Current Topics in Medicinal Chemistry - Volume 9, Issue 16, 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 the two themed issues (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. In this issue, six reviews are presented. The first review by Ghosh et al. focuses on antitumor antibiotics such as CC-1065, duocarmycin, and yatakemycin. The mode of actions of these natural products and their chemically synthesized analogs are reviewed, followed by the coverage of progress in bioconjugation and prodrug formation as examples to extend the scope of drug development from natural products. Also related to microbial diversity, Li et al. discussed the potential of exploiting this genetic reservoir based on metagenomics research and its implication in drug discovery from numerous non-culturable microorganisms. Marine natural products are the most exciting source of novel compounds in drug discovery nowadays. Chakraborty et al. highlighted recent research on some of the anticancer natural products from various families of marine organisms. Marinebased low molecular weight and oligomeric chitosan and their biological activities are also reviewed by Yin et al., and their potential application as nutraceutical ingredients for chronic diseases discussed. In the area of reviews covering bioactive natural products from terrestrial plants, Acuna et al. provided a comprehensive coverage of polyisoprenylated benzophenones from Clusiaceae and their various biological activities such as antioxidant, antiinflammation, antimicrobial, and cytotoxic, and the related cellular and molecular mechanisms. Pentacyclic triterpenoids and saponins are common natural products presented in herbs of traditional medicines, their apoptosis-inducing activity and the structure-activity relationships and the potential antitumor application are reviewed and discussed by Wang et al. 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.

CC-1065, the duocarmycins and yatakemycin are members of a family of ultrapotent antitumour antibiotics that have been the subject of extensive investigations due to their mode of action and potential in the design of new anticancer therapeutics. The natural products and their analogues exert their effects through a sequence selective alkylation of duplex DNA in the minor groove at the N3 of adenine. An understanding of their structure and its effect on biological activity has been derived through chemical synthesis and has also generated new potential lead compounds. These studies form the first section of the review. The desire to progress these compounds to clinic has also led to studies of bioconjugation and prodrug formation and this is discussed in the second section of the review. The combination of synthesis with key biological experiments is a powerful tool to define the requirements for the development of natural products as potential therapeutic agents. The studies described herein form an excellent paradigm for the study and development of other natural products.

Microorganisms of millions species exist in every corner of the Earth, and form a dynamic genetic reservoir that are not clearly revealed and categorized due to barrier in current cultivation technology. Their applications in biomedical and environmental aspects are more than satisfactory. However, the situation has drastically changed during the turn of the century because of the rapid development of phylogenetic studies based on rRNA sequencing independent of standard laboratory cultivation. More recently, high throughput sequencing technology which enables direct sequencing of community DNA for metagenomic analyses are making a direct impact on our understanding of microbial diversity, ecology, and secondary metabolism. In this review, we highlight some recent progress and innovation on metagenomic research with an emphasis on natural product drug discovery. The rapid path of accumulating decoded metagenomics would be an efficient guide on direct access to the genomes of numerous non-culturable microorganisms for their genomic diversity and associated chemical prosperity for potential medicinal applications.

The chemical and biological diversity of the different marine evolutionary group is endless and therefore, this is an amazing resource for the discovery of new anticancer drugs. Comprising 34 of the 36 Phyla of life, marine ecosystems are indeed our last genetic diversity and biotechnological boundary; terrestrial systems possess only 17 Phyla. Sponges, coelenterates and microorganisms are the foremost resources of therapeutic compounds. Algae, echinoderms, tunicates, mollusks, bryozoans are also the sources of anticancer drugs from marine resources. We highlight the past and current status of marine anticancer pharmacology using different marine groups.

Chitosan is one of the most abundant marine-based biopolymers. Low molecular weight and oligomeric chitosans are water-soluble hydrolysates of chitosan. They have been shown to have a wide range of biological activities and industrial applications. In particular, low molecular weight and oligomeric chitosans have been reported to have the health benefits such as immunity regulation, anti-tumor, liver protection, blood lipids lowering, anti-diabetic, antioxidant and anti-obesity. In this paper, the preparation and analytical methods, and bioactivities of these low molecular weight and oligomeric chitosans were reviewed, with the latest progresses introduced and discussed.

Many new polyisoprenylated benzophenones with a bicyclo[3.3.1]-nonane-2,4,9-trione core structure have been isolated from plants in the Clusiaceae family, and their potent biological properties have been the subject of several studies. This review summarizes the biological activities reported for these secondary metabolites including cytotoxic, antimicrobial, antioxidant, and anti-inflammatory activities. Our efforts during the past years have foremost been directed towards isolating new polyisoprenylated benzophenones, as well as understanding the possible target and mechanism of action through which these compounds arrest cancer cells and inhibit the progression of the cell-cycle. The transcription of genes is affected in cancer cells treated with polyisoprenylated benzophenones; the oncogene c-Myb is down-regulated and endoplasmatic stress genes XBP1, ATF4, and DDIT3/CHOP are turned on. Consequently, the expression of iNOS and cell cycle regulators such as cyclin D and E are reduced. Evidence presented by independent investigators suggests that polyisoprenylated benzophenones affect the mediators in the Akt/mTOR stress pathway, although the specific target remains to be discovered. In addition, benzophenones isolated from plants display high antioxidant capacity and protect cells from oxidative stress and the formation of ROS involved during the inflammatory process. Since antiviral activity was initially reported for guttiferone A, potent synthetic analogues have been developed as effective new non-nucleoside reverse transcriptase inhibitors (NNRTI) to treat drug resistant HIV-1. In addition, benzophenones exert antimicrobial effects particularly against MRSA. The structure-activity relationships of polyisoprenylated benzophenones from natural sources and those of synthetic analogues are included in this review. Absorption, metabolism, and elimination of benzophenones are also discussed.

Pentacyclic triterpenoids exert their antitumor activity through different mechanisms, one of which is apoptosis induction. Although there are many reports on the apoptosis inducing activity of pentacyclic triterpenoids, a systematic survey and discussion on their structure-activity relationships (SARs) is still lacking. In this review, we summarized such activity of oleanane, ursane and lupane type triterpenoids, the most abundant pentacyclic triterpene prototypes in plants. Their structural characteristics responsible for the activity are also discussed, in order to unravel their SARs for the apoptotic induction and benefit further investigations on the antitumor triterpenoids.