title: Metallocene-based inhibitors of cancer-associated carbonic anhydrase enzymes IX and XII.
abstract: In this study, 20 metallocene-based compounds comprising extensive structural diversity were synthesized and evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. These compounds proved moderate to good CA inhibitors in vitro, with several compounds displaying selectivity for cancer-associated isozymes CA IX and CA XII compared to off-target CA I and CA II. Compound 6 was the most potent ferrocene-based inhibitor with K(i)s of 5.9 and 6.8 nM at CA IX and XII, respectively. A selection of key drug-like parameters comprising Log P, Log D, solubility, and in vitro metabolic stability and permeability were measured for two of the ferrocene-based compounds, regioisomers 1 and 5. Compounds 1 and 5 were found to have characteristics consistent with lipophilic compounds, however, our findings show that the lipophilicity of the ferrocene moiety is not well modeled by replacement with either a naphthyl or a phenyl moiety in software prediction tools.
authors.affiliation: Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland 4111, Australia.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Salmon
authors.forename: Michael L
authors.initials: ML
authors.lastname: Williams
authors.forename: Quoc K
authors.initials: QK
authors.lastname: Wu
authors.forename: Julia
authors.initials: J
authors.lastname: Morizzi
authors.forename: Daniel
authors.initials: D
authors.lastname: Gregg
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Poulsen
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D018938:Caco-2 Cells; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000378:metabolism*; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D005296:Ferrous Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D000075163:Metallocenes; D008862:Microsomes, Liver / Q000378:metabolism; D010539:Permeability; D012428:Ruthenium; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; D056831:Coordination Complexes; D003517:Cyclopentanes; D005296:Ferrous Compounds; D000075163:Metallocenes; D014230:Triazoles; D012428:Ruthenium; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII; C004998:ferrocene