Current Medicinal Chemistry - Volume 10, Issue 21, 2003

Natural products are the valuable source of structurally diverse compounds which possess therapeutic potential for treatment of human diseases. Many of the clinically used therapeutic agents are of natural products origin, used either in the naturally occurring forms or as the derivatives or analogs after structural optimization. The influence of natural products upon drug discovery has been well recognized and documented. Natural products have been the source of inspiration to drug discovery and are believed to continue playing an important role in future. It is the aim of this special issue on Natural Products as an Inexhaustible Source for Drug Discovery to illustrate the successful examples of modern drugs derived from natural products and to highlight new trends in drug lead discovery and molecular target information mining based on the structural diversity of natural products. Selection of the reviews for this special issue of Current Medicinal Chemistry was made largely based on the topics of invited lectures delivered at The Third International Symposium for Chinese Medicinal Chemists (ISCMC-2002) held during December 28-31, 2002 at HKUST, Hong Kong SAR, China. The first two reviews highlight the contribution of traditional Chinese medicine (TCM) to modern treatment of disease. The comprehensive review by Y. Li and Y.-L. Wu covers the updated knowledge and progress on chemistry, pharmacology and mode of action of the antimalarial herbal principle, Qinghaosu (Artemisinin). In particular, recent results on molecular targets of Qinghaosu action were presented as well as medicinal applications of Qinghaosu and derivatives other than the antimalarial drug. Huperzine A, an acetylcholinesterase inhibitor, is another excellent example of modern drug originated from TCM for treatment of the Alzheimer's disease. The updated review by D. Bai et al. covers recent progress made during 1999-2002 in clinical, pharmacological and chemical studies on Huperzine A with an emphasis on structural biological advancement with X-ray crystallography and molecular modelling studies on the complex of Huperzine A with acetylcholinesterase. The third review by X. Hao et al. summaries a systematic study on the chemical principles of Spiraea japonica complex consisting of seven varieties from the Yunnan Province of China. The results form the basis for a chemotaxonomy study on the complex. Moreover, some diterpene alkaloids were revealed to exhibit promising anti-inflammation, anti-platelet aggregation and neuroprotective activities. The fourth review on enediyne prodrugs by W.-M. Dai illustrates an example of drug design inspired by the mode of action of natural products. A unique strategy toward in situ formation of 10-membered ring enediynes was demonstrated via rearrangement of an allylic double bond, supported by the biological results and LC-MS analysis of the reaction products. Molecular structural diversity has becoming a major concern in drug lead discovery and optimization in recent years. Combinatorial libraries are required to possess natural products-like structural elements for increasing lead hints rate and drugable compounds. The following two reviews outline the state-of-the-art of chemical and biological combinatorial synthesis of structurally diverse compounds of natural products relevance. The team of Z. Yang et al. presents an excellent review on the metal-catalyzed carbon-carbon bond formation reactions applied to the diversity-oriented synthesis of natural product scaffolds using solid phase combinatorial chemistry. Valuable know-hows on selection of synthetic strategy and development of synthetic chemistry are provided. The review by B. Shen et al. highlights the recent advancement in enediyne biosynthesis covering the methodologies developed, the findings achieved so far, and more excitingly, the opportunities for a combinatorial biosynthesis of novel enediynes. The final review by H. Jiang et al. demonstrates the power of computational chemistry methodology applied to drug lead discovery and molecular target information mining. The virtual screening approach using natural product database takes the advantage of molecular docking and structural diversity of natural products, in particular the knowledge of active chemical principles and associated medicinal applications of TCM. Successful examples and the methodologies used are outlined. It is hoped that the scientists involved in natural products and the related research fields will find the selection of these reviews, covering from traditional medicinal chemistry methodologies to new frontiers in drug discovery, is beneficial and informative. I would like to thank the authors for their valuable contributions to this special issue. I also would like to dedicate this issue to Prof. Wei-Shan Zhou, a pioneering practitioner in the chemistry of Qinghaosu, of Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, on the occasion of his 80th birthday.

This article reviews the discovery and the further studies on qinghaosu and its derivatives or analogs over the last decades in the fields of medicinal chemistry and some pharmacology research, with an emphasis on the progress achieved in China.

HupA is a potent, reversible AChEI, which crosses the blood-brain barrier smoothly, and shows high specificity for AChE with a prolonged biological half-life. It has been approved as the drug for the treatment of AD in China, and marketed in USA as a dietary supplement. HupA has been the subject of investigations by an ever-increasing number of researchers since 1980's. In the last four years, HupA has been further studied in many aspects such as the chemical synthesis, structural modification, structureactivity relationship, various biological effects, and mechanisms of action. A number of papers dealing with the computational modeling and X-ray crystallographic studies of HupA-AChE complex have also been published. This review represents a comprehensive documentation of the progress in the studies on HupA during the period of 1999-2002.

The characteristic components of Spiraea japonica complex, which consists of seven varieties, are the hetisine- and atisine-type diterpene alkaloids, and the atisanetype diterpenes. From this complex, 20 hetisines, 37 atisines and 7 diterpenes were isolated during 1964-2001, including the observations of the isomerization of spiraea diterpene alkaloids having the oxazolidine ring and the interconversion of the oxazolidine rings, the configuration of the oxygen substitution at C-15 of the atisinetype alkaloids, and the interconversion relationship between the two main subtypes of the hetisine-type alkaloids. The chemotaxonomy based on structures of the reported diterpene alkaloids were suggested. The studies on the anti-inflammation, anti-platelet aggregation and neuroprotective bioactivities of the alkaloids from S. japonica var. acuta were reviewed as well.

Cyclodeca-1,5-diyn-3-ene, the parent core of naturally occurring 10- membered ring enediyne antitumor antibiotics, decomposes at 37°C with a t1 / 2 value of 18 h. A prodrug approach was envisaged by in situ formation of the core structure via rearrangement of an allylic double bond. Three synthetic methods including intramolecular lithium acetylide addition to aldehyde, intramolecular Nozaki-Hiyama- Kishi reaction, and intramolecular Sonogashira cross-coupling have been established for synthesis of the enediyne precursors, (E)-3-acyloxy-4-(arylmethylidene)cyclodeca- 1,5-diynes. The latter are transformed into 10-membered ring enediynes in the presence of a catalytic amount of Ln(fod)3 under mild reaction conditions. Alternatively, the enediyne precursor dissociates in buffer solution into an allylic cation or a quinone methide intermediate, which reacts with a nucleophile (such as H2O) to form the bioactive enediyne. LC-MS data confirmed formation of the 10-membered ring enediyne from the precursor, which exhibits DNA cleavage activity and cytotoxicity against P388 cancer cell line.

Combinatorial chemistry can be used to synthesize diversified molecules on a large scale. As with all large-scale experiments, this process requires a major investment in equipment, consumables and time. Therefore, careful design is critical. As the complexity of the libraries to be generated increases, additional considerations become important. What are the issues that should be considered when planning combinatorial chemistry projects? Which features in the design strategy are critical to consider ensuring that all of the potential products will be synthesized? How are the reactants selected to optimize product synthesis and yield? Over the last several years, through an experimental process, we have successfully developed and optimized our synthetic strategy. Our approach incorporates a number of critical components into a tightly controlled process that generates molecules with maximal structural complexity. This complexity emanates from carbon-carbon bond formation, which is extremely stable and it is reminiscent of complex natural product molecules. Our studies have illustrated that transition metal catalysts are powerful reagents that can be used to drive the synthesis of diverse small molecules from less complex starting materials. In this review, we will describe some of our recent efforts to synthesize natural product-like molecules and their derivative structures to successfully create libraries of complex molecules for drug discovery applications. Our diversityoriented synthesis methods incorporate transition metal catalysts, as a versatile tool for creating carboncarbon bonds and structural complexity, and the branched reaction pathway, as a method for incorporating diversity into the molecular scaffolds. We will review our combinatorial chemistry program, focusing on the decisions that we made for (1) the scaffold selection; (2) the design of a diversity oriented approach for library synthesis; (3) the incorporation of the branched reaction pathway to generate natural product-like molecules from the same starting material; and (4) the process steps that we selected for chemistry development and library generation.

This review gives a brief account on the current status of enediyne biosynthesis and the prospective of applying combinatorial biosynthesis methods to the enediyne system for novel analog production. Methods for cloning enediyne biosynthetic gene clusters are first reviewed. A unified paradigm for enediyne biosynthesis, characterized with (a) the enediyne PKS, (b) the enediyne PKS accessory enzymes, and (c) tailoring enzymes, is then presented. Strategies and tools for novel enediyne analog production by combinatorial biosynthesis are finally discussed. The results set the stage to decipher the molecular mechanism for enediyne biosynthesis and lay the foundation to engineer novel enediynes by combinatorial biosynthesis for future endeavors.

Natural products, containing inherently large-scale structural diversity than synthetic compounds, have been the major resources of bioactive agents and will continually play as protagonists for discovering new drugs. However, how to access this diverse chemical space efficiently and effectively is an exciting challenge for medicinal chemists and pharmacologists. While virtual screening, which has shown a great promise in drug discovery, will play an important role in digging out lead (active) compounds from natural products. This review focuses on the strategy of virtual screening based on molecular docking and, with successful examples from our laboratory, illustrates the efficiency of virtual screening in discovering active compounds from natural products. On the other hand, the sequencing of the human genome and numerous pathogen genomes has resulted in an unprecedented opportunity for discovering potential new drug targets. Chemogenomics has appeared as a new technology to initiate target discovery by using active compounds as probes to characterize proteome functions. Natural products are the ideal probes for such research. Binding affinity fingerprint is a powerful chemogenomic descriptor to characterize both small molecules and pharmacologically relevant proteins. Therefore, this review also discusses binding affinity fingerprint strategy for identifying target information from the genomic data by using natural products as the probes.