微管抑制类抗癌药物——大自然抗癌药物的瑰宝

<正>天然产物一直是药物开发的重要来源,除少部分作为药品直接应用于临床外,大部分都作为先导药物,经过化学修饰等衍生出一系列相关药物。大量的天然产物及其衍生物已在疾病治疗、新药研发和生命科学(包括医学)研究等领域得到广泛应用。癌症化疗一定程度上也受惠于天然产物,已有多种化合物在肿瘤临床治疗方面取得巨大成功,其中以长春花碱和紫杉醇等构成的微管抑制剂最为典型。长春花碱的发现和应用长春花碱(Vinblastine)是较早应用于癌症治疗的天然产物,而它的发现源于一次偶然。爱德华·克里克·诺布尔     

真菌天然产物异源生产研究进展

真菌天然产物是天然药物的重要来源之一,大规模真菌基因组序列测序的完成表明真菌具有产生丰富的次级代谢产物的潜能。然而,许多真菌或生长缓慢,或不适宜在实验室条件下培养,或难以进行遗传操作,或化合物产量极低等,这些因素导致大量有价值的真菌天然产物无法获得。利用异源表达系统对真菌天然产物进行生产是发现新天然产物及解析其生物合成途径的有效手段,并为定向的以合成生物学的手段去合成重要活性分子奠定基础。本文对目前用于真菌天然产物生产的各种异源表达系统进行了综述,并结合最新的DNA组装技术展望了异源表达系统在真菌天然产物研究中的应用价值和前景。     

正青霉属真菌次生代谢产物的研究进展

<正>青霉属(Eupenicillium)真菌作为有性型青霉属的重要分支之一,种类多样,目前已收载了62种。研究发现,该属真菌的次生代谢产物种类多样,具有丰富的化学多样性。本文从菌株来源、化合物结构及其生物活性等方面,综述了自1974年第一个正青霉属真菌天然产物到2016年9月已报道的共66个正青霉属真菌来源的重要天然产物,且50%的化合物表现出细胞毒、抑菌、抗氧化和抗寄生虫等生物活性,为药物的研发提供了潜在的先导化合物,具有很好的研究及药用开发价值。     

后基因组时代的真菌天然产物发现

真菌产生的次级代谢产物是新药发现的重要来源之一,然而近年来传统的真菌天然产物发现方法在大量真菌基因组测序完成的时代遇到了很大的挑战。如何利用这些基因组数据来发现真菌中新的天然产物已成为后基因组时代天然产物发现的研究重点和热点。本综述先后介绍了真菌天然产物的类型及其相应基因簇和骨架酶的特征,基于基因组挖掘技术发展而来的天然产物发现新策略,以及利用合成生物学理念和技术在真菌天然产物发现中的应用现状,最后展望了后基因组时代中的天然产物发现研究前沿及基因组数据在后基因组时代对真菌天然产物发现的应用前景。     

源自海洋真菌的抗肿瘤活性天然产物研究新进展

近年来,海洋真菌因其能够产生大量结构新颖、活性显著的代谢产物而受到广泛关注,其中许多代谢产物具有较强的抗肿瘤活性。本文按照海洋真菌的来源进行分类,从海洋动物来源真菌、红树林来源真菌、海洋沉积物来源真菌、海藻来源真菌、海水来源真菌等5个方面,综述了2014~2016年4月以来发表的具有抗肿瘤活性的海洋真菌来源的新天然产物,主要介绍天然产物的化学结构和生物活性,为具有抗肿瘤活性的海洋真菌天然产物的进一步研究开发提供参考。     

革兰氏阴性细菌LuxR/Ⅰ型群体感应抑制剂研究进展

细菌群体感应(Quorum sensing,QS)被视为对抗细菌感染与解决细菌耐药性问题的新靶点。以AHLs为信号分子的LuxR/Ⅰ型群体感应系统广泛存在于革兰氏阴性菌包括多种临床致病菌中,因此寻找LuxR/Ⅰ型群体感应抑制剂(Quorum sensing inhibitors,QSIs)是研发抗革兰氏阴性致病菌药物的重要途径。迄今为止,已知的LuxR/Ⅰ型小分子QSIs来源包括化学合成、天然产物与已知药物库的化合物,大分子则包括群体感应淬灭酶与群体感应淬灭抗体。本文总结了近年来LuxR/Ⅰ型QSIs研究进展,为新型抗菌药物研发提供理论依据。     

戊二酰亚胺类天然产物生物合成研究进展

微生物天然产物是天然药物的重要组成部分,而天然产物的良好生物活性很大程度上取决于发挥药效的结构基团。这些特殊药效基团的生物合成,通常是利用小分子羧酸、氨基酸等结构简单的初级代谢产物,经过复杂的生物化学过程,最终合成结构复杂活性多样的天然产物。戊二酰亚胺类天然产物是一类重要的细菌来源天然产物,它们具有良好的生物活性,是潜在的先导化合物,部分化合物已被开发成分子探针。本文综述了近年来微生物来源的戊二酰亚胺类天然产物及其生物合成研究,包括Iso-Migrastatin、Lactimidomyin、Cycloheximide、Streptimidone、Gladiostatin、Sesbanimide等,对戊二酰亚胺类天然产物的生物合成研究,将有效促进通过基因组挖掘策略寻找新型戊二酰亚胺类天然产物。     

海洋曲霉来源的新天然产物

海洋真菌由于其遗传背景复杂、代谢产物种类多且产量高,已成为海洋微生物新天然产物的主要来源,从我们对2010–2013年初的海洋微生物来源新天然产物的统计来看,研究最多的是曲霉属(Aspergillus)真菌,占海洋真菌来源新天然产物的31%。本文从菌株来源、化合物结构及其生物活性等方面,综述了自1992年第一个海洋曲霉天然产物到2014年8月已报道的共512个海洋曲霉来源的新天然产物。这些海洋天然产物具有丰富的化学多样性,且36%的化合物表现出细胞毒、抑菌、抗氧化和抗寄生虫等生物活性;含氮化合物是其主要的结构类型、约占曲霉源海洋天然产物总数的52%,也是出现活性化合物比例最高的结构类型、约40%的含氮化合物具有生物活性,其中脱氢二酮哌嗪生物碱halimide的化学衍生物plinabulin已结束II期临床研究,并于2015年第三季度开始在美国和中国进行III期临床研究,用于治疗转移性的晚期非小细胞肺癌。     

革兰氏阴性细菌LuxR/I型群体感应抑制剂研究进展

摘要：细菌群体感应（Quorum sensing, QS）被视为对抗细菌感染与解决细菌耐药性问题的新靶点。以AHLs为信号分子的LuxR/I型群体感应系统广泛存在于革兰氏阴性菌包括多种临床致病菌中,因此寻找LuxR/I型群体感应抑制剂（Quorum sensing inhibitors, QSIs）是研发抗革兰氏阴性致病菌药物的重要途径。迄今为止,已知的LuxR/I型小分子QSIs来源包括化学合成、天然产物与已知药物库的化合物,大分子则包括群体感应淬灭酶与群体感应淬灭抗体。本文总结了近年来LuxR/I型QSIs研究进展,为新型抗菌药物研发提供理论依据。     

海绵来源真菌天然产物的研究进展

随着海洋药物及其药物先导化合物研究的不断深入,海绵来源微生物,因其种类繁多、代谢产物复杂多样,引发了科研工作者的兴趣。许多化合结构新颖、具有强烈生物活性的化合物从海绵来源真菌中发现,包括多肽、生物碱、聚酮类、萜类等。本文仅就近几年来所报道的海绵来源真菌新天然产物的结构类型及其生物活性做简要介绍。     

Synthetic biology of avermectin for production improvement and structure diversification

Natural products are still key sources of current clinical drugs and innovative therapeutic agents. Since wild‐type microorganisms only produce natural products in very small quantities, yields of production strains need to be improved by breaking down the precise genetic and biochemical circuitry. Herein, we use avermectins as an example of production improvement and chemical structure diversification by synthetic biology. Avermectins are macrocyclic lactones produced by Streptomyces avermitilis and are well known and widely used for antiparasitic therapy. Given the importance of this molecule and its derivatives, many efforts and strategies were employed to improve avermectin production and generate new active analogues. This review describes the current status of synthetic strategies successfully applied for developing natural‐product‐producing strains and discusses future prospects for the application of enhanced avermectin production.     

Strategies for mining fungal natural products

Fungi are well known for their ability to produce a multitude of natural products. On the one hand their potential to provide beneficial antibiotics and immunosuppressants has been maximized by the pharmaceutical industry to service the market with cost-efficient drugs. On the other hand identification of trace amounts of known mycotoxins in food and feed samples is of major importance to ensure consumer health and safety. Although several fungal natural products, their biosynthesis and regulation are known today, recent genome sequences of hundreds of fungal species illustrate that the secondary metabolite potential of fungi has been substantially underestimated. Since expression of genes and subsequent production of the encoded metabolites are frequently cryptic or silent under standard laboratory conditions, strategies for activating these hidden new compounds are essential. This review will cover the latest advances in fungal genome mining undertaken to unlock novel products.     

植物天然产物微生物重组合成研究进展

植物天然产物是小分子药物、营养品、化妆品、香精香料等的主要来源之一,在国民经济中发挥重要的作用。目前植物天然产物主要依赖于植物提取,这种生产方式占用耕地、生长周期长,而且植物活性成分往往含量低、生产成本高。通过解析植物天然产物生物合成途径,在微生物细胞中重构,创建细胞工厂,实现利用可再生原料发酵合成,为植物天然产物的供给提供了新的路线。本文重点介绍了中国科学院天津工业生物技术研究所在萜类、黄酮类、苯丙素类等重要类型植物天然产物微生物重组合成方面的研究进展,简要探讨了当前研究面临的挑战及未来前景。     

Uridine natural products: Challenging targets and inspiration for novel small molecule inhibitors

Nucleoside derivatives, in particular those featuring uridine, are familiar components of the nucleoside family of bioactive natural products. The structural complexity and biological activities of these compounds have inspired research from organic chemistry and chemical biology communities seeking to develop novel approaches to assemble the challenging molecular targets, to gain inspiration for enzyme inhibitor development and to fuel antibiotic discovery efforts. This review will present recent case studies describing the total synthesis and biosynthesis of uridine natural products, and de novo synthetic efforts exploiting features of the natural products to produce simplified scaffolds. This research has culminated in the development of complementary strategies that can lead to effective uridine-based inhibitors and antibiotics. The strengths and challenges of the juxtaposing methods will be illustrated by examining select uridine natural products. Moreover, structure–activity relationships (SAR) for each natural product-inspired scaffold will be discussed, highlighting the impact on inhibitor development, with the aim of future uridine-based small molecule expansion.     

Bioactive molecules from protists: Perspectives in biotechnology

For hundreds of years, mankind has benefited from the natural metabolic processes of microorganisms to obtain basic products such as fermented foods and alcoholic beverages. More recently, microorganisms have been exploited for the production of antibiotics, vitamins and enzymes to be used in medicine and chemical industries. Additionally, several modern drugs, including those for cancer therapy, are natural products or their derivatives. Protists are a still underexplored source of natural products potentially of interest for biotechnological and biomedical applications. This paper focuses on some examples of bioactive molecules from protists and associated bacteria and their possible use in biotechnology.     

丝状真菌次级代谢产物生物合成的表观遗传调控

丝状真菌产生的次级代谢产物是新药的重要来源之一,其生物合成过程受到众多因素的调控。最近的研究表明,表观遗传对多种丝状真菌次级代谢产物的生物合成具有调控作用。DNA和组蛋白的甲基化与乙酰化修饰是目前所知的丝状真菌主要的表观遗传调控形式。通过过表达或缺失相关表观修饰基因和利用小分子表观遗传试剂改变丝状真菌染色体的修饰形式,不仅可以提高多种已知次级代谢产物产量,而且可以通过激活沉默的生物合成基因簇诱导丝状真菌产生新的未知代谢产物。丝状真菌表观遗传学正逐渐成为真菌菌株改良的新策略以及挖掘真菌次级代谢产物合成潜力的强有力手段。     

Natural Products: An Alternative to Conventional Therapy for Dermatophytosis?

The increased incidence of fungal infections, associated with the widespread use of antifungal drugs, has resulted in the development of resistance, making it necessary to discover new therapeutic alternatives. Among fungal infections, dermatophytoses constitute a serious public health problem, affecting 20–25 % of the world population. Medicinal plants represent an endless source of bioactive molecules, and their volatile and non-volatile extracts are clearly recognized for being the historical basis of therapeutic health care. Because of this, the research on natural products with antifungal activity against dermatophytes has considerably increased in recent years. However, despite the recognized anti-dermatophytic potential of natural products, often advantageous face to commercial drugs, there is still a long way to go until their use in therapeutics. This review attempts to summarize the current status of anti-dermatophytic natural products, focusing on their mechanism of action, the developed pharmaceutical formulations and their effectiveness in human and animal models of infection.     

Novel biologically active natural and unnatural products

Natural products have been used as medicinal agents for many years. In addition, these compounds have served as the starting points for semisynthetic analogs with improved properties. This review highlights work on several classes of natural products and their derivatives, including both well established and emerging structural classes that are in, or nearing, clinical use for a variety of important indications.     

Application of triazoles in the structural modification of natural products

Nature products have been extensively used in the discovery and development of new drugs, as the most important source of drugs. The triazole ring is one of main pharmacophore of the nitrogen-containing heterocycles. Thus, a new class of triazole-containing natural product conjugates has been synthesised. These compounds reportedly exert anticancer, anti-inflammatory, antimicrobial, antiparasitic, antiviral, antioxidant, anti-Alzheimer, and enzyme inhibitory effects. This review summarises the research progress of triazole-containing natural product derivatives involved in medicinal chemistry in the past six years. This review provides insights and perspectives that will help scientists in the fields of organic synthesis, medicinal chemistry, phytochemistry, and pharmacology.