Jiahua Cui

Design, Synthesis, and Biological Evaluation of Shikonin and Alkannin Derivatives as Potential Anticancer Agents via a Prodrug Approach

To minimize the cytotoxicity of shikonin and alkannin that arises through the generation of reactive oxygen species (ROS) and alkylation of the naphthazarin ring, two series of novel core‐scaffold‐modified shikonin and alkannin derivatives were designed. These derivatives, which differ in their configurational and positional isomerism (R‐, S‐, and 2‐ and 6‐isomers) were synthesized in high enantiomeric excess (>99 % ee). The selectivity of the dimethylated derivatives was significantly higher than the parent shikonin in vitro, but some side effects were still observed in vivo. Surprisingly, the dimethylated diacetyl derivatives with poor anticancer activity in vitro showed tumor‐inhibiting effects similar to paclitaxel without any toxicity in vivo. The anticancer activity of these derivatives is in agreement with their low ROS generation and alkylating capacity, emphasizing their potential as prodrugs. This strategy provides means to address the nonspecific cytotoxicity of naphthazarin analogues toward normal cells.

Advance in Anti-tumor Mechanisms of Shikonin, Alkannin and their Derivatives

Shikonin, alkannin and their derivatives, the main ingredient of Lithospermum erythrorhizon and Arnebia euchroma (Royle) Johnst native to Inner Mongolian and Northwest of China respectively, hold promising potentials for antitumor effects via multiple-target mechanisms. This review will emphasize the importance of their antitumor activity in apoptosis, necroptosis and immunogenic cell death, and expound the relationship of their antitumor activity and naphthoquinone scaffold that could generate ROS and alkylating agent. Meanwhile, the antitumor mechanisms of naturally-occurring shikonin, alkannin and their derivatives, which were divided into the direct interaction involved in alkylating agent, covalently binding the DNA and protein, as well as the indirect interaction mediated by ROS, nonspecifically influencing the mitochondria or multiple signal pathways, will be systematically summarized and discussed.

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 diisopinocampheylchloroborane(DIP-Cl), a series of shikonin and alkannin derivatives was designed, synthesized and their anticancer activities against various kinds of cell lines were evaluated. The in vitro biological experiments demonstrated that compound S-10, a 5,8-O-dimethyl-1,4-dioxime alkannin derivative, not only displayed excellent antiproliferative activity against cancer cells, but also exhibited low 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.

Development of 2-arylbenzo[h]quinolone analogs as selective CYP1B1 inhibitors

The CYP1B1 enzyme is regarded as a potential target for cancer prevention and therapy. Based on the structure of α-naphthoflavone (ANF), diverse 2-arylbenzo[h]quinolone derivatives were designed, synthesized and evaluated as selective CYP1B1 inhibitors. Compared with ANF, although few of the title compounds possessed comparable or slightly higher CYP1B1 inhibitory activity, these compounds displayed a significantly increased selectivity toward CYP1B1 over CYP1A2. Among them compounds 5e, 5g and 5h potently inhibited the activity of CYP1B1 with IC50 values of 3.6, 3.9 and 4.1 nM respectively, paralleled by an excellent selectivity profile. On the basis of predicted clog P values, these target compounds may exhibit improved water-solubility compared to ANF. In particular, 5h showed a great superiority in the reversal of CYP1B1-mediated docetaxel resistance in vitro. The current study may serve as a good starting point for the further development of more potent as well as specific CYP1B1 inhibitors capable of reversing CYP1B1-mediated anticancer-drug resistance.

Chemistry and Pharmacology of Thioflavones

Thioflavone derivatives are the thio analogs of the core constituent of the natural product class of flavones. Based on the position and oxidation level of sulfur, they can be divided into three major categories: 4-thioflavones, 1-thioflavones and 1-thioflavones 1,1-dioxide. In recent years, great efforts have been made to develop an approach for the synthesis of thioflavones, especially 1- thioflavones with high functional group compatibility, high yields, low toxicity as well as proceeding under a mild condition, and a variety of synthetic protocols have been developed, the method of choice being dependent on the nature of substrates. As isosteric analogs of biologically active flavones, thioflavones also exhibit various pharmaceutical properties, such as antimicrobial, anticancer and neuroprotective activities. Replacement of the oxygen atom on flavone skeleton by a sulfur atom resulted in modified biological effects due in most part to the change of the structural properties. However, these varying effects depend on the substituents present and the test species. To provide a comprehensive vision of this class of compounds, this review primarily focuses on the structure, synthetic methods, biological properties as well as structure-activity relationships of thioflavones.

Cytotoxicity of Synthesized 1,4-Naphthoquinone Oxime Derivatives on Selected Human Cancer Cell Lines

In an effort to develop potent and selective antitumor agents, a series of 1,4-naphthoquinone oxime derivatives were designed and synthesized. The cytotoxicity of these compounds were evaluated against five human cancer cell lines (colorectal cancer cell: HCT-15, breast cancer cell: MDA-MB-231, liver cancer cell: BEL-7402, colorectal cancer cell: HCT-116 and ovarian cancer cell: A2780) in vitro. Among them, compound 14 was found to be the most potent cytotoxic compound against three cell lines (MDA-MB-231, BEL-7402 and A2780) with IC50 values of 0.66±0.05, 5.11±0.12 and 8.26±0.22 µM, respectively. Additionally, the length of the side chains and the position of the substituent may also affect the cytotoxic activity of the naphthoquinone oxime derivatives. In general, compound 14 effectively inhibited breast cancer cell proliferation and may become a promising anticancer agent.