title: 8-Halo-substituted naphtho[2,3-b]thiophene-4,9-diones as redox-active inhibitors of keratinocyte hyperproliferation with reduced membrane-damaging properties.
abstract: A series of 8-chloronaphtho[2,3-b]thiophene-4,9-diones and also some 8-bromo analogues were prepared. The compounds were evaluated for their potencies to suppress keratinocyte hyperproliferation using the human keratinocyte line HaCaT as the primary test system. Structure-activity relationship studies revealed that replacement of the phenolic group of an earlier series with an 8-halogen atom retained the inhibitory potency against keratinocyte hyperproliferation with IC50 values in the submicromolar range. 8-Chloro-substitution led to inhibitors that were more potent than their bromo analogues. Concomitantly, halo-substitution eliminated membrane-damaging properties as assessed by LDH release from the cytoplasm of the keratinocytes which, in contrast, were induced by the corresponding phenolic analogues. Finally, selective compounds were characterized for their ability to participate in redox cycling to generate superoxide in enzymatic and keratinocyte-based studies.
authors: PharmaCampus, Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms University, Corrensstraße 48, D-48149, Münster, Germany.
authors: Cathrin
authors: C
authors: Lindenschmidt
authors: PharmaCampus, Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms University, Corrensstraße 48, D-48149, Münster, Germany.
authors: Dirk
authors: D
authors: Krane
authors: PharmaCampus, Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms University, Corrensstraße 48, D-48149, Münster, Germany.
authors: Silke
authors: S
authors: Vortherms
authors: PharmaCampus, Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms University, Corrensstraße 48, D-48149, Münster, Germany.
authors: Lars
authors: L
authors: Hilbig
authors: PharmaCampus, Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms University, Corrensstraße 48, D-48149, Münster, Germany.
authors: Helge
authors: H
authors: Prinz
authors: PharmaCampus, Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms University, Corrensstraße 48, D-48149, Münster, Germany. Electronic address: kmuller@uni-muenster.de.
authors: Klaus
authors: K
authors: Müller
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D054879:Halogenation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D009281:Naphthalenes; D011809:Quinones; D013876:Thiophenes; D013481:Superoxides; C456965:naphtho(2,3-b)thiophene
keywords: Antiproliferative activity; HaCaT cells; Naphtho[2,3-b]thiophene-4,9-diones; Quinone; Redox activation; Superoxide radical