title: Carbonic anhydrase inhibition with natural products: novel chemotypes and inhibition mechanisms.
abstract: Five genetically distinct classes of carbonic anhydrases (CAs, EC 4.2.1.1) are present in organisms all over the phylogenetic tree (α-, β-, γ-, δ-, and ζ-families). These metalloenzymes catalyze CO(2) hydration to bicarbonate and protons. Inhibition of α-CAs from vertebrates, including humans, with sulfonamides was exploited clinically for decades for various classes of diuretics and systemically acting antiglaucoma agents, whereas newer inhibitors are used as topically acting antiglaucoma drugs, anticonvulsants, antiobesity, antipain and antitumor agents/diagnostic tools. Recently, novel interesting chemotypes, in addition to the sulfonamide and sulfamate were discovered, many of which are based on natural products, such as phenols/polyphenols, phenolic acids, and coumarins. Their detailed mechanism of inhibition has been explained by means of kinetic and X-ray crystallographic studies, and can be used for the rational drug design of other agents. Possible applications for these new chemotypes in drug design of CA inhibitors are envisaged and discussed in detail in this review.
authors.affiliation: Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Rm. 188, Via della Lastruccia 3, 50019, Sesto Fiorentino, Florence, Italy. claudiu.supuran@unifi.it
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000818:Animals; D001688:Biological Products / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D003198:Computer Simulation; D003374:Coumarins / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D010636:Phenols / Q000737:chemistry / Q000378:metabolism; D011073:Polyamines / Q000737:chemistry / Q000378:metabolism
chemical_list: D001688:Biological Products; D002257:Carbonic Anhydrase Inhibitors; D003374:Coumarins; D010636:Phenols; D011073:Polyamines; D002256:Carbonic Anhydrases
references.citation: Bioorg Med Chem Lett. 2008 Mar 1;18(5):1583-7
references.pmid: 18242985
references.citation: Bioorg Med Chem. 2009 Apr 1;17(7):2654-7
references.pmid: 19297172
references.citation: Bioorg Med Chem. 2005 Jan 17;13(2):483-9
references.pmid: 15598570
references.citation: Bioorg Med Chem Lett. 2010 Aug 1;20(15):4511-4
references.pmid: 20580555
references.citation: Biochim Biophys Acta. 2010 Feb;1804(2):362-73
references.pmid: 19679201
references.citation: Nature. 2008 Mar 6;452(7183):56-61
references.pmid: 18322527
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16233-8
references.pmid: 19805286
references.citation: Bioorg Med Chem. 2008 Aug 1;16(15):7424-8
references.pmid: 18579385
references.citation: J Biol Chem. 2006 Feb 24;281(8):4993-9
references.pmid: 16321983
references.citation: Bioorg Med Chem. 2010 Apr 15;18(8):2822-8
references.pmid: 20363143
references.citation: Bioorg Med Chem Lett. 2010 Jun 15;20(12):3467-74
references.pmid: 20529676
references.citation: Bioorg Med Chem Lett. 2010 Sep 1;20(17):5050-3
references.pmid: 20674354
references.citation: Bioorg Med Chem. 2009 Jul 1;17(13):4503-9
references.pmid: 19450983
references.citation: Bioorg Med Chem. 2010 Jan 1;18(1):14-8
references.pmid: 19962903
references.citation: J Biomol Screen. 2008 Apr;13(4):265-75
references.pmid: 18349420
references.citation: Curr Pharm Des. 2008;14(7):622-30
references.pmid: 18336307
references.citation: Microbiology (Reading). 2010 Jan;156(Pt 1):23-29
references.pmid: 19833770
references.citation: J Enzyme Inhib Med Chem. 2009 Apr;24 Suppl 1:1-39
references.pmid: 19330638
references.citation: Bioorg Med Chem. 2007 Jul 1;15(13):4336-50
references.pmid: 17475500
references.citation: Bioorg Med Chem. 2008 Oct 15;16(20):9101-5
references.pmid: 18819808
references.citation: Nat Rev Drug Discov. 2008 Feb;7(2):168-81
references.pmid: 18167490
references.citation: Curr Top Med Chem. 2007;7(9):901-8
references.pmid: 17504135
references.citation: FEBS Lett. 2004 Nov 19;577(3):439-45
references.pmid: 15556624
references.citation: J Med Chem. 2010 Mar 11;53(5):2277-85
references.pmid: 20158185
references.citation: Bioorg Med Chem. 2009 Apr 15;17(8):3207-11
references.pmid: 19231207
references.citation: J Med Chem. 2010 Jan 28;53(2):850-4
references.pmid: 20028100
references.citation: J Biol Chem. 2008 Sep 12;283(37):25475-25484
references.pmid: 18617510
references.citation: Curr Pharm Des. 2008;14(7):603-14
references.pmid: 18336305
references.citation: J Med Chem. 2010 Aug 12;53(15):5511-22
references.pmid: 20590092
references.citation: Phytochemistry. 2010 Apr;71(5-6):598-604
references.pmid: 20137795
references.citation: Med Res Rev. 2003 Mar;23(2):146-89
references.pmid: 12500287
references.citation: J Med Chem. 2010 Jan 14;53(1):335-44
references.pmid: 19911821
references.citation: Bioorg Med Chem Lett. 2008 Sep 15;18(18):5066-70
references.pmid: 18723348
references.citation: J Am Chem Soc. 2009 Mar 4;131(8):3057-62
references.pmid: 19206230
references.citation: Bioorg Med Chem. 2010 Mar 15;18(6):2159-2164
references.pmid: 20185318