紫草素-中药植物天然产物:生物合成、遗传调控、结构修饰与医药功能

Shikonins as natural products from traditional Chinese medicinal plants: their biosynthesis, genetic regulation, structural modifications, and pharmaceutical functions

紫草素是来源于我国传统中药植物紫草科植物的一类具有萘醌结构的天然产物,临床常用于主治疮疡和皮肤炎等病症.紫草素因具有多重生物学活性和较高的药用价值,近年来一直被国内外关注,并且随着生物合成、结构鉴定与修饰、遗传调控和组学等技术的迅速发展,研究者对其生物合成功能基因挖掘、高效又低毒的分子结构修饰及其构效、作用机理等多个方面,均开展了较为广泛的研究.为此,本文系统地概括了近一个世纪以来对天然紫草素的结构鉴定及其在紫草科植物中的分布、生物合成、遗传调控、结构修饰、生物学活性及其医药功能的研究进展.其中,参与香叶基氢醌和去氧紫草宁的羟化、紫草宁和阿卡宁酰基化途径的关键酶基因的鉴定,促进完善了已知的紫草素生物合成途径;特别是通过化学结构修饰所获得的大量半合成紫草素衍生物可显著提高其抗肿瘤靶向性,以及紫草素主要通过抑制NF-κB/STAT3等信号通路发挥抗肿瘤、抗炎、抗菌作用,揭示了紫草素萘醌环和支链羟基修饰的有效性及其作用的分子机制.总之,上述国内外的相关研究进展无疑极大地推动了紫草素的基础及应用研究的深入开展,文末还展望了紫草素在新药创制方面的应用前景.

Shikonins are natural products having naphthoquinone structures used in clinical treatments for sores and dermatitis. These compounds are frequently extracted from a kind of important traditional Chinese medicinal plants, Boraginaceae. Due to their effective multiple biological activities and high medicinal values, shikonins have attracted increasing attentions from domestic and foreign researchers. Also, with the rapid development in gene identification, regulation and omics, researchers have extensively explored the functional gene mining of shikonins biosynthesis. Moreover, the structural modification of shikonins has been conducted at high efficiency and low toxicity, which influences their biological activity and mechanism. Thus, in this paper, we systematically summarized the structural identification of natural shikonins and their distributions in Boraginaceae in the past century. Meanwhile,we also clearly discussed the biosynthesis and genetic regulations, as well as the structural modifications and biological activities of shikonins. Among them, the identification of the key enzyme genes involved in the hydroxylation of geranyl hydroquinone and deoxyshikonin, as well as those involved in the acylation of shikonin and alkannin has improved the shikonin biosynthesis pathway greatly. Furthermore, several semisynthetic derivatives obtained through structural modifications have significantly improved the antitumor targeting of shikonins. As reported, the antitumor, anti-inflammatory, and antibacterial effects of shikonins acted mainly by inhibiting NF-κB/STAT3 and other signaling pathways, which revealed the effectiveness of the modification on the naphthoquinone ring and the branched hydroxyl of shikonins, and further clarified the molecular mechanisms. Collectively, the above research progresses domestically and abroad have undoubtedly promoted the in-depth development of basic and applied research of shikonins.Finally, the prospect of shikonins as candicates was also briefly discussed for developing novel drugs.