Current Drug Targets - Volume 12, Issue 11, 2011

Secondary metabolism plays a major role in the evolution of organisms as they represent a source of highly diversified molecular scaffolds able to interact with multiple protein targets [1, 2]. Such interactions may both serve as molecular clues to deter competitors, or alternatively facilitate symbiosis [3, 4]. Thus, natural products are building blocks to generate and respond to evolutionary pressure. In the past millenia, humankind has relied on natural products for the elaboration of medicines and poisons [5, 6]. Indeed, some of the most influential molecules were discovered from medicinal and poisonous plants [7]. Insights into molecular mechanisms and the elucidation of macromolecular structures in the last fifty years has led to a targetbased approach in the discovery and design of novel drug leads. Despite the opportunities offered by fully synthetic libraries and biologics, natural products continue to play important roles as lead compounds and unique probes to manipulate biological systems. The still widely unexplored pools of secondary metabolites currently found in microorganisms, plants and animals in distinct ecological niches are highly dynamic and have most likely been selected for addressing a wide range of biological functions [8, 9]. This may be the reason why natural products have yielded a high number of molecules for drug development. The biosynthetic pathways leading to molecular diversity in microorganisms provide a new frontier for the rational generation of novel types of secondary metabolites. Moreover, a central aim of biological research is to elucidate the many roles of macromolecules in complex, dynamic living systems [10]. As uncovered in this issue, basic research directed against different organisms is revealing unexpected insights into fundamental biological roles of natural products and how these could be exploited in drug discovery. The review articles included in this hot topic issue of Current Drug Targets summarize current examples of how natural product diversity is being used in biological research and drug discovery, thus highlighting the natural products' outstanding properties and bioactivities from different perspectives. Overall, natural products are the prototype players in chemical biology. In the first review [11], Ramesha et al. provide an overview of the different approaches towards bioprospecting chemodiversity. The relationship between biological diversity and chemical diversity is discussed and non-random approaches in lead finding are indicated. In particular, chemical ecology-oriented algorithms are presented......

Biological diversity and its constituent chemical diversity have served as one of the richest sources of bioprospecting leading to the discovery of some of the most important bioactive molecules for mankind. Despite this excellent record, in the recent past, however, bioprospecting of biological resources has met with little success; there has been a perceptible decline in the discovery of novel bioactive compounds. Several arguments have been proposed to explain the current poor success in bioprospecting. Among them, it has been argued that to bioprospect more biodiversity may not necessarily be productive, considering that chemical and functional diversity might not scale with biological diversity. In this paper, we offer a critique on the current perception of biodiversity and chemodiversity and ask to what extent it is relevant in the context of bioprospecting. First, using simple models, we analyze the relation among biodiversity, chemodiversity and functional redundancies in chemical plans of plants and argue that the biological space for exploration might still be wide open. Second, in the context of future bioprospecting, we argue that brute-force high throughput screening approaches alone are insufficient and cost ineffective in realizing bioprospecting success. Therefore, intelligent or non-random approaches to bioprospecting need to be adopted. We review here few examples of such approaches and show how these could be further developed and used in the future to accelerate the pace of discovery.

Small bioactive molecules are pre-requisite for any discovery discipline. Being aware of the fact that bioactivity is not randomly dispersed in the vast chemical space, chemists have been developing hypothesis that can provide access to these islands of bioactivities. Natural products have always been a source of inspiration and their structural motifs provide biologically relevant starting points for library synthesis. In addition to that, Diversity Oriented Synthesis (DOS) and Biology Oriented Synthesis (BIOS) have emerged other tools to guide synthesis design and help enrich compound collections in biological activities. Coherent developments in chem- and bioinformatic tools and in organic synthesis methods targeting efficient synthesis of compound collections are required to identify interesting molecules that can be employed as probes in chemical biology research and as drug candidates in medicinal chemistry investigations.

After decades of neglect in industrial research the comeback of natural products is due since improved screening approaches are at disposal, yielding a multitude of new compounds from natural sources. Besides traditional compound libraries peptides are characterized by an enormous structural complexity, thus increasing the chance of finding a hit in a screening. Emphasizing antibacterial compounds structural complexity is a prerequisite for their success. This review focuses on the screening approaches employed for the discovery of mostly antibacterial, non-ribosomal peptides derived from natural sources. Traditional screening methodologies as well as genetic approaches are discussed in this context. Utilizing genetic engineering methods e.g., precursor-directed biosynthesis, mutasynthesis, combinatorial biosynthesis, as well as chemoenzymatics to achieve greater structural diversity is thoroughly discussed and exemplified by recent discoveries.

Sesquiterpene lactones are a large group of secondary plant metabolites mostly known from the Asteraceae family. They exert a broad variety of different biological activities. This review attempts to critically summarise the knowledge on the anti-inflammatory and cytotoxic activity of SLs, with a special focus on parthenolide and helenalin. Recent advances on their molecular modes of action, allergic potential and also QSAR studies with SLs are presented. Therapeutic areas are highlighted in which SLs may play a role in the future. Thus, SLs may possess therapeutic relevance as single components for the local treatment of inflammation, such as rheumatoid complaints. In cancer therapy, SLs may be favourable in dual therapy or in the inhibition of leukaemia cell growth. In each case, native SLs serve as leads that have to be optimised in terms of their specificity, pharmacokinetics and absorption, distribution, metabolism and excretion (=ADME) properties. Finally, appropriate in vivo studies will decide whether SLs will become therapeutics or remain interesting research compounds.

Many proteins are transported from the nucleus to the cytoplasm by the exportin CRM1, which recognizes cargo proteins through a leucine rich nuclear export signal (NES). This nuclear export process can be inhibited by several small molecules, both natural products and fully synthetic compounds. The structural basis for the inhibition of nuclear export by leptomycin (LMB) based on disruption of the protein/protein interaction between CRM1 and cargo proteins is discussed. The chemistry and inhibition of nucleocytoplasmic transport of leptomycin, anguinomycin and derivatives, goniothalamin, JBIR-02, valtrate, dihydrovaltrate, ACA, peumusolide A and several synthetic compounds are presented. Consequences for the design of nuclear export inhibitors are discussed, and the potential of these compounds as anticancer agents is evaluated.

Natural products continue to be a source of inspiration for chemists and biologists alike. The search for biologically active natural products has provided troves of information about biological processes, and natural products continue to be some of the most powerful and useful probes of biological processes available. Complex and unusual molecular architectures provide the impetus for new reaction development and push the limits of known synthetic chemistry. In addition to serving as tools for basic research, natural products represent starting points for drug discovery efforts in many cases. This review details the impressive chemical diversity present in the family of molecules that inhibit the proteasome and other aspects of the ubiquitin-proteasome pathway. To date, over 60 natural products that inhibit the ubiquitin-proteasome pathway have been identified. Although early work recognized inhibitors of the proteasome itself, more modern research has revealed that inhibition of many aspects of this critical pathway is possible. One powerful example of this is the inhibition of the interaction between p53 and MDM2 (an E3 ubiquitin ligase). Natural product proteasome inhibitors have served as powerful tools to unravel the intricacies of the ubiquitin-proteasome and related pathways. Several of these natural products have been developed into anticancer drug candidates, and one proteasome inhibitor has already been approved for the treatment of multiple myeloma. Despite the wealth of information available about naturally occurring proteasome inhibitors and related compounds, it is clear that exciting research about this class of molecules will continue well into the future.

Inflammation, although first characterized by Cornelius Celsus, a physician in first Century Rome, it was Rudolf Virchow, a German physician in nineteenth century who suggested a link between inflammation and cancer, cardiovascular diseases, diabetes, pulmonary diseases, neurological diseases and other chronic diseases. Extensive research within last three decades has confirmed these observations and identified the molecular basis for most chronic diseases and for the associated inflammation. The transcription factor, Nuclear Factor-kappaB (NF-κB) that controls over 500 different gene products, has emerged as major mediator of inflammation. Thus agents that can inhibit NF-κB and diminish chronic inflammation have potential to prevent or delay the onset of the chronic diseases and further even treat them. In an attempt to identify novel anti-inflammatory agents which are safe and effective, in contrast to high throughput screen, we have turned to “reverse pharmacology” or “bed to benchside” approach. We found that Ayurveda, a science of long life, almost 6,000 years old, can serve as a “goldmine” for novel anti-inflammatory agents used for centuries to treat chronic diseases. The current review is an attempt to provide description of various Ayurvedic plants currently used for treatment, their active chemical components, and the inflammatory pathways that they inhibit.

Cyanobacteria are considered a promising source for new pharmaceutical lead compounds and a large number of chemically diverse and bioactive metabolites have been obtained from cyanobacteria over the last few decades. This review highlights the structural diversity of natural products from freshwater and terrestrial cyanobacteria. The review is divided into three areas: cytotoxic metabolites, protease inhibitors, and antimicrobial metabolites. The first section discusses the potent cytotoxins cryptophycin and tolytoxin. The second section covers protease inhibitors from freshwater and terrestrial cyanobacteria and is divided in five subsections according to structural class: aeruginosins, cyanopeptolins, microviridins, anabaenopeptins, and microginins. Structure activity relationships are discussed within each protease inhibitor class. The third section, antimicrobial metabolites from freshwater and terrestrial cyanobacteria, is divided by chemical class in three subsections: alkaloids, peptides and terpenoids. These examples emphasize the structural diversity and drug development potential of natural products from freshwater and terrestrial cyanobacteria.

Nature provides science and society with a virtually unlimited supply of structurally diverse and biologically active molecules; the natural products. While some are directly useful in commercial applications, others are valuable for studying and understanding biological phenomena at the molecular level. An example is the signaling of nerve cells, which has been explored in considerable detail using a number of bioactive natural products. This review concerns primarily a part of the GABA inhibitory system of the central nervous system, the GABAA receptors, and natural products that have been reported to affect GABAA receptors in various ways. As the major inhibitory neurotransmittor, GABA plays a central role in the function of the central nervous system and modulates the activities of all neurons. Malfunctions in the GABA-operated systems cause a number of severe mental disorders, which consequently, at least in theory, can be treated with drugs. The natural products discussed in this review, acting on the GABAA receptors, are divided into the three main classes; terpenoids, polyacetylenic alcohols, and flavonoids. In addition, in a second part of the review, it is exemplified how knowledge about quantitative structure-activity relationships for a molecular target can be used to design novel, potent and selective compounds targeting the benzodiazepine binding site of the GABAA receptors.

This review provides a detailed account on the biological activities of structurally diverse secondary metabolites from marine sponges having 2-aminoimidazole, glycociamidine and/or 2-thiohydantoin ring functions. This review will complement two previous short reviews which did however not address the potential of these natural products for drug discovery. We will discuss the naturally occurring alkaloids and give an account on their structure activity relationships.