Theoretical Study of the Radical Scavenging Activity of Shikonin and Its Derivatives

A series of shikonin derivatives have been designed and their radical scavenging activity has been characterized by the B3LYP/6-31 ＋G（d） approach. The hydrogen bond properties of the studied structures were investigated using the atoms in molecules （AIM） theory. The calculated results reveal that the hydrogen bond is important for good scavenging activity. The introduction of electron-drawing （electron-donating） groups increases （decreases） the scavenging activities of radical and radical cations of shikonin derivatives. Shikonin derivatives appear to be good candidates for the single-electron-transfer mechanism, particularly for -N（CH3）2 derivative. Taking this system as an example, we present an efficient method for the investigation of radical scavenging activity from theoretical point of view. With the current work, we hope to highlight the radical scavenging activity of hydroxynaphtho- quinones derivatives and stimulate the interest for further studies and exploitation in pharmaceutical industry.

Design, Synthesis and Anticancer Activity of Shikonin and Alkannin Derivatives with Different Substituents on the Naphthazarin Scaffold

Based on the asymmetric reduction of alkannin ketone derivative 4 by diisopinocampheylchloro- borane（DIP-C1）, a series of shikonin and alkannin derivatives was designed, synthesized and their anticancer activi- ties against various kinds of cell lines were evaluated. The in vitro biological experiments demonstrated that com- pound S-10, a 5,8-O-dimethyl-l,4-dioxime alkannin derivative, not only displayed excellent antiproliferative activity against cancer cells, but also exhibited 10w toxicity towards normal cells. It could induce HCT-116 cell apoptosis, but had no impact on the cell cycle. The underlying anticancer mechanism of S-10 is most likely different from other shikonin and alkannin derivatives.

Design and synthesis of biotinylated dimethylation of alkannin oxime derivatives

DMAKO-05,a novel dimethylation of alkannin oxime derivative,exhibits remarkable anticancer activity as well as excellent cellular selectivity and thus has been considered as a promising antineoplastic agent for colorectal carcinoma and melanoma.However,its potent cytotoxicity is not closely associated with reactive oxygen species（ROS） and bioreductive alkylation.Its specific antitumor target（s） has still remained elusive.To recognize the molecular target（s） of DMAKO-05 and its analogs,four biotinylated DMAKO derivatives were designed and prepared.The biotin moiety was successfully introduced in the molecule through a modified Mitsunobu reaction,which kept its anticancer activity.Moreover,the cellbased investigation demonstrated that replacement of the linker C4 chain with another alkyl chain（C6 or C8） gave rise to the enhancement of cytotoxicity.Among these biotinyl derivatives,both compound 16 and 8c exhibited more potent anticancer activity than DMAKO-05 against MCF-7 cells and were comparatively effective to alkannin toward HCT-15 cells.As expected,they might be thought as ideal chemical probes.Collectively,our present work could provide an available approach for the identification of the potential antineoplastic target（s） of DMAKO derivatives.