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
| Autor: | Alexandra Reichstein, Jan Tentrop, Klaus Müller, Sven Bannwitz, Helge Prinz, Silke Vortherms |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Keratinocytes
Dicumarol Stereochemistry Cell Line chemistry.chemical_compound Structure-Activity Relationship Superoxides Drug Discovery medicine NAD(P)H Dehydrogenase (Quinone) Structure–activity relationship Humans Psoriasis Furans Cell Proliferation NADPH-Ferrihemoprotein Reductase Oxadiazoles L-Lactate Dehydrogenase Chemistry Superoxide Cell Membrane In vitro Quinone HaCaT medicine.anatomical_structure Biochemistry Molecular Medicine Dermatologic Agents Keratinocyte Intracellular Naphthoquinones |
| Zdroj: | Journal of medicinal chemistry. 55(16) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|