Drug discovery from natural products

Natural product compounds are the source of numerous therapeutic agents. Recent progress to discover drugs from natural product sources has resulted in compounds that are being developed to treat cancer, resistant bacteria and viruses and immunosuppressive disorders. Many of these compounds were discovered by applying recent advances in understanding the genetics of secondary metabolism in actinomycetes, exploring the marine environment and applying new screening technologies. In many instances, the discovery of a novel natural product serves as a tool to better understand targets and pathways in the disease process. This review describes recent progress in drug discovery from natural sources including several examples of compounds that inhibit novel drug targets.     

合成生物学与天然产物开发

天然产物依然是临床用药的重要来源。合成生物学的诞生为天然产物的开发提供了全新的机遇,传统的微生物药物、植物天然产物等研究领域都因合成生物学而获得新生。重点介绍了合成生物学在天然产物开发中的应用,包括新化合物及其生物合成元件的筛选,基于理性设计的天然产物异源生物合成,人工底盘细胞的系统优化等。     

Bioactive natural products from endophytes: A review

Endophytes, microorganisms that reside in the internal tissues of living plants without causing any immediate overt negative effects, have been found in every plant species examined to date and recognized as potential sources of novel natural products for exploitation in medicine, agriculture, and industry with more and more bioactive natural products isolated from the microorganisms. In this review, we focus mainly on bioactive natural products from endophytic microorganisms by their different functional roles. The prospect and facing problems of isolating natural products from endophytes are also discussed. Published in Russian in Prikladnaya Biokhimiya i Mikrobiologiya, 2008, Vol. 44, No. 2, pp. 153–158. The text was submitted by the authors in English.     

Bioactive natural products from endophytes: a review

Endophytes, microorganisms that reside in the internal tissues of living plants without causing any immediate overt negative effects, have been found in every plant species examined to date and recognized as potential sources of novel natural products for exploitation in medicine, agriculture, and industry with more and more bioactive natural products isolated from the microorganisms. In this review, we focus mainly on bioactive natural products from endophytic microorganisms by their different functional roles. The prospect and facing problems of isolating natural products from endophytes are also discussed.     

Impact of natural products in modern drug development

Usage of natural substances as therapeutic agents in modern medicine has sharply declined from the predominant position held in the early decades of last century, but search for bioactive molecules from nature (plants, animals, microflora) continues to play an important role in fashioning new medicinal agents. With the advent of modern techniques, instrumentation and automation in isolation and structural characterisation, we have on hand an enormous repository of natural compounds. In parallel to this, biology has also made tremendous progress in expanding its frontiers of knowledge. An interplay of these two disciplines constitutes the modern thrust in research in the realm of compounds elaborated by nature. The purpose of this article is to underline how natural products research continues to make significant contributions in the domain of discovery and development of new medicinal products. It is proposed to present the material under several heads, each of which has made natural products research relevant in the search for new and better medication.     

Bioactive natural products from blue-green algae

Since 1981 we have cultured and prepared lipophilic and hydrophilic extracts from more than 1500 strains representing some 400 species of blue-green algae. Screening for a wide variety of potentially useful bioactivities, including cytotoxic, multi-drug-resistance reversal, antifungal, and antiviral effects, has led to the discovery and identification of numerous novel bioactive metabolites including peptides, macrolides and glycosides.A systematic evaluation of the chemical and environmental factors that influence the production of secondary metabolites inScytonema ocellatum, which produces tolytoxin (a macrocyclic lactone that depolymerizes actinin vivo to disrupt cell division in eukaryotic organisms), has shown that cyanophytes can be manipulated in culture to improve growth and product yields.     

源于海洋真菌的抗肿瘤天然产物

海洋真菌因其特殊的生存环境和代谢机制而具有产生新型生物活性物质的潜力。近年来随着对海洋微生物研究的深入,从海洋真菌中发现了越来越多的具有抗肿瘤活性且结构新颖的天然产物。这些海洋真菌有的分离自海水、海泥或海洋沉积物,有的来自于海洋生物体。本文综述了近几年来从海洋真菌中分离得到的抗肿瘤天然产物的研究状况。     

New antibiotics from bacterial natural products

For the past five decades, the need for new antibiotics has been met largely by semisynthetic tailoring of natural product scaffolds discovered in the middle of the 20(th) century. More recently, however, advances in technology have sparked a resurgence in the discovery of natural product antibiotics from bacterial sources. In particular, efforts have refocused on finding new antibiotics from old sources (for example, streptomycetes) and new sources (for example, other actinomycetes, cyanobacteria and uncultured bacteria). This has resulted in several newly discovered antibiotics with unique scaffolds and/or novel mechanisms of action, with the potential to form a basis for new antibiotic classes addressing bacterial targets that are currently underexploited.     

New bioactive natural products from Launaea nudicaulis

Ethyl acetate soluble fraction of methanolic extract of Launaea nudicaulis was subjected to chromatographic purification to get four new compounds including a quinic acid derivative (1), a pentahydroxy acetylene analog: trideca-12-ene-4,6-diyne-2,8,9,10,11-pentaol (2), a flavone glycoside (3) and a sesquiterpene lactone (4) together with 10 known compounds. The structures of the new isolates were established by using 1D, 2D NMR techniques and high-resolution mass spectrometry, whereas, the known isolates were identified based on 1D NMR and mass spectrometric information and in comparison with the reported data in the literature. The structure of 4 was also confirmed through single X-ray crystallographic analysis. Cholistaquinate (1) exhibited significant activity in DPPH free radical scavenging assay with an IC₅₀ value of 60.7 μM, whereas, nudicholoid (4) exhibited a moderate inhibitory activity against the enzyme butyrylcholinesterase with an IC₅₀ value of 88.3 μM.     

Antioxidative activity of natural products from plants

A variety of flavonoids, lignans, an alkaloid, a bisbenzyl, coumarins and terpenes isolated from Chinese herbs was tested for antioxidant activity as reflected in the ability to inhibit lipid peroxidation in rat brain and kidney homogenates and rat erythrocyte hemolysis. The pro-oxidant activities of the aforementioned compounds were assessed by their effects on bleomycin-induced DNA damage. The flavonoids baicalin and luteolin-7-glucuronide-6'-methyl ester, the lignan 4'-demethyldeoxypodophyllotoxin, the alkaloid tetrahydropalmatine, the bisbenzyl erianin and the coumarin xanthotoxol exhibited potent antioxidative activity in both lipid peroxidation and hemolysis assays. The flavonoid rutin and the terpene tanshinone I manifested potent antioxidative activity in the lipid peroxidation assay but no inhibitory activity in the hemolysis assay. The lignan deoxypodophyllotoxin, the flavonoid naringin and the coumarins columbianetin, bergapten and angelicin slightly inhibited lipid peroxidation in brain and kidney homogenates. It is worth stressing that the compounds with antioxidant effects in this assay, with the exception of tetrahydropalmatin and tanshinone I, have at least one free aromatic hydroxyl group in structure. Obviously, the aromatic hydroxyl group is very important for antioxidative effects of the compounds. None of the compounds tested exerted an obvious pro-oxidant effect.     

Antioxidative properties of lycopene and other carotenoids from tomatoes: synergistic effects

Lycopene is the major carotenoid in tomatoes. Tomatoes contain a matrix of many bioactive components, including vitamin C, vitamin E, other carotenoids (a-, beta-, gamma- carotene, lutein), and flavonoids. Their synergistic interactions, when used in combination, may be responsible for the observed beneficial effects of tomato-based products. This study investigated the synergistic antioxidant activity of lycopene in combination with beta-carotene, vitamin E, and lutein. A liposome system was used to test the synergistic antioxidant activity. The carotenoid mixtures were more efficient in protecting liposome from oxidation than the individual carotenoid. Mixtures of lycopene and vitamin E appear to have the greatest synergistic antioxidant activity.     

Drug discovery prospect from untapped species: indications from approved natural product drugs

Due to extensive bioprospecting efforts of the past and technology factors, there have been questions about drug discovery prospect from untapped species. We analyzed recent trends of approved drugs derived from previously untapped species, which show no sign of untapped drug-productive species being near extinction and suggest high probability of deriving new drugs from new species in existing drug-productive species families and clusters. Case histories of recently approved drugs reveal useful strategies for deriving new drugs from the scaffolds and pharmacophores of the natural product leads of these untapped species. New technologies such as cryptic gene-cluster exploration may generate novel natural products with highly anticipated potential impact on drug discovery.     

Thiazole/oxazole-modified microcins: complex natural products from ribosomal templates

With billions of years of evolution under its belt, Nature has been expanding and optimizing its biosynthetic capabilities. Chemically complex secondary metabolites continue to challenge and inspire today's most talented synthetic chemists. A brief glance at these natural products, especially the substantial structural variation within a class of compounds, clearly demonstrates that Nature has long played the role of medicinal chemist. The recent explosion in genome sequencing has expanded our appreciation of natural product space and the vastness of uncharted territory that remains. One small corner of natural product chemical space is occupied by the recently dubbed thiazole/oxazole-modified microcins (TOMMs), which are ribosomally produced peptides with posttranslationally installed heterocycles derived from cysteine, serine and threonine residues. As with other classes of natural products, the genetic capacity to synthesize TOMMs has been widely disseminated among bacteria. Over the evolutionary timescale, Nature has tested countless random mutations and selected for gain of function in TOMM biosynthetic gene clusters, yielding several privileged molecular scaffolds. Today, this burgeoning class of natural products encompasses a structurally and functionally diverse set of molecules (i.e. microcin B17, cyanobactins, and thiopeptides). TOMMs presumably provide their producers with an ecological advantage. This advantage can include chemical weapons wielded in the battle for nutrients, disease-promoting virulence factors, or compounds presumably beneficial for symbiosis. Despite this plethora of functions, many TOMMs await experimental interrogation. This review will focus on the biosynthesis and natural combinatorial diversity of the TOMM family.     

Synergistic effects of multiple natural products in pancreatic cancer cells

Pancreatic cancer (PC) remains the fourth most common cause of cancer related death in the United States. Therefore, novel strategies for the prevention and treatment are urgently needed. Numerous dietary and pharmacological agents have been proposed as alternative strategies for the prevention and/or treatment of PC. Isoflavone is a prominent flavonoid found in soy products and has been proposed to be responsible for lowering the incidence of PC in Asians. Similarly, curcumin, an active ingredient of turmeric, that inhibits growth of malignant neoplasms, has a promising role in the prevention and/or treatment of PC. Here we examined whether isoflavone together with curcumin could elicit a greater inhibition of growth of PC cells than either agent alone, and also sought to determine the molecular mechanism of action. We found that the inhibition of cell growth and induction of apoptosis was significantly greater in the combination group than that could be achieved by either agent alone. These changes were associated with decreased Notch-1 expression and DNA binding activity of NF-kappaB and its target genes such as Cyclin D1, Bcl-2, and Bcl-xL. Moreover, we found that the combination of four natural agents at lower concentration was much more effective. Collectively, our results suggest that diet containing multiple natural products should be preferable over single agents for the prevention and/or treatment of PC. The superior effects of the combinatorial treatment could partly be attributed to the inhibition of constitutive activation of Notch-1 and NF-kappaB signaling pathways.     

Endophytes: exploiting biodiversity for the improvement of natural product-based drug discovery

Abstract

Endophytes, microorganisms that colonize internal tissues of all plant species, create a huge biodiversity with yet unknown novel natural products, presumed to push forward the frontiers of drug discovery. Next to the clinically acknowledged antineoplastic agent, paclitaxel, endophyte research has yielded potential drug lead compounds with antibacterial, antiviral, antioxidant, insulin mimetic, anti-neurodegenerative and immunosuppressant properties. Furthermore, while being implicated in livestock neurotoxicosis, some endophyte-produced alkaloids have been shown to display insecticidal activity. The endophyte-host relationship is postulated to be a ‘balanced antagonism’. Moreover, the plausibility of horizontal gene transfer (HGT) hypothesis is taken into account. Knowledge of the genetic background of endophytic natural product biosynthesis is discussed on the basis of loline alkaloids, ergopeptines, lolitrems and maytansinoids. The current dynamic progress in genomics will contribute to a better understanding of endophytic microbes and to further exploiting them as a source of pharmaceutically relevant compounds.