Carbonic anhydrase inhibitors. Inhibition of mammalian isoforms I-XIV with a series of natural product polyphenols and phenolic acids.
A series of phenolic acids and phenol natural products, such as p-hydroxybenzoic acid, p-coumaric acid, caffeic acid, ferulic acid, gallic acid, syringic acid, quercetin, and ellagic acid, were investigated for their inhibitory effects against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). All mammalian isozymes of human (h) or murine (m) origin hCA I-hCA XII, mCA XIII and hCA XIV were inhibited in the low micromolar or submicromolar range by these (poly)phenols (K(I)s in the range of 0.87-7.79 microM). p-Hydroxybenzoic acid was the best inhibitor of all isozymes (K(I)s of 0.87-35.4 microM) and the different isozymes showed very variable inhibition profiles with these derivatives. Phenols like the ones investigated here possess a CA inhibition mechanism distinct of that of the sulfonamides/sulfamates used clinically or the coumarins. Unlike the sulfonamides, which bind to the catalytic zinc ion, phenols are anchored at the Zn(II)-coordinated water molecule and bind more externally within the active site cavity, making contacts with various amino acid residues. As this is the region with the highest variability between the many CA isozymes found in mammals, this class of compounds may lead to isoform-selective inhibitors targeting just one or few of the medicinally relevant CAs.
Innocenti
Alessio
A
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
Beyza Öztürk Sarıkaya
S
S
Ataturk University, Sciences Faculty, Department of Chemistry, 25240-Erzurum, Turkey.
Gülçin
İlhami
İ
Ataturk University, Sciences Faculty, Department of Chemistry, 25240-Erzurum, Turkey; İbrahim Çeçen University, School of Health Services, TR-04100-Agri, Turkey.
Supuran
Claudiu T
CT
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
D000818:Animals; D001685:Biological Factors / Q000737:chemistry / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D062385:Hydroxybenzoates / Q000737:chemistry / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D059808:Polyphenols; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001685:Biological Factors; D002257:Carbonic Anhydrase Inhibitors; D005419:Flavonoids; D062385:Hydroxybenzoates; D007527:Isoenzymes; D010636:Phenols; D059808:Polyphenols; D002256:Carbonic Anhydrases; C017616:phenolic acid