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Durchschein, C; Hufner, A; Rinner, B; Stallinger, A; Deutsch, A; Lohberger, B; Bauer, R; Kretschmer, N.
Synthesis of Novel Shikonin Derivatives and Pharmacological Effects of Cyclopropylacetylshikonin on Melanoma Cells.
Molecules. 2018; 23(11): [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Deutsch Alexander
Kretschmer Nadine
Lohberger Birgit
Rinner Beate
Stallinger Alexander
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Number of Figures: 7
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Abstract:
Despite much research in the last centuries, treatment of malignant melanoma is still challenging because of its mostly unnoticeable metastatic spreading and aggressive growth rate. Therefore, the discovery of novel drug leads is an important goal. In a previous study, we have isolated several shikonin derivatives from the roots of Onosma paniculata Bureau & Franchet (Boraginaceae) which evolved as promising anticancer candidates. β,β-Dimethylacrylshikonin (1) was the most cytotoxic derivative and exhibited strong tumor growth inhibitory activity, in particular, towards melanoma cells. In this study, we synthesized eighteen novel shikonin derivatives in order to obtain compounds which exhibit a higher cytotoxicity than 1. We investigated their cytotoxic potential against various melanoma cell lines and juvenile skin fibroblasts. The most active compound was (R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl cyclopropylacetate (cyclopropylacetylshikonin) (6). It revealed significant stronger tumor growth inhibitory activity towards two melanoma cell lines derived from metastatic lesions (WM164 and MUG-Mel2). Further investigations have shown that 6 induced apoptosis caspase-dependently, increased the protein levels of cleaved PARP, and led to double-stranded DNA breaks as shown by phosphorylation of H2AX. Cell membrane damage and cell cycle arrest were not observed.
Find related publications in this database (using NLM MeSH Indexing)
Apoptosis - drug effects
Boraginaceae - chemistry
Cell Cycle Checkpoints - drug effects
Cell Line, Tumor -
Cell Membrane - drug effects
Cell Proliferation - drug effects
DNA Breaks, Double-Stranded - drug effects
Histones - genetics
Humans -
Melanoma - drug therapy
Melanoma - pathology
Naphthoquinones - chemical synthesis
Naphthoquinones - chemistry
Naphthoquinones - pharmacology
Phosphorylation - drug effects
Plant Roots - chemistry
Skin - drug effects

Find related publications in this database (Keywords)
shikonin derivatives
cyclopropylacetylshikonin
apoptosis
melanoma
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