Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
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):
Doi: 10.3390/molecules23112820
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- Co-Autor*innen der Med Uni Graz
- Deutsch Alexander
- Kretschmer Nadine
- Lohberger Birgit
- Rinner Beate
- Stallinger Alexander
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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