Combinatorial Chemistry & High Throughput Screening - Volume 13, Issue 10, 2010

Medicinal herbs have been used to treat human diseases in China for thousands of years. There has been great interest in the research and development of bioactive components from herbal medicines. Significant pharmacological properties have been demonstrated for many herbs over recent decades. Not only important in China, herbal preparations are becoming increasingly popular in Europe and North America as complementary therapeutics. Traditional Chinese Medicine (TCM) is usually a mixture of herbal plants or extracts which comprise hundreds of different constituents with widely differing physiochemical properties. The qualification and quantitative analysis of active constituents from this mixture is often a challenging task especially when the relevant compounds might be present in minute amounts only. Additional challenge is batch-to-batch inconsistency of constituents due to the natural variability of the herbal plants. Thus, there is a substantial need to use modern bioassay and analytical techniques, including developing high throughput and sensitive technologies, to determine active constituents and to monitor the quality control of herbal medicines. The rapid growth in proteomics, genomics and metabonomics provides a lot of new tools for the integration of traditional Chinese medicine with modern technology and systems biology. This special issue aims at providing the readers of CCHTS with a perspective of the technology developments and their applications in the rapid progress of up-to-date research in TCM. I would like to express my thanks to all the contributors for their valuable articles and to the referees for their constructive comments as well as to Professor Rathnam Chaguturu, the Editor-in-Chief, for his continuing support during the preparation of this issue.

Throughout the centuries, traditional Chinese medicine has been a rich resource in the development of new drugs. Modern drug discovery, which relies increasingly on automated high throughput screening and quick hit-to-lead development, however, is confronted with the challenges of the chemical complexity associated with natural products. New technologies for biological screening as well as library building are in great demand in order to meet the requirements. Here we review the developments in these techniques under the perspective of their applicability in natural product drug discovery. Methods in library construction, component characterization, biological evaluation, and other screening approaches including NMR and X-ray diffraction are discussed.

The epidermal growth factor receptor (EGFR) has become an important molecular target in cancer therapy. Various small molecules and therapeutic antibodies targeting EGFR family members have been developed during recent years and are established in clinical oncology. However, increasing clinical application of EGFR tyrosine kinase inhibitors has resulted in the development of resistance to EGFR-targeting drugs due to the selection of EGFR-mutated variants. This phenomenon forced the search for novel EGFR inhibitors with activity towards EGFR-mutant tumors. This review describes recent achievements in natural products derived from medicinal plants as novel EGFR inhibitors.

Traditional Chinese medicines (TCMs), a key branch of natural medicines, play an important role in the treatment of diseases because of their reliable clinical performance. Identification of their active compounds constitutes a bottleneck in the development of TCMs. Screening and analysis of active compounds is a challenge in TCM research. This review summarizes recent progress in the development of biological fingerprinting strategies for screening and analyzing bioactive compounds in TCMs using molecular recognition, metabolism and omics tools. The evaluated strategies include the following techniques: microdialysis/centrifugal ultrafiltration-HPLC, biochromatography, metabolic fingerprinting analysis, 2-dimensional biochromatography and omics fingerprinting analysis.

Traditional Chinese medicines (TCMs) have been used for disease prevention and therapy in China for a long history and are becoming increasingly popular over the world. However, TCMs are complex mixtures and contain usually hundreds of chemically different constituents, which make the quality control of crude drugs and their medical preparations extremely difficult. Therefore, better analytical strategies to assure their efficacy, safety and consistency are in great demand. The present work provides an overview of the development of quality control for TCMs based on microscopic and molecular identification, quantitative and qualitative analysis, fingerprint, combination of fingerprint and multi-component quantification, as well as activity-integrated fingerprint over the last five years. The biological fingerprinting analysis of TCMs with targeting absorption, distribution, metabolism, excretion by chromatographic and chemometric method are also highlighted due to its broad application in the quality control of TCMs. The comprehensive methods analyzed with modern hyphenated techniques are strongly recommended to assess the authenticity, quality consistency and stability of TCMs.

Traditional Chinese medicine (TCM) has been used for more than 4000 years. By comparison with large combinatorial chemistry libraries and natural products of the West for high-throughput screening (HTS) of new drugs discovery, an advantage of TCM is that the preparation has clear efficacies on the therapy of some diseases. Although the effective components are not clear, the clear efficacies of TCM have been identified for long time practice, Therefore, TCMs should be valuable lead compound libraries with a definite therapy efficacy from the viewpoint of HTS. Nevertheless, current HTS technologies are not easily adapted to investigate TCMs because they are designed for screening a relatively pure known chemical at a known concentration. In contrast, TCMs are mixtures of unknown compounds in unknown concentrations that may differ markedly between samples from different plants. This article reviews the current and future researches on the enzyme inhibitors screening from TCM.

The use of chromatographic fingerprints from herbal products where the whole chromatographic profile is applied, is an approach to evaluate the quality of the investigated product. In this paper, recent developments in the set-up and data analysis of chromatographic fingerprints for herbal products are discussed. First, different set-ups for fingerprint development are reviewed. Prior to the fingerprint development, a suitable sample preparation, e.g. extraction, should be considered. In a second instance, this review focuses on the data analysis with regards to the different fingerprint applications. Usually, chemometric data pretreatment is necessary. This is discussed first, followed by a short overview of the data handling techniques used in the two main application areas of herbal fingerprints, i.e. quality assurance and classification or calibration. The quality assurance, involving identification and quality control of the herbal products, is reviewed, followed by the use of fingerprints in classification or modelling. The different application areas are illustrated and discussed with several case studies.

At present, high throughput screening (HTS) programs in drug discovery rely mainly on compound libraries from combinational chemistry. Similarly, natural flora has been used as a prominent origin for new and potent herbal drugs. Herbal medicines have been used worldwide for thousands of years to cure many diseases. As such, herbal secondary metabolites show a remarkable structural diversity that supplements chemically synthesized compound analogs in drug discovery screening. Unfortunately, there is often a considerable deterioration in the quality of herbal drugs in such screening programs as there are time-consuming manual processes involved in the isolation of active ingredients from the highly complex mixtures of herbal plant products. The quality and quantity of herbal samples are critical for the success of HTS programs. In the recent past, there have been substantial improvements in HTS due to the miniaturization and integration of microchip (e.g., Herbochip®, DNA chip, protein chip, cell chip, etc.)-based technologies so as to design herbal drugs that compete with synthetic drug analogs. Here we will review various technologies used for HTS of herbal medicines. Finally, we will summarize our efforts to develop a novel chip-based HTS assay to explore the antioxidant and radioprotective properties of herbal plants.

Counter-current chromatography (CCC) is a unique support-free liquid-liquid partition chromatography winning wide applications in the separation of various components from natural or synthetic mixtures. It has been one of the prime methods for isolating compounds from Traditional Chinese Medicines (TCM) and other comprehensive natural products. Although early CCC models produced a long-standing false image that CCC is a time-consuming technique, rapid and high-performance CCC devices and methods for high throughput analysis of natural mixtures have been advanced. For instances, multi-channel CCC, dual CCC, elution-extrusion CCC, and solvent simplification protocols can provide high throughput CCC analysis and produce high purity of compounds or large natural product libraries for drug discovery. This review summarizes the recent advancements of CCC in the high throughput analysis of natural product with an emphasis on the developments of instruments and methods.

Chromatographic fingerprinting technique of traditional Chinese medicine (TCM) has proved to be a comprehensive strategy for assessing the intact quality of herbal medicine. In general, one could use the chromatographic techniques to obtain a relatively complete picture of herbal medicines, which are in common called chromatographic fingerprints of herbal medicines to represent the so-called phytoequivalence. Based on this, the features of chromatographic fingerprints of herbal medicines have been discussed in some detail. The technique based on chromatographic fingerprinting is essentially a kind of high-throughput and integral tools to explore the complexity of herbal medicines. In order to further control the comprehensive quality of TCMs, some new strategies are proposed to trace the chemical changes of chromatographic fingerprints both in product processing and/or after their administration by modern chromatographic techniques and chemometrics. Combined with metabolomics, it seems possible for one to reveal the working mechanism of TCMs and to further control their intrinsic quality. Finally, the intensive study of chromatographic fingerprinting coupled with multivariate analysis tools developed in bioinformatics and chemometrics are emphasized in order to achieve the aim to reveal the working mechanisms of TCMs and to further control and strengthen TCM's intrinsic quality in a comprehensive manner.

Traditional Chinese medicines (TCMs) are generally mixtures of herbal plants or extracts which comprise hundreds of different constituents with widely difference in the content and physiochemical properties. In order to analyze bioactive compounds in TCMs and control the quality, a large number of analytical tools have been developed, among which capillary electrophoresis (CE) has become a powerful technique with increasing importance. Some formats of CE, including capillary zone electrophoresis, micellar electrokinetic chromatography, non-aqueous CE and capillary electrochromatography have been widely employed for the analysis of TCMs. The general characteristics of these formats are briefly described, and their applications to the analysis of TCMs during the past five years are summarized.

Ping Zhou holds an Honors MS in Botany from the Wuhan University, China (1994) and a Ph.D. in Analytical Chemistry (1997) from the same university. From 1997 to 1998, he worked at the Faculty of Pharmaceutical Sciences, University of Tokushima, Japan, as a foreign researcher in Pharmacognosy. He joined the Wuhan University as an associate professor in 1999. From 2008-2009, he worked at the Institute for Biological Sciences, National Research Council Canada, as a visiting scholar in biological mass spectrometry. He is the Vice Director of Centre for Analysis & Measurement of Wuhan University and the Vice Chairman of Young Academic Committee of Chinese Association for Instrumental Analysis. His scientific interests include separation and analysis of active biomolecules, capillary electrophoresis and biological mass spectrometry. Some selected publications are cited below.

Due to an oversight on the part of the authors, Emirhan Nemutlu, Sedef Kir, Hakan Eroglu, Doruk Katlan, Aykut Ozek, Ozgur Ozyuncu and M. Sinan Beksac, incorrect name of one of the co-author was published in the article entitled “Comparison of Pharmacokinetic Profiles of Moxifloxacin in Caesarean versus Non-Pregnant Sectioned Women by Fully Validated HPLC with Fluorescence Detection”, Combinatorial Chemistry & High throughput Screening, 2010, Vol. 13, Issue no. 6, pp. 502-509. The correct name of the author is Ozgur Ozyuncu instead of Ozgur Oyuncu.