Carbonic anhydrase inhibitors: DNA cloning and inhibition studies of the alpha-carbonic anhydrase from Helicobacter pylori, a new target for developing sulfonamide and sulfamate gastric drugs.
We have cloned and sequenced Helicobacter pylori alpha-class carbonic anhydrase (hpCA) from patients with different gastric mucosal lesions, including gastritis (n=15), ulcer (n=6), and cancer (n=16). Although several polymorphisms were newly identified such as 12Ala, 13Thr, 16Ile, and 168Phe, there was no significant relevance of any polymorphism with gastric mucosal lesion types. A library of sulfonamides/sulfamates has been investigated for the inhibition of hpCA, whereas new derivatives have been obtained by attaching 4-tert-butyl-phenylcarboxamido/sulfonamido tails to benzenesulfonamide/1,3,4-thiadiazole-2-sulfonamide scaffolds. All types of activity for inhibition of hpCA have been detected. Dorzolamide and simple 4-substituted benzenesulfonamides were weak inhibitors (KI 873-4360 nM). Sulfanilamide, orthanilamide, some of their derivatives, and indisulam showed better activity (KI 413-640 nM), whereas most of the clinically used inhibitors, such as methazolamide, ethoxzolamide, dichlorophenamide, brinzolamide, topiramate, zonisamide, etc., acted as medium-potency inhibitors (KI 105-378 nM). Some potent hpCA inhibitors were detected too (KI 12-84 nM) among acetazolamide, 4-amino-6-chloro-1,3-benzenedisulfonamide and some newly designed compounds incorporating lipophilic tails. Some of the newly prepared derivatives had selectivity ratios for inhibiting hpCA over hCA II in the range of 1.25-3.48, showing thus some selectivity for inhibiting the bacterial enzyme. Since hpCA is essential for the survival of the pathogen in acid, it might be used as a new pharmacologic tool in the management of drug-resistant H. pylori.
Nishimori
Isao
I
Department of Gastroenterology, Kochi Medical School, Nankoku, Kochi 783-8505, Japan.
Minakuchi
Tomoko
T
Morimoto
Kaori
K
Sano
Shuichi
S
Onishi
Saburo
S
Takeuchi
Hiroaki
H
Vullo
Daniela
D
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
D000595:Amino Acid Sequence; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000235:genetics*; D003001:Cloning, Molecular; D004269:DNA, Bacterial / Q000235:genetics*; D005753:Gastric Mucosa / Q000382:microbiology*; D005756:Gastritis / Q000382:microbiology; D016480:Helicobacter pylori / Q000201:enzymology*; D006801:Humans; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D013274:Stomach Neoplasms / Q000382:microbiology; D013276:Stomach Ulcer / Q000382:microbiology; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D002257:Carbonic Anhydrase Inhibitors; D004269:DNA, Bacterial; D013449:Sulfonamides; D013451:Sulfonic Acids; C005741:sulfamic acid; D002256:Carbonic Anhydrases