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Synthesis of Novel Shikonin Derivatives and Pharmacological Effects of Cyclopropylacetylshikonin on Melanoma Cells

Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, Universitaetsplatz 4, 8010 Graz, Austria
Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Universitaetsplatz 1, 8010 Graz, Austria
Division of Biomedical Research, Medical University of Graz, Roseggerweg 48, 8036 Graz, Austria
Division of Hematology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria
Department of Orthopedics and Trauma, Medical University Graz, Auenbruggerplatz 5, 8036 Graz, Austria
Author to whom correspondence should be addressed.
Molecules 2018, 23(11), 2820;
Received: 9 October 2018 / Revised: 19 October 2018 / Accepted: 20 October 2018 / Published: 30 October 2018
(This article belongs to the Section Natural Products Chemistry)
PDF [19967 KB, uploaded 30 October 2018]


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. View Full-Text
Keywords: shikonin derivatives; cyclopropylacetylshikonin; apoptosis; melanoma shikonin derivatives; cyclopropylacetylshikonin; apoptosis; melanoma

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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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, 2820.

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