Current Drug Targets - Volume 7, Issue 3, 2006

Cancer still belongs to the second-leading cause of death in industrialized countries. The fate of many cancer patients, for whom cure of their disease is not a reality, is becoming ever more of an issue. There are unprecedented efforts to uncover new treatment, and the knowledge on cancer has increased dramatically over the past four decades (Fig. 1A). Medicinal plants and other marine and terrestrial natural sources are a fertile ground to find compounds with pharmacological features. The recent developments in drug discovery from natural resources can be traced back to fundamental observations in the first half of the 20th century. The term "allelopathy" coined by the plant physiologist Hans Molisch in 1937 describes the effect of products of a donor plant on abiotic and biotic environmental factors. In line with this term is the name "allelochemics" coined by Whittaker and Feeny in 1971 for compounds by which organisms of one species affect the growth, health, behaviour or population biology of other species, excluding nutrients and vitamin-like compounds. Typically, allelochemicals are secondary metabolites, which are - in contrast to primary metabolites - not essential for the nutrition of plants. Secondary metabolites are regarded as defence against competitors, herbivores and pathogens and signal compounds to attract insects for reproduction. Therefore, secondary metabolites represent an important part of the plants' life strategies to maintain survival and reproductive fitness. Fortunately, many secondary metabolites of terrestrial and marine organisms exert pharmacological features. It is, however, quite clear that the pharmacological activities of secondary metabolites does not represent an altruistic behaviour of other organisms towards humans but rather a pleasing side effect. Although medicinal herbs gradually lost importance in the course of chemistry's progress in industrialized countries during the 20th century, the current thriving revival of phytotherapy is followed by an increasing scientific interest in bioactive compounds as lead drugs for semi-synthetic modification. As a matter of fact, the number of biomedical publications dealing with natural products is constantly increasing in recent years (Fig. 1A). Cancer therapy and especially natural products are important topics of cancer research (Fig. 1B). A smaller, but increasing number of papers deals with the prevention of cancer. It comes as no surprise that natural products belong to the major players in cancer research, since a considerable portion of antitumor agents currently used in the clinic are of natural origin. Drugs of different classes are part of the armatorium to fight the war against cancer, e.g., Vinca alkaloids (vincristine, vinblastine, vindesine, vinorelbine), taxanes (paclitaxel, docetaxel), epipodophyllotoxines (etoposide, teniposide), camptothecin and its derivatives (topothecan, irinothecan), anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin), and others. Over the past years, there was a major shift in the development of cancer drugs, from screening of cytotoxic drugs to the development of molecularly targeted drugs. The conceptual idea is that the knowledge of the mechanism(s) of a drug provides a better approach to reach improved clinical results on the basis of patients' molecular characteristics. The complexity of this task requires the interaction of scientists of different fields. I was fortunate to attract a panel of reputed experts from different fields working on innovative small molecules of natural origin. Due to the broad spectrum of the subject covered their work is being presented in two separate issues of Current Drug Target, which appear consecutively as part I and II of the title "Small molecules of natural origin for cancer therapy and chemoprevention". In part I the articles are organized in two chapters.1. Pharmacognosy: bioactive molecules from nature Michael Heinrich and Paul Bremner (London, UK) give a valuable introduction to ethnobotany and ethnopharmacy and their role for anti-cancer drug development. The authors span the bow from the ethnic origin of knowledge about medicinal plants to the Convention of Biological Diversity (Rio Convention) and the specific targeting of cancer-related molecules by natural products. William P. Jones, Young-Won Chin, and A. Douglas Kinghorn (Columbus, OH, USA) emphasize the role of ethnobotany and botanical medicine to foster the identification of new drugs and discuss chances of high-throughput screenings with natural products. Semi-synthetic derivatization of natural products has a major impact for drug discovery. The authors point to chemical informatics comparisons between natural products and synthetic compounds showing that natural products have considerably higher "drug-likeliness" than synthetic compounds. It may sound as a platitude that many drugs currently used in the clinic are from natural origin. However, thinking this notion.......

Local and traditional knowledge has been the starting point for many successful drug development projects over the last decades. Here we discuss some examples of anti-cancer drugs which have had enormous impact as anticancer agents (camptothecan, taxol and derivatives) and a few examples of drugs currently under various stages of preclinical development. Ethnobotanists investigate the relationship between humans and plants in all its complexity, and such research is generally based on a detailed observation and study of the use a society makes of plants. The requirements of modern research on natural products as, for example, outlined in the Convention on Biological Diversity (Rio Convention) and the overall approach in ethnobotanical research are also discussed. Selected phytochemicalpharmacological studies based on traditional plant use are used to highlight the potential of ethnobotany driven anti-cancer research. The link between traditionally used plants and targets of the NF-κB pathway is discussed using on an EUfunded, multidisciplinary project as an example. Lastly the potential of chemopreventive agents derived from traditional food plants is briefly addressed.

This review details the contribution to modern medicine and pharmacy made by natural products and drugs derived from natural products, with an emphasis on essential medicines and new introductions to the market. Areas covered include recent advances in the development of drugs derived from marine organisms, microbes, terrestrial animals, and vascular plants, and current issues regarding botanical medicines. The role of natural products in drug discovery and development is evaluated, particularly with regard to their value as sources of drug leads with "drug-like" properties. A rationale for the success of natural products research in providing new drugs and drug prototypes is presented, drawing on lines of evidence from chemical informatics and chemical ecology. Several innovative strategies for natural products drug discovery and evaluation of botanical medicines are also reviewed.

Natural Products have been the most significant source of drugs and drug leads in history. Their dominant role in cancer chemotherapeutics is clear with about 74% of anticancer compounds being either natural products, or natural product-derived. The biodiversity of the world provides a resource of unlimited structural diversity for bioprospecting by international drug discovery programs such as the ICBGs and NCDDGs, the latter focusing exclusively on anticancer compounds. However, many sources of natural products remain largely untapped. Technology is gradually overcoming the traditional difficulties encountered in natural products research by improving access to biodiverse resources, and ensuring the compatibility of samples with high throughput procedures. However, the acquisition of predictive biodiversity remains challenging. Plant and organism species may be selected on the basis of potentially useful phytochemical composition by consulting ethnopharmacological, chemosystematic, and ecological information. On the conservation/political front, the Convention on Biological Diversity (CBD) is allaying the anxiety surrounding the notion of biopiracy, which has defeated many attempts to discover and develop new natural products for human benefit. As it becomes increasingly evident and important, the CBD fosters cooperation and adaptation to new regulations and collaborative research agreements with source countries. Even as the past inadequacies of combinatorial chemistry are being analyzed, the intrinsic value of natural products as a source of drug leads is being increasingly appreciated. Their rich structural and stereochemical characteristics make them valuable as templates for exploring novel molecular diversity with the aim of synthesizing lead generation libraries with greater biological relevance. This will ensure an ample supply of starting materials for screening against the multitude of potentially "druggable" targets uncovered by genomics technologies. Far from being mutually exclusive, biodiversity and genomics should be the driving force of drug discovery in the 21st century.

Over the last twenty-five to thirty years, exploration of the marine fauna and microbial flora has progressed from a random search by natural product chemists who liked to dive and wished to combine their hobby with their profession, to fully integrated programs of systemic investigation of the chemical agents elaborated by marine organisms of all phyla (as presumably defensive agents against predators) for their potential as leads to human-use drug candidates where the putative mechanisms have been identified as modulation of, and/or interaction with, potential molecular targets, rather than just exhibiting general cytotoxicity. This review is not exhaustive but is meant to cover the highlights of such agents and is arranged on a (nominal) target basis rather than by organism or chemical class.

Antimitotic agents have been the most successful pharmacological agents for the treatment of cancer. The term "antimitotic agent" has traditionally been synonymous with tubulin-targeting compounds, but as a consequence of the large number of new compounds and mechanisms that have been identified recently, a much broader definition is currently needed. This review attempts to provide a broad overview of compounds and their cognate protein targets which result in a block in mitosis. Focus has been placed on agents that act directly on the mitotic machinery rather than on targets further upstream such as growth factor receptors.

Multifunctional rational drug design of protein tyrosine kinases inhibitors allows a potent drug to be utilized to treat more than one disease for greater patient benefits. Many protein tyrosine kinases (PTK), including Janus kinase 3 (JAK3) and Bruton's tyrosine kinase (BTK), have been identified as potential drug targets to treat diverse diseases including cancer and disorders of the immune system. Here we review advances in JAK3 and BTK inhibitors and describe the therapeutic potential of these potent agents in the clinical setting.

The prolonged duration requiring alteration of multi-genetic and epigenetic molecular events for cancer development provides a strong rationale for cancer prevention, which is developing as a potential strategy to arrest or reverse carcinogenic changes before the appearance of the malignant disease. Cell cycle progression is an important biological event having controlled regulation in normal cells, which almost universally becomes aberrant or deregulated in transformed and neoplastic cells. In this regard, targeting deregulated cell cycle progression and its modulation by various natural and synthetic agents are gaining widespread attention in recent years to control the unchecked growth and proliferation in cancer cells. Infact, a vast number of experimental studies convincingly show that many phytochemicals halt uncontrolled cell cycle progression in cancer cells. Among these phytochemicals, natural flavonoids have been identified as a one of the major classes of natural anticancer agents exerting antineoplastic activity via cell cycle arrest as a major mechanism in various types of cancer cells. This review is focused at the modulatory effects of natural flavonoids on cell cycle regulators including cyclin-dependent kinases and their inhibitors, cyclins, p53, retinoblastoma family of proteins, E2Fs, check-point kinases, ATM/ATR and survivin controlling G1/S and G2/M check-point transitions in cell cycle progression, and discusses how these molecular changes could contribute to the antineoplastic effects of natural flavonoids.

The transcription factor hypoxia-inducible factor-1 (HIF-1) regulates the expression of more than 70 genes involved in cellular adaptation and survival under hypoxic stress. Activation of HIF-1 is associated with numerous physiological and pathological processes that include tumorigenesis, vascular remodeling, inflammation, and hypoxia/ischemiarelated tissue damage. Clinical studies suggested that HIF-1 activation correlates directly with advanced disease stages and treatment resistance among cancer patients. Preclinical studies support the inhibition of HIF-1 as a major molecular target for antitumor drug discovery. Considerable effort is underway, in government laboratories, industry and academia, to identify therapeutically useful small molecule HIF-1 inhibitors. Natural products (low molecular weight organic compounds produced by plants, microbes, and animals) continue to play a major role in modern antitumor drug discovery. Most of the compounds discovered to inhibit HIF-1 are natural products or synthetic compounds with structures that are based on natural product leads. Natural products have also served a vital role as molecular probes to elucidate the pathways that regulate HIF-1 activity. Natural products and natural product-derived compounds that inhibit HIF-1 are summarized in light of their biological source, chemical class, and effect on HIF-1 and HIF-mediated gene regulation. When known, the mechanism(s) of action of HIF-1 inhibitors are described. Many of the substances found to inhibit HIF-1 are non-druggable compounds that are too cytotoxic to serve as drug leads. The application of high-throughput screening methods, complementary molecular-targeted assays, and structurally diverse chemical libraries hold promise for the discovery of therapeutically useful HIF-1 inhibitors.

Natural products represent a rich resource for drug discovery and are currently being exploited to target tumour angiogenesis. A vast array of products of natural origin have been shown to have anti-angiogenic potential in preclinical models, including purified endogenous inhibitors, and exogenous compounds derived from varied species of plant, animal and micro-organism. Over a dozen of these agents have now entered clinical trial. This review discusses evidence for the efficacy of this drug class and key issues in the translation of pre-clinical results into the development of efficacious drugs for clinical use.