Current Topics in Medicinal Chemistry - Volume 9, Issue 17, 2009

Natural products have been used for thousands of years in human history for prevention and treatment of diseases, or for maintaining general wellness. Bioactive natural products are also the important sources of many current therapeutic agents, either in original forms or derivatives made from the natural lead compounds. During the past decades, new tools and strategies such as the combinatorial chemistry, high-throughput screening and computer-aided drug design have been introduced into drug discovery and development process and this certainly helps accelerating the pre-clinical studies in pharmaceutical industry. On the other hand, however, pharmaceutical industry is still in great need of the unique chemical diversity and biological relevancy observed in the natural products, resulting from millions of years' evolution. The chemical diversity of natural products comes from the biodiversity of organisms on earth. As such, the topics for these two themed issues on bioactive natural products (issues 16 and 17) would reflect this type of diversity and cover natural products from microbes to higher plants and from marine to terrestrial environment. As a continuation to issue 16, we are delighted to offer the CTMC readers another five reviews as follows. For the microbe-derived natural products, Zhan provided overview on the recent progress in biosynthesis research of bioactive aromatic polyketides from microorganisms with a focus on new enzymes or methods used in building the novel polyketide biosynthetic machinery. Natural products and herbal remedies for treatment of allergic inflammation, such as allergic rhinitis are reviewed by Kulka with discussions on their molecular mechanisms. This unique pharmacological perspective of bioactive natural products emphasizes the importance of biological activity - novel chemical structure is exciting, but new therapeutical applications are equally valuable. Bioactive natural products are important lead for drug discovery, and many therapeutic agents actually come from the chemical derivation and synthesis based on the natural leads. Dai provided in-depth coverage on a chemo-enzymatic transformation of taxanes, and the reversal activity towards multidrug resistance (MDR) tumor cells. These works demonstrate a powerful approach for natural products-based lead compound discovery by combining biotransformation with chemical conversion in structure diversification of natural products. In the review by Chen, the synthesis as well as biological activity of nordihydroguaiaretic acid and its derivatives, which have been extensively explored for their potential uses in the treatment of cancers, diabetes, viral, bacterial infections, and inflammation, are comprehensively documented. In closing this issue, Chang et al. reviewed the synthesis and biological activity of Wuweizisu C and analogues, lignans from a popular Chinese medicinal herb, illustrating this successful drug discovery strategy of combining ethnopharmacological knowledge and modern medicinal chemistry technology. Finally, we would like to thank Dr. Allen B. Reitz, for the invitation to be the Guest Editor of this special issue. We wish to offer our sincere appreciation to all the contributors for their dedication and hard work.

Aromatic polyketides represent important members of the family of polyketides, which have displayed a wide assortment of bioactive properties, such as antibacterial, antitumor, and antiviral activities. Bacterial aromatic polyketides are mainly synthesized by type II polyketide synthases (PKSs). Whereas malonyl-CoA is exclusively used as the extender unit, starter units can vary in different aromatic polyketide biosynthetic pathways, leading to a variety of polyketide backbones. Once the polyketide chains are elongated by the minimal PKSs to the full length, the immediate tailoring enzymes including ketoreductases, oxygenases and cyclases will work on the nascent chains to form aromatic structures, which will be further decorated by those late tailoring enzymes such as methyltransferases and glycosyltransferases. The mechanistic studies on the biosynthetic pathways of aromatic polyketides such as oxytetracycline and pradimicin A have been extensively carried out in recent years. Engineered biosynthesis of novel “unnatural” polyketides has been achieved in heterologous hosts such as Streptomyces coelicolor and Escherichia coli. This review covers the most recent advances in aromatic polyketide biosynthesis, which provide new enzymes or methods for building novel polyketide biosynthetic machinery.

The impact of natural products on human health has been enormous, and the study of natural products continues to influence research in the fields of chemistry, biology, and ecology. Historically, the majority of our medicines originate from natural products and their synthetic derivatives, many of which have taught us valuable lessons about biology. While advances in synthetic and combinatorial chemistry have given rise to notable successes in the development of new drugs, the perceived value of natural products in the treatment of allergic disease has yet to be fully explored. The immune system is a highly complex, intricately regulated group of cells whose integrated function is essential to health. Cells of the immune system may interact in a cell-cell manner and may also respond to intercellular messages including hormones, cytokines, and effector molecules produced by various cells. These effector molecules include histamine, kinins, leukotrienes, prostaglandins, and serotonin. The immune system can be modified by diet, pharmacologic agents, environmental pollutants, and naturally occurring food chemicals, such as vitamins and flavonoids. Allergic inflammation is mediated by several types of immune cells all of which can be effected by these naturally occurring bioactive compounds but this review will focus on mast cells and their mediators since these cells are the focal point of allergic reactions such as allergic rhinitis. The molecular mechanisms and scientific validity of some herbal remedies currently used clinically in the treatment of allergic rhinitis will be explored.

Over 200 derivatives have been obtained through chemo-enzymatic transformation of the taxanes derived from cell cultures of Taxus chinensis. The reversal activity towards MDR tumor cells and cyto-toxicity of most these compounds were evaluated, and several derivatives exhibited powerful MDR reversal activity. The substrate-specificities of the two most important biotransformation reactions-C-7β and 9α hydroxylations, were investigated and preliminarily concluded. In addition, some key intermediates in hypothetically biosynthetic pathway of taxoid were obtained. These results indicate that biotransformation combined with chemical transformation is a powerful approach to structural diversification of natural products, lead compound discovery and the study on the structure activity relationships of the derivatives. Moreover, biotransformation may mimic some steps in biosynthetic pathway of natural products and provide useful hints as to their biogenetic study.

Nordihydroguaiaretic acid is a natural occurring lignan mainly isolated and commercially produced from desert plant, creosote bush (Larrea divaricata Cav. Or Corillea tridentate), which can be widely found in the border zone of southern of USA and northern of Mexico. During past 100 years, extensive research has demonstrated that nordihydroguaiaretic acid and its synthetic analogues are potentially useful in treating diseases related to cancers, diabetes, viral, bacterial infections, and inflammation. Remarkably, terameprocol, a tetra-O-methyl derivative of nordihydroguaiaretic acid, is currently in Phase I/II clinical trials as an anticancer agent. This review deals with the chemical synthesis and bioactivities of nordihydroguaiaretic acid and its structurally-related derivatives, which possess anticancer, antioxidant, antimicrobial, anti-inflammatory and immunosuppressive activities. The review consists of the data reported in over 100 publications.

Lignans are widely distributed in nature. The earliest recorded medicinal use of lignans dated back to over 1000 years ago. Lignan-rich plant products were also active ingredients in Chinese and Japanese folk medicines for the treatment of various diseases. The dried root and stem of this plant are listed in the Chinese pharmacopoeia for the treatment of rheumatoid arthritis, gastric, duodenal ulcers and many other diseases. This review highlights synthetic strategies for the Wuweizisu C analogs and the important pharmacological activities as well as therapeutic findings related to the treatment of HBV and other diseases. Notably a significant and ongoing project on Wuweizisu C and its analogs has led to the discovery and development of two potent derivatives α-DDB and BICYCLOL which are currently in clinical trials against HBV, especially in lowering elevated SGPT levels. Further design, synthesis, and evaluation of Wuweizisu C analogs are discussed.