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== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
Carbonic anhydrases (CAs) are a superfamily of metalloenzymes widespread in all life, classified into seven genetically different families (alpha(-)theta). These enzymes catalyse the reversible hydration of carbonic anhydride (CO(2)), generating bicarbonate (HCO(3)(-)) and protons (H(+)). Fifteen isoforms of human CA (hCA I(-)XV) have been isolated, their presence being fundamental for the regulation of many physiological processes. In addition, overexpression of some isoforms has been associated with the outbreak or progression of several diseases. For this reason, for a long time CA inhibitors (CAIs) have been used in the control of glaucoma and as diuretics. Furthermore, the search for new potential CAIs for other pharmacological applications is a very active field. Amino acids constitute the smallest fundamental monomers of protein and, due to their useful bivalent chemical properties, are widely used in organic chemistry. Both proteinogenic and non-proteinogenic amino acids have been extensively used to synthesize CAIs. This article provides an overview of the different strategies that have been used to design new CAIs containing amino acids, and how these bivalent molecules influence the properties of the inhibitors.
Two series of 2-benzylpiperazines have been prepared and tested for the inhibition of physiologically relevant isoforms of human carbonic anhydrases (hCA, EC 4.2.1.1). The new compounds carry on one nitrogen atom of the piperazine ring a sulfamoylbenzamide group as zinc-binding moiety, and different alkyl/acyl/sulfonyl groups on the other nitrogen. Regio- and stero-isomers are described. The majority of these compounds showed Ki values in the low-medium nanomolar range against hCA I, II and IV, but not IX. In many instances interaction with the enzyme was enantioselective. The binding mode has been studied by means of X-ray crystallography and molecular modelling. Two compounds, evaluated in rabbit models of glaucoma, were able to significantly reduce intraocular pressure, making them interesting candidates for further studies.


Amino Acids as Building Blocks for Carbonic Anhydrase Inhibitors.,Chiaramonte N, Romanelli MN, Teodori E, Supuran CT Metabolites. 2018 May 24;8(2). pii: metabo8020036. doi: 10.3390/metabo8020036. PMID:29795039<ref>PMID:29795039</ref>
2-Benzylpiperazine: A new scaffold for potent human carbonic anhydrase inhibitors. Synthesis, enzyme inhibition, enantioselectivity, computational and crystallographic studies and in vivo activity for a new class of intraocular pressure lowering agents.,Chiaramonte N, Bua S, Ferraroni M, Nocentini A, Bonardi A, Bartolucci G, Durante M, Lucarini L, Chiapponi D, Dei S, Manetti D, Teodori E, Gratteri P, Masini E, Supuran CT, Romanelli MN Eur J Med Chem. 2018 May 10;151:363-375. doi: 10.1016/j.ejmech.2018.04.002. Epub , 2018 Apr 3. PMID:29635168<ref>PMID:29635168</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

Latest revision as of 11:35, 10 October 2018

Crystal structure of human carbonic anhydrase I in complex with the 4-(4 acetyl-3-benzylpiperazine-1 carbonyl)benzene-1-sulfonamide inhibitorCrystal structure of human carbonic anhydrase I in complex with the 4-(4 acetyl-3-benzylpiperazine-1 carbonyl)benzene-1-sulfonamide inhibitor

Structural highlights

6evr is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, , ,
Activity:Carbonate dehydratase, with EC number 4.2.1.1
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[CAH1_HUMAN] Reversible hydration of carbon dioxide. Can hydrates cyanamide to urea.[1]

Publication Abstract from PubMed

Two series of 2-benzylpiperazines have been prepared and tested for the inhibition of physiologically relevant isoforms of human carbonic anhydrases (hCA, EC 4.2.1.1). The new compounds carry on one nitrogen atom of the piperazine ring a sulfamoylbenzamide group as zinc-binding moiety, and different alkyl/acyl/sulfonyl groups on the other nitrogen. Regio- and stero-isomers are described. The majority of these compounds showed Ki values in the low-medium nanomolar range against hCA I, II and IV, but not IX. In many instances interaction with the enzyme was enantioselective. The binding mode has been studied by means of X-ray crystallography and molecular modelling. Two compounds, evaluated in rabbit models of glaucoma, were able to significantly reduce intraocular pressure, making them interesting candidates for further studies.

2-Benzylpiperazine: A new scaffold for potent human carbonic anhydrase inhibitors. Synthesis, enzyme inhibition, enantioselectivity, computational and crystallographic studies and in vivo activity for a new class of intraocular pressure lowering agents.,Chiaramonte N, Bua S, Ferraroni M, Nocentini A, Bonardi A, Bartolucci G, Durante M, Lucarini L, Chiapponi D, Dei S, Manetti D, Teodori E, Gratteri P, Masini E, Supuran CT, Romanelli MN Eur J Med Chem. 2018 May 10;151:363-375. doi: 10.1016/j.ejmech.2018.04.002. Epub , 2018 Apr 3. PMID:29635168[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Briganti F, Mangani S, Scozzafava A, Vernaglione G, Supuran CT. Carbonic anhydrase catalyzes cyanamide hydration to urea: is it mimicking the physiological reaction? J Biol Inorg Chem. 1999 Oct;4(5):528-36. PMID:10550681
  2. ↑ Chiaramonte N, Bua S, Ferraroni M, Nocentini A, Bonardi A, Bartolucci G, Durante M, Lucarini L, Chiapponi D, Dei S, Manetti D, Teodori E, Gratteri P, Masini E, Supuran CT, Romanelli MN. 2-Benzylpiperazine: A new scaffold for potent human carbonic anhydrase inhibitors. Synthesis, enzyme inhibition, enantioselectivity, computational and crystallographic studies and in vivo activity for a new class of intraocular pressure lowering agents. Eur J Med Chem. 2018 May 10;151:363-375. doi: 10.1016/j.ejmech.2018.04.002. Epub , 2018 Apr 3. PMID:29635168 doi:http://dx.doi.org/10.1016/j.ejmech.2018.04.002

6evr, resolution 1.50Å

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