic tertiary sulfonamides under basic (pH= 9) crystallization conditions 33 . Since hCAs do not possess any peptidase activity, they concluded that the base-catalyzed hydrolysis of the saccharin isothiazolone ring happened before the inhibitor entered the active site, and proved their hypothesis by testing both open and closed analogs against a panel of hCAs (hCA I, hCA II, hCA IX and hCA XII).…”

Section: Introductionmentioning

confidence: 99%

Open saccharin-based secondary sulfonamides as potent and selective inhibitors of cancer-related carbonic anhydrase IX and XII isoforms

D’Ascenzio

Guglielmi

Carradori

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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A large number of novel secondary sulfonamides based on the open saccharin scaffold were synthesized and evaluated as selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). They were obtained by reductive ring opening of the newly synthesized N-alkylated saccharin derivatives and were shown to be inactive against the two cytosolic off-target hCA I and II (Kis > 10 µM). Interestingly, these compounds inhibited hCA IX in the low nanomolar range with Kis ranging between 20 and 298 nM and were extremely potent inhibitors of hCA XII isoenzyme (Kis ranging between 4.3 and 432 nM). Since hCA IX and XII are the cancer-related isoforms recently validated as drug targets, these results represent an important goal in the development of new anticancer candidates. Finally, a computational approach has been performed to better correlate the biological data to the binding mode of these inhibitors.

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X-ray crystallography-promoted drug design of carbonic anhydrase inhibitors

Cited by 73 publications

References 24 publications

Thermodynamic, kinetic, and structural parameterization of human carbonic anhydrase interactions toward enhanced inhibitor design

Thermodynamic, kinetic, and structural parameterization of human carbonic anhydrase interactions toward enhanced inhibitor design

Non-Classical Inhibition of Carbonic Anhydrase

Open saccharin-based secondary sulfonamides as potent and selective inhibitors of cancer-related carbonic anhydrase IX and XII isoforms

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