Synthesis of Novel Shikonin Derivatives and Pharmacological Effects of Cyclopropylacetylshikonin on Melanoma Cells
AbstractDespite 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. View Full-Text
- Supplementary File 1:
PDF-Document (PDF, 4214 KB)
Share & Cite This Article
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, 2820.
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):2820.Chicago/Turabian Style
Durchschein, Christin; Hufner, Antje; Rinner, Beate; Stallinger, Alexander; Deutsch, Alexander; Lohberger, Birgit; Bauer, Rudolf; Kretschmer, Nadine. 2018. "Synthesis of Novel Shikonin Derivatives and Pharmacological Effects of Cyclopropylacetylshikonin on Melanoma Cells." Molecules 23, no. 11: 2820.
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.