title: An Unusual Natural Product Primary Sulfonamide: Synthesis, Carbonic Anhydrase Inhibition, and Protein X-ray Structures of Psammaplin C.
abstract: Psammaplin C is one of only two described natural product primary sulfonamides. Here we report the synthesis of psammaplin C and evaluate the inhibition profile against therapeutically relevant carbonic anhydrase (CA) zinc metalloenzymes. The compound exhibited unprecedented inhibition of an important cancer-associated isozyme, hCA XII, with a Ki of 0.79 nM. The compound also displayed good isoform selectivity for hCA XII over other CAs. We present the first reported protein X-ray crystal structures of psammaplin C in complex with human CAs. We engineered the easily crystallized hCA II enzyme to mimic both the hCA IX and hCA XII binding sites and then utilized protein X-ray crystallography to determine the binding pose of psammaplin C within the hCA II, hCA IX, and hCA XII mimic active sites, all to high resolution. This is the first time a natural product primary sulfonamide inhibitor has been assessed for inhibition and binding to CAs.
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Don Young Road, Nathan, Queensland 4111, Australia.
authors.forename: Prashant
authors.initials: P
authors.lastname: Mujumdar
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Don Young Road, Nathan, Queensland 4111, Australia.
authors.forename: Kanae
authors.initials: K
authors.lastname: Teruya
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Don Young Road, Nathan, Queensland 4111, Australia.
authors.forename: Kathryn F
authors.initials: KF
authors.lastname: Tonissen
authors.affiliation: Polo Scientifico, Neurofarba Department, and Laboratorio di Chimica Bioinorganica, Universitádegli Studi di Firenze , Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.affiliation: Polo Scientifico, Neurofarba Department, and Laboratorio di Chimica Bioinorganica, Universitádegli Studi di Firenze , Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: CSIRO , 343 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Peat
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Don Young Road, Nathan, Queensland 4111, Australia.
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Poulsen
mesh_terms: D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D001688:Biological Products; D002257:Carbonic Anhydrase Inhibitors; D013450:Sulfones; C578914:psammaplin C; D002256:Carbonic Anhydrases