title: Synthesis and structure-activity relationships of lapacho analogues. 1. Suppression of human keratinocyte hyperproliferation by 2-substituted naphtho[2,3-b]furan-4,9-diones, activation by enzymatic one- and two-electron reduction, and intracellular generation of superoxide.
abstract: A series of linearly anellated lapacho quinone analogues substituted at the 2-position of the tricyclic naphtho[2,3-b]furan-4,9-dione system were synthesized and evaluated for their ability to suppress keratinocyte hyperproliferation using HaCaT cells as the primary test system. While very good in vitro potency with IC(50) values in the submicromolar range was attained with electron-withdrawing substituents, some compounds were found to induce plasma membrane damage, as evidenced by the release of LDH activity from cytoplasm of the keratinocytes. The most potent analogue against keratinocyte hyperproliferation was the 1,2,4-oxadiazole 18, the potency of which was combined with comparably low cytotoxic membrane damaging effects. Structure-activity relationship studies with either metabolically stable or labile analogues revealed that the quinone moiety was required for activity. Selected compounds were studied in detail for their capability to generate superoxide radicals both in isolated enzymatic one- and two-electron reduction assays as well as in a HaCaT cell-based assay.
authors: Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University, Hittorfstraße 58-62, D-48149 Münster, Germany.
authors: Alexandra
authors: A
authors: Reichstein
authors: Silke
authors: S
authors: Vortherms
authors: Sven
authors: S
authors: Bannwitz
authors: Jan
authors: J
authors: Tentrop
authors: Helge
authors: H
authors: Prinz
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*; D003879:Dermatologic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001728:Dicumarol / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000737:chemistry; D009251:NADPH-Ferrihemoprotein Reductase / Q000737:chemistry; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011565:Psoriasis / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000737:chemistry / Q000378:metabolism*
chemical_list: C576405:2-(3-ethyl-1,2,4-oxadiazol-5-yl)naphtho(2,3-b)furan-4,9-dione; D003879:Dermatologic Agents; D005663:Furans; D009285:Naphthoquinones; D010069:Oxadiazoles; D013481:Superoxides; D001728:Dicumarol; D007770:L-Lactate Dehydrogenase; D009251:NADPH-Ferrihemoprotein Reductase; D016660:NAD(P)H Dehydrogenase (Quinone)