Current Organic Chemistry - Volume 14, Issue 16, 2010

Plants are the fundamental basis of sophisticated traditional medicines for thousands of years, and continue to be used as valuable medicinal materials in countries where conventional medicine is an important part of the national health care system. During the last decade, medicinal plants, with the characteristics of multiple constituents, multiple actions, and multiple targets, have expanded globally and gained considerable popularity. Meanwhile, natural products from plants provide an unparalleled source of chemical diversity for discovery of important and interesting biologically active molecules. Over 50% of the drugs introduced to the market during the last 20 years are derived directly or indirectly from plant natural products. Undoubtedly, plants will continue to play a major role as lead compounds in the discovery of drug and drug targets. Plants belong to complex multi-component system, and multidisciplinary approaches are thus required to develop validated research methodologies and to increase the productivity in drug discovery and development. It will be the aim of this special issue on Plant Natural Products in Drug Discovery to illustrate the recent advances and to highlight new trends in chemical compositions, sample preparation, analytical techniques, pharmacokinetics, and drug lead discovery based on plant extracts or plant natural products. It is hoped that the scientists involved in natural products and related research fields will find the selection of these reviews, ranging from traditional medicinal chemistry methodologies to new frontiers in plants research and drug discovery, beneficial and informative. Sample preparation is essential for isolating desired components from complex plant matrices and greatly influences the reliability and accuracy of analysis of plant-derived medicines. The first review by H. Kataoka, from School of Pharmacy, Shujitsu University, summarizes current trends in sample preparation techniques for the analysis of plant-derived medicines, focusing primarily on newly developed techniques, such as supercritical-fluid extraction, solid-phase microextraction, and liquid-phase microextraction. Structural elucidation is one of the most challenging tasks for access to plant natural products. The second review, written by X.C. Li et al., from National Center for Natural Products, the University of Mississippi, illustrates the applicability of the time dependent density functional theory calculation of electronic circular dichroism spectra in determining the absolute configuration of structurally diverse natural products and complex chiral molecules. For the purpose of lead discovery, or for the scientific validation of a medicinal plant, active principals in complex matrices need to be analyzed. Analysis of constituents in medicinal plants has been one of the hottes topics for the past 20 years. Gas chromatography, liquid chromatography and electromigration methods are the three most widely used techniques for analysis of plants. The article by L. Mondelloa et al., from Dipartimento Farmaco-chimico, Universita di Messina, reviews modern gas chromatography and hyphenated techniques for analysis of plant extracts including gas chromatography-mass spectrometry, multidimensional gas chromatography, etc. The review by J.L. Wolfendera et al., from School of Pharmaceutical Sciences, University of Geneva, focuses on advances in liquid chromatography hyphenated techniques and direct MS or NMR analysis for profiling crude extracts and for the rapid identification of natural products. The paper by M. Ganzera and I. Nischang, from University of Innsbruck and Johannes-Kepler-University introduces the use of capillary electrochromatography for natural product analysis, including the theoretical background and recent applications. As one typical example, the review by L.W. Qi et al., from Key Laboratory of Modern Chinese Medicines, China Pharmaceutical University, Ministry of Education, is dedicated to Radix Astragali (Astragalus) covering latest advancements and trends in chemistry, analysis, pharmacology and pharmacokinetics. Pharmacokinetic studies are an integral part of modern drug development, and an increasing attention has been paid to pharmacokinetics of plant medicines. The paper by S.F. Zhou et al., from School of Health Sciences, RMIT University, highlights the pharmacokinetic properties and disposition pathways of commonly used plant natural products and the possible clinical and toxicological implications. The review by C.G. Lim and M.A.G. Koffas, from Department of Chemical and Biological Engineering, University at Buffalo, discusses the bioavailability of the major classes of stilbenes and flavonoids, with an emphasis on their absorption, distribution, metabolism and excretion properties...

Plants and other natural sources have been useful in discovering drugs for treating patients with diabetes mellitus. Examples include the α-glucosidase inhibitor acarbose, and galegine, which contributed to the discovery and development of the biguanides. There are many traditionally used herbal medicines that lower blood glucose in experimental models, and, currently, there is considerable interest in exploring these plant extracts for compounds that might also be useful in the clinic or that might have novel effects, such as stimulation of β-cell proliferation. Often, neither their mechanism nor their active components have been defined, so it is possible that novel mechanisms of action and novel compounds will be discovered. In addition, there has been very little use of large collections of natural products in random screening campaigns against accepted therapeutic targets: there is great potential to find new chemical scaffolds for drugs with improved properties. This paper will provide an overview of recent activities relating to the use of natural products from plants as a source of compounds that might be beneficial in treating patients with diabetes.

Determination of absolute configuration (AC) is one of the most challenging features in the structure elucidation of chiral natural products, especially those with complex structures. With revolutionary advancements in the area of quantum chemical calculations of chiroptical spectroscopy over the past decade, the time dependent density functional theory (TDDFT) calculation of electronic circular dichroism (ECD) spectra has emerged as a very promising tool. The principle is simply based on the comparison of the calculated and experimental ECD spectra: the more closely they match, the more reliable conclusion for the AC assignment can be drawn. This review attempts to use several examples representing monomeric flavonoids, rotationally restricted biflavonoids, complex hexahydroxydiphenoyl- containing flavonoids, conformationally flexible and restrained sesquiterpenoids, cembrane-africanene terpenoids, dihydropyranocoumarins, alkaloids, and dihydroxanthones to illustrate the applicability of this approach in determining the AC of structurally diverse natural products. The findings clearly indicate that the TDDFT calculation of ECD spectra can quantify the contribution of individual conformers and the interaction of multiple chromophores, making it possible to determine the AC of complex chiral molecules. The calculated electronic transitions and molecular orbitals provide new insight into the interpretation of ECD spectra at the molecular level.

Natural products have served as major sources of drugs for centuries, and about half of the pharmaceuticals in use today are derived from natural products. Therefore, screening and analysis of the bioactive components in medicinal plants are now indispensable for the discovery of new drugs and quality control of plant pharmaceuticals. Sample preparation is essential for isolating desired components from complex matrices and greatly influences the reliable and accurate analysis of plant-derived medicines. This review will summarize current trends in sample preparation techniques for the analysis of plant-derived medicines, focusing primarily on newly developed techniques, such as ultrasonic extraction (USE), microwave-assisted extraction (MAE), pressurized-liquid extraction (PLE), supercritical- fluid extraction (SFE), solid-phase extraction (SPE), solid-phase microextraction (SPME), and liquid-phase microextraction (LPME). The general characteristics and applications of each method in the analysis of plant-derived medicines are described.

Many Chinese herbs have been tested against herpes simplex virus (HSV) in search for new anti-herpetic agents. Extracts and novel molecules such as polysaccharides, tannins, terpenes, lignans, saponins, lectins and flavonoids have been found to be effective as anti-herpetic agents. Using different in vitro and in vivo models, novel compounds isolated from Chinese herbal medicines (CHM) have been tested and demonstrated with strong inhibitory effects on HSV through different mechanisms. CHM like Camellia sinensis, Mentha piperita, Myrica rubra, Pterocarya stenoptera, Smilax glabra and Terminalia arjuna are effective even at early stage of HSV infection to hinder viral attachment and penetration. Other CHM including Chamaecyparis obtuse, Glycyrrhiza glabra, Lobelia chinesis and Ocimum basilicum are capable of interfering in viral replication. Nelumbo nucifera, Pithecellobium clypearia, Polygonum cuspidatum and Schefflera heptaphylla have been reported to block host cellular machineries while Plantago major and Prunella vulgaris have shown to induce immunomodulatory effect. It is also noticeable that some CHM showed dual and even multiple roles in combating HSV infection. Structural modifications of CHM derived compounds by changing the degree of sulfation and oxygenation, transforming specific moiety, addition of chemical groups and increasing molecular weight resulted in enhanced anti-herpetic activity with high selectivity and low toxicity. It is a hopeful attempt to develop topical microbicides which possess multiple actions on the early or late stage of HSV infections from CHM. In this review, we focus on the promising results and the working mechanisms on the anti-herpetic activities of several CHM and the potential of their clinical applications.

Polyphenols such as flavonoids and stilbenes are abundant in our daily diet, and their roles in the protection and prevention of various diseases are substantial. However, bioavailability varies among polyphenols and the actual compounds acting on the designated tissues are often not the native molecules consumed in the diet. Hereby, we review the bioavailabilty of the main classes of stilbenes and flavonoids, namely flavanones, flavones, isoflavones, flavanols, flavonols and anthocyanins, emphasizing on their absorption, distribution, metabolism and excretion (ADME). The bioavailability summary can be useful for future experimental design, especially research studies emphasizing the bioactivity on targeted tissues and organs. In addition, we review the bioefficacy of the polyphenols, focusing on the recent advances on health benefits both in vivo and in vitro. Other issues of importance, such as structure, food source and synthesis methods, are also considered.

Modern gas chromatography, with the development of advanced analytical techniques, has become a fundamental tool for the separation and characterization of plant extracts. These last issues are absolutely important if considering the widespread use of plant derivatives not only in pharmaceutical/food industry but also, for a large part, in traditional and alternative medicine, which require a high level of quality and safety. Hence, the development of new, powerful hyphenated GC techniques were reviewed in this article, including Gas Chromatography-Mass Spectrometry (GC-MS), Solid Phase Microextraction-Gas Chromatography (SPME-GC), Gas Chromatography- Fourier-transformed Infrared Spectroscopy (GC-FTIR), Multidimensional Gas Chromatography (MDGC) and Comprehensive Gas Chromatography (GCxGC). Several applications of each technique were reported and illustrated.

This review focuses on the application and implication of CEC for natural product analysis, with special emphasis on reports published after 2005. The basic concepts and principles of CEC are outlined, and the techniques advantages and disadvantages are discussed in context with the available stationary phase format. Special attention is given to the application of packed beds and monolithic formats of CEC with both silica-based and in situ formed polymeric stationary phases. The most promising applicative platforms are presented and their potential for natural product analysis is discussed.

Plant-derived natural products have been an important source of several clinically useful anti-cancer agents. Plants continue to play a major role in drug discovery as evidenced by the number of promising new agents in clinical development based on selective activity against cancer-related molecular targets. Due to improvements in tumor targeting technology, some agents which failed in earlier clinical studies are also stimulating renewed interest. We wish to draw the attention of readers to the rapidly evolving recognition that a significant number of natural product drugs/leads are possibly produced by endophytic fungi and microbes residing in the plant tissues. We consider that this area of natural product research should be expanded significantly.

Radix Astragali (Astragalus) has been used in Traditional Chinese Medicine for over 2000 years, and still widely used in Asian countries to enhance the immune system and to protect the body against various stresses. In Europe and the United States, Astragalus is commonly used as nutritional dietary supplements and additives to foods and beverages. During the last several years, we have witnessed a steady expansion in the number of publications made associated with this herb. This review focuses on latest advancements and trends in chemistry, analysis, pharmacology and pharmacokinetics of Radix Astragali. Several types of constituents including triterpene saponins, flavonoids and astragalus polysaccharides have been summarized, and astragalus polysaccharides are still a challenging issue. With the rapid development of analytical techniques, a great number of methods have been developed for the identification and quantification of the plant material, extracts, and products of Radix Astragali. Separation was achieved using thin layer chromatography (TLC), high performance liquid chromatography (HPLC), callipary electrophoresis (CE), and high-speed counter-current chromatography (HSCCC). Among these techniques HPLC and hyphenated methods like HPLC with ultraviolet (UV), evaporative light scattering detection (ELSD), or mass spectrometry (MS) are by far the most employed. Radix Astragali has attracted ever-increasing attention in a variety of biological activity studies; its immunomodulatory effects, cardioprotective effects, antihyperglycemic effects, hepatoprotective effects and anticancer effects were strengthened in this review. Pharmacokinetic studies showed that the flavonoids could be absorbed and metabolized in vivo, and their major metabolic pathways are glucuronidation and sulfation, while the bioavailability of saponins is extremely low.

Thanks to the important advances registered over the last decade in analytical techniques, profiling methods for the analysis of crude extracts from plant origin or from other biological sources have evolved into powerful tools for dereplication, quality assessment and metabolomics. Metabolite profiling of crude extracts represents a challenging analytical task since these mixtures are composed of hundreds of natural products. According to the type of study the focus can be put on major bioactive constituents or minor significant biomarkers. In many cases, a rapid on-line or at-line identification of the compound(s) of interest and in some case of all detected constituents (metabolomics) is required. The most common techniques for these types of analyses consist of a spectroscopic method hyphenated to high performance liquid chromatography (HPLC), such as liquid chromatography photodiode array detection (LC-PDA), mass spectrometry (LC-MS) or nuclear magnetic resonance (LC-NMR). With the evolution of multivariate data analysis (MVDA) methods, profiling extracts may also rely on direct NMR or MS analysis without prior HPLC separation, which requires high resolution instruments. In this review most of the current technologies for profiling natural products in various matrices will be presented and discussed. Various applications in the field of dereplication, quality assessment or metabolomics will illustrate the latest analytical strategies employed.

harmacokinetic studies have become an integral part of modern drug development, but these studies are not regulatory needs for herbal remedies. This paper highlights the pharmacokinetic properties and disposition pathways of commonly used plant natural products and the possible clinical and toxicological implications. For a plant natural product, the pharmacological effect is achieved when the bioactive agents or the metabolites reach and sustain proper levels at their sites of action. Both the dose levels and fates of active components in the body govern their target-site concentrations after administration of a herbal product. In this regard, a safe and optimal use of herbal products requires a full understanding of their pharmacokinetic profiles. Recently, there are increasing pharmacokinetic studies of herbal products, but these studies are mainly focused on a small number of herbal remedies including St John's wort, milk thistle, curcumin, echinacea, danshen, ginseng, ginkgo, and ginger. For the majority of herbal remedies used in folk medicines, data on their disposition and biological fate in humans are lacking or in paucity. Many herbal compounds undergo Phase I and/or Phase II metabolism in vivo, with cytochrome P450s (CYPs) and uridine diphosphate glucuronosyltransferases (UGTs) playing a major role. Some herbal ingredients are substrates of P-glycoprotein which is highly expressed in the intestine, liver, brain and kidney. As such, the activities of these drug metabolizing enzymes and drug transporters are determining factors for the in vivo bioavailability, disposition and distribution of herbal remedies. To optimize the use of herbal remedies, further clinical studies to explore their biological fate including the disposition pathways and kinetics in the human body are certainly needed.