Rubing Wang

Shikonin and its derivatives: a patent review

Introduction: Shikonin and its derivatives are the main components of red pigment extracts from Lithospermum erythrorhizon, whose medicinal properties have been confirmed for a long history, and have aroused great interest as the hallmark molecules responsible for their significant biological activities, especially for their striking anticancer effects. Areas covered: Areas covered in this paper include a review of the total synthesis, biological effects and mechanisms of shikonin and its derivatives for their anticancer activities in the past decade, basing on literature and patents. The current state and problems are also discussed. Expert opinion: At present, screening for anticancer shikonin derivatives is based on cellular level to find compounds with stronger cytotoxicity. Though several compounds have been discovered with striking cytotoxicity in vitro, however, no selectivity was observed and undoubtedly, the further outcomes have been disappointing because of their great damage to normal cells. Meanwhile, the presumed mechanisms of action are also established in terms of their cytotoxicity. From a pharmacological point of view, most of the shikonin derivatives are at an early stage of their development, and thus it is difficult to determine the exact effectiveness in cancer treatment. With research in this field going deeper, it can be expected that, despite the difficulties, shikonin derivatives as potential anticancer agents will soon follow.

Synthesis and evaluation of novel alkannin and shikonin oxime derivatives as potent antitumor agents

A set of forty alkannin and shikonin oxime derivatives were firstly designed and synthesized. Their cytotoxicities against three kinds of tumor cells and a normal cell line were tested and compared with alkannin and shikonin. The cell-based investigation demonstrated that some oxime derivatives were more or comparatively effective to the lead compounds, especially their selective and excellent antitumor activities towards K562 cells with no toxicity in normal cells. We may conclude that oximate modification to the mother nucleus of alkannin and shikonin is an available approach to acquire potent antitumor agents.

An efficient synthesis of 2-formyl-1,4,5,8-tetramethoxynaphthalene

An improved synthetic method of 2-formyl-1,4,5,8-tetramethoxynaphthalene in 73% overall yield is described. This method has several advantages compared with the reported synthesis: first, the reactant is cheaper and the yield is higher; second, the reaction condition is milder and the reagent used is more friendly to environment; third, the workup of each step is simpler; fourth, the protocol reported is more suitable for large-scale preparation.

Kinesin spindle protein (KSP) inhibitors in combination with chemotherapeutic agents for cancer therapy.

A diverse group of proteins, the activities of which are precisely orchestrated during mitosis, have emerged as targets for cancer therapeutics; these include the Aurora kinases (AKs), Polo‐like kinases (PLKs), and the kinesin spindle protein (KSP). KSP is essential for the proper separation of spindle poles during mitosis. Agents that target KSP selectively act on cells undergoing cell division, which means that KSP inhibitors are mitosis‐specific drugs, and have demonstrated remarkable activities in vitro. However, a significant obstacle to the success of KSP inhibitors is that these compounds, with tremendous efficacy in vitro, have demonstrated little or even no antitumor activity in vivo. Accumulated data suggest that a combination of KSP inhibitors with various cytostatic drugs will result in a more powerful tumor‐killing effect than monotherapy. Combination therapies might predominate and represent the next frontier in the discovery research of KSP inhibitors as potential anticancer drugs. Few published studies have reviewed combination therapy using KSP inhibitors. Herein we provide a comprehensive review of the literature on KSP inhibitor monotherapy and therapeutic combinations. The current state and problems are also discussed.

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.

Antitumor Activity of DMAKO-05, a Novel Shikonin Derivative, and Its Metabolism in Rat Liver Microsome

The antitumor activity of shikonin derivatives is largely dependent on the generation of superoxide radicals and the alkylation activity of their naphthoquinone moiety. However, our recent study showed that 1,4-dioxime-5,8-dimethoxynaphthalene (DMAKO-05), a novel shikonin derivative, displayed more potential antitumor activity and less toxicity compared to fluorouracil (5-FU) both in vitro and in vivo, even though the hydroxyl and carbonyl groups of its naphthoquinone structure were shielded. To understand the underlying mechanisms, we investigated the metabolism of DMAKO-05 in rat liver microsomes. The kinetic analysis indicated that DMAKO-05 underwent a biphasic metabolism in rat liver microsomes. The inhibition experiments showed that CYP1A and CYP3A were the major enzymes in the metabolism of DMAKO-05, along with partial contribution from CYP2A. In addition, the structures of eight DMAKO-05 metabolites, which were characterized by accurate mass and MS/MS fragmentograms, implied that DMAKO-05 was mainly metabolized through the oxygenation of its naphthoquinone nucleus and the hydrolysis of its side chain, instead of the oxidation of hydroxyimine to ketone. Therefore, DMAKO-05 should not be considered as a traditional naphthoquinone prodrug.

A partial synthesis of 5,8-O-dimethylshikonin and 6-isomer of 5,8-O-dimethylshikonin

A convenient synthesis of 5, 8-O-dimethylshikonin and the 6-isomer of 5,8-O-dimethylshikonin was developed in 81.8% total yield from shikonin. (R)-4-Methyl-1-(1,4,5,8-tetramethoxynaphthalen-2-yl)pent-3-en-1-ol was prepared in a one-pot two-step approach and then oxidised with ceric ammonium nitrate. This is simpler and the overall yield is higher than previous methods. The reaction conditions are milder and more environmentally friendly to environment, avoiding the use of the toxic and expensive reagents methyl iodide and chloromethyl ether and are more applicable to large-scale preparation. This is important because shikonin and its closely related derivatives have attracted much attention in view of their antitumor activities.