Current Bioactive Compounds - Volume 5, Issue 1, 2009

Natural products isolated from plant, animal or fermentation have long been the main source for the chemotherapeutic intervention of cancer. However, in the later part of the 20th century, the advances of combinatorial chemistry have taken centerstage in the drug discovery process and natural product synthesis took a temporary backseat for these new chemical processes. Combinatorial techniques have resulted into large libraries in a very cost-efficient manner that can be screened for their biological activities. However, only a surprising low number of compounds found in such libraries have advanced to an FDA approved drug. This relative low success rate is primarily due to the lack of diveristy of new scaffolds with respect to their structural complexity, stereochemistry and chemical space. During the last decade, diversity oriented synthesis of small molecule libraries has become increasingly important in the search and development of new pharmaceutical leads. New synthetic methods are allowing for efficient and rapid production of highly diverse libraries of small yet complex molecules that can be screened for biological relevance. Screening of these libraries does not only lead to the identification of new drug leads, but also to potential new therapeutic protein targets and protein-drug interaction. These new leads can subsequently be optimized, by combinatorial chemistry, to generate new drug candidates. In order to maximize the potential of new scaffold libraries, the combination of natural product synthesis and diveristyoriented synthesis has resulted in a renewed focus on natural product inspired design of small molecule scaffolds. In this approach, common structural features found in natural product pharmacophores, are incorporated in a new scaffold libraries and tested for its biological relevance. In this context, the present issue highlights some of the recent trends with emphasis on natural product inspired scaffold syntheses.

The phenanthroindolizidine and phenanthroquinolizidine alkaloids, typified by tylophorine and cryptopleurine, are a family of plant-derived small molecules with significant therapeutic potential. The plant extracts have been used in herbal medicine and the isolated compounds have displayed a range of promising therapeutic activity such as antiameobicidal, anti-viral, anti-inflammatory and anti-cancer activity. Despite their therapeutic protential, no compounds in this class have fully passed clinical trials. Drawbacks include low in vivo anti-cancer activity, central nervous system toxicity and low natural availability. A number of biological effects of these compounds, such as protein and nucleic acid synthesis suppression, have been identified, but the specific biomolecular targets have not yet been identified. Significant effort has been expended in the synthesis and structure-activity-relationship (SAR) studies of these compounds with the hope that a new drug will emerge. This review will highlight important contributions to the isolation, synthesis, SAR and mechanism of action of the phenanthroindolizidine and pheanthroquinolizidine alkaloids.

Natural products and small molecules inspired by them are enjoying a resurgence of interest because they intersect biological space effectively and selectively. On account of their unprecedented structural diversity and biological activities oxindole natural products continue to attract the interest of chemists and biologists alike. Quarternary or spirocyclic 3-alkyl(aryl)-3-hydroxy-2-oxindole scaffold is at the core of several natural products with a wide spectrum of biological activities. Convolutamydines, arundaphine, donaxaridine, maremycins, paratunamide, celogentin K, TMC-95AD, neuroprotectin B, flustraminol A and B, 3-hydroxy welwitindolinones and pyrrolidinoindoline-type alkaloid, CPC-1 are some examples of a growing list of bioactive 3-substituted-3-hydroxy-2-oxindole natural products. Simultaneous with the extraordinary progress in the development of selective synthetic methods, a number of drug discovery programs have now started to recognize the importance of this ‘privileged’ scaffold, because of the potent anti-oxidant, anti-cancer, anti- HIV, neuroprotective and other biological properties and diverse modes of action of this class of natural products and analogs inspired by them. There is strong impetus for the continued synthesis of novel diversity libraries based on the 3- substituted-3-hydroxy-2-oxindole core for the potential treatment of proliferative and other diseases and a clear understanding of underlying cellular pathways involved. In fact, this process is well underway as exemplified by the recent synthesis of novel spirocyclic tetrahydrofuran- and isoxazolidine-2-oxindole libraries capable of achieving growth inhibition of lung adenocarcinoma (A549) cells, hepatocellular carcinoma (HepG2) cells and human breast cancer cell line, MCF-7. This review covers the isolation, diverse structure, activity, synthesis, and known medicinal chemistry of 3- substituted-3-hydroxy-2-oxindoles.

This review will focus on the ability of the 2-aminoimidazole to occupy a unique subset of chemical space which makes it an ideal pharmacophore for the development of small molecule collections for discovery based research. These observations rely both on the use of 2-aminoimidazoles as building blocks in medicinal chemistry as well as the recent discovery of alkaloids from sponges of the genus Leucetta which exhibit a diverse range of biological activities around a relatively limited structural core. The preparation of these compounds will also be highlighted.

The tumor vasculature is quite an attractive target for anti-cancer/anti-tumor therapy because the blood vessels provide the route for nutrient/waste and oxygen/carbon dioxide exchanges as well as a convenient route for tumor metastatic spread. The complex interplay of the tumor with the local blood vasculature is intriguing. Targeting the vasculature in an effort to control the tumor life cycle is therefore very complex yet enticing as a treatment option. In reviewing the literature discussing vascular targeting/disrupting agents, it is sometimes less than clear as to what exactly defines or differentiates a vascular targeting agent (VTA; antiangiogenic or stopping tumors from producing new blood vessels) from a vascular disrupting agent (VDA; disrupting the "established" tumor vasculature). Although, there appears to be differences between these two strategies of modifying the tumor vasculature including differences in the administration schedules. The use of the VTA/VDA terms in scientific reports is not always clear since some agents may also exhibit activities attributed to a VTA and/or a VDA. However these agents are defined, the important goal is to severely cripple and/or “shut-down” the tumor's ability to maintain viability and to subsequently become metastatic and hence are important in the armamentarium of anti-tumor/anti-cancer treatment strategies. This brief review of selected literature reports attempts to summarize some of the chemical structural elements associated with these types of agents and asks the question “Are there common chemical structural features emerging that may assist in a differentiating theme?”