Natural Products Chemistry: What’s the Next Step?

Norberto P. Lopes; Paulo Cezar Vieira

摘要

Plants and other living organisms have long been used as sources for different useful human products. Traditional medicines have always been a source for the cure of many diseases since antiquity. However, their rational use was possible only after the initial understanding of what were or were not the “proven biological activities” of the compounds present in plants and other natural product sources such as microbes and later marine invertebrates. These molecules are normally known as “secondary metabolites” meaning that they are not part of the regular metabolism of the organism that is required to maintain life but that they have other, usually not known properties. Then the search for new bioactive compounds (secondary metabolites) was developed, and as a consequence, a number of new molecules with different spectra of activities were found.(1)This approach generated wonderful examples that can illustrate how materials derived from plants and microbes became medicines. Recently, in 2015, the Nobel Prize in Physiology or Medicine was divided into two, with half going to William C. Campbell and Satoshi O?mura “for their discoveries concerning a novel therapy against infections caused by roundworm parasites” and the other half to You-you Tu “for her discoveries concerning a novel therapy against Malaria”. Even though half of the prize refers to products from microorganisms, the molecules are also known as natural products. The discovery by You-you Tu is a typical example of how the traditional medicines can be the source of products of plant origin that can be transformed into drugs. Recently, Pye and co-workers provided insight for future discovery of bioactive natural products. Quantitative examination applying a data set of all published microbial and marine-derived natural products suggests a potential for discovery that is truly new, but significant innovation will be required to successfully find novel bioactive compounds.(2)Numerous examples of bioactive natural products are known; however, their discoveries have always been associated with the development of new analytical techniques for both isolation and purification and for structural elucidation. Sometimes the isolation process is tedious and time consuming, and frequently, the most used approach known as bioguided isolation leads to the bioactive compound; however, in some cases, all the efforts result in a known compound or a new series of compounds with high toxicity. Usually, the natural products as found in living organisms may not be used directly as a drug, but their chemical “skeleton” becomes the inspiration for the development of structurally modified compounds with superior biological properties. This is often referred to as being “more drug-like” than the initial compound.Plants continue to be a rich source of interesting compounds; however, in the past decades there has been a change leading to the study other organisms, and certainly, microbes have caught the attention of scientists. Just to remember one example, the discovery of penicillin can be cited as one of the most remarkable findings on the area of natural products. The study of microorganisms and now their genomes has brought new insights for the chemistry of natural products, with the capability to generate chemical diversity by using genome mining, mutasynthesis, combinatorial biosynthesis, metagenomics, and synthetic biology. Natural products can be used for many other purposes, such as in agriculture, in cosmetics, as dyes, as paints, as inks, etc. In addition, they are involved in ecological processes that include different organisms.Sometime ago, Schreiber, a renowned chemist from Harvard University, in his paper “Small molecules: The Missing Link in the Central Dogma” stated “small molecules have critical roles at all levels of biological complexities and yet remain orphans of the central dogma. Chemical biologists, working with small molecules, expand our understanding of these central elements of life”.(3)Even though the search for new drugs from plants and other organisms is still exciting and attractive, chemistry has played a key role in the explanation of biological and biochemical observations, opening a number of opportunities in the area. Each single organism (plant, marine or terrestrial animals, microorganism, algae, among others) interacts with the ecosystem by different strategies, including chemical signals and/or chemical defenses. In this sense, secondary metabolites can be understood as words of an ecological and evolutionary language that governs the synchronization and modulation of metabolic pathways, organismic and biogeographic.(4) Also, the natural products can have unknown physiological functions that must be deeply understood in the future.(5)Using a simple generalization, we can suggest that natural products are chemical phenotypes of an organism opening new challenges for researchers. Once the classical bioassay-guided isolation methods

机译：长期以来，植物和其他生物是各种有用人类产品的来源。自古代以来，传统药物一直是治愈许多疾病的来源。但是，只有在初步了解植物和其他天然产物来源（例如微生物和后来的海洋无脊椎动物）中存在的化合物的“经过验证的生物活性”之后，才能合理使用它们。这些分子通常被称为“次级代谢产物”，这意味着它们不是维持生命所需的有机体正常代谢的一部分，而是具有其他通常未知的特性。然后寻找新的生物活性化合物（次生代谢物），结果发现了许多具有不同活性谱的新分子。（1）这种方法产生了很好的例子，可以说明植物和微生物的物质来源。变成了药物。最近，在2015年，诺贝尔生理学或医学奖被一分为二，其中一半奖给了威廉·坎贝尔（William C. Campbell）和中村聪（Satoshi O？mura），“他们的发现是针对round虫寄生虫感染的新型疗法”，另一半奖给了屠幼友“因为她发现了一种抗疟疾的新疗法”。即使奖金的一半是来自微生物的产品，但这些分子也被称为天然产品。涂有有的发现是一个典型的例子，说明传统药物如何成为植物来源产品的来源，并可以转化为药物。最近，Pye及其同事为未来发现生物活性天然产品提供了见识。使用所有已发表的微生物和海洋来源的天然产物的数据集进行的定量检查表明，发现的潜力确实是新的，但要成功找到新型生物活性化合物，还需要进行重大创新。[2]已知许多生物活性天然产物的例子;然而，他们的发现始终与分离和纯化以及结构解析的新分析技术的发展有关。有时，分离过程很繁琐且耗时，通常，最常用的方法是生物引导分离，从而产生生物活性化合物。然而，在某些情况下，所有的努力都导致了已知化合物或一系列新的高毒性化合物。通常，在生物体内发现的天然产物可能无法直接用作药物，但其化学“骨架”成为开发具有卓越生物学特性的结构修饰化合物的灵感。与最初的化合物相比，这通常被称为“更像毒品”。植物仍然是有趣化合物的丰富来源。然而，在过去的几十年中，发生了改变，导致了对其他生物的研究，当然，微生物引起了科学家的注意。仅需记住一个例子，青霉素的发现可以说是天然产物领域最引人注目的发现之一。对微生物及其基因组的研究为天然产物的化学提供了新的见解，并具有利用基因组挖掘，突变合成，组合生物合成，宏基因组学和合成生物学产生化学多样性的能力。天然产物可用于许多其他目的，例如农业，化妆品，染料，油漆，油墨等。此外，它们还参与了包括不同生物的生态过程。有时，著名的施雷伯（Schreiber）哈佛大学的化学家在他的论文“小分子：中央教条中的缺失环节”中指出：“小分子在生物复杂性的各个水平上都起着关键作用，但仍然是中央教条的孤儿。化学生物学家与小分子合作，使我们对生命的这些核心要素有了更深入的了解。”（3）尽管从植物和其他生物中寻找新药仍然令人兴奋和有吸引力，但化学在解释人类生命中起着关键作用。生物和生化观察，为该地区带来了许多机会。每个生物（植物，海洋或陆地动物，微生物，藻类等）都通过不同的策略与生态系统相互作用，包括化学信号和/或化学防御。从这个意义上讲，次生代谢物可以理解为一种生态和进化语言的词，它控制着生物和生物地理代谢途径的同步和调节。（4）此外，天然产物可能具有未知的生理功能，必须深入理解（5）通过简单的概括，我们可以认为天然产物是生物的化学表型，这为研究人员带来了新的挑战。曾经的经典生物测定指导的分离方法

Natural Products Chemistry: What’s the Next Step?

摘要

著录项

相似文献

相关主题

期刊订阅