Natural products anti-tumor activity

Taxol has had a most unusual clinical development history. As with many natural products that have been discovered to provide therapeutic benefit to humans, it was the extract of a plant that provided the first hint of the oncological potential of this product. Natural product chemists typically subject purified plant extracts to screening for therapeuhc achvity. In 1963, an extract of the bark of the Pacific yew tree (Taxus brevifolia (Figure 7.2) showed anti-tumor activity. This early work was done by Monroe Wall and Monsukh Wani of the Research Triangle Institute (RTI) under the auspices of the National Cancer Institute (NCI) [3]. 

Recent studies further suggest that LF may have a role in the development and progression of tumors (Tsuda et al., 2002). Orally administered bovine LF has been found to inhibit the development of tumors in the colon, oesophagus and lung carcinogenesis in a rat or mouse model, but the mode of action remains to be resolved (Sekine et al., 1997 Ushida et al., 1999 Kuhara et al., 2000). The anti-tumor activity may be mediated by the enhanced cytokine production or the activating effect on natural killer cells and be independent of the iron-saturation level. 

Recently it was demonstrated that transfection of tumor cells with an antitumor peptide induced a protective immune reponse. Inoculation of mice with murine BD-2-transfected leukemia cells enhanced cytotoxic T lymphoc)des (CTL) and natural killer (NK) anti-tumor activity, with augmented IL-12 and IFN-y production. Animals vaccinated with transfected cells were protected against a challenge with parental cells (50% protection) and the vaccination generated leukemia-specific memory CTL [210]. 

The AD reaction was central in the preparation of (+)-cw-sylvaticin 41,27 a natural product found to have potent anti-tumor activity. The ability of this compound to inhibit ATP production by blockade of the mitochondrial complex I was thought to be the origin of this biological outcome. The AD reaction, in this example, exploited the preference of this reaction for the oxidation of 1,2-frans-alkenes over monosubstituted alkenes. The E,E-isomer of tetradecatetraene 42 could be chemoselectively dihydroxylated at both internal alkenes, while the terminal alkenes remained untouched. Thus, 43 was generated in excellent chemical yield. 

Diazo compounds (natural). Various types of D. c. occur in nature. Thus, derivatives of diazoacetic acid ( azaserine) and diazoketones ( 2-amino-6-diazo-5-oxohexanoic acid) are known as metabolic products of streptomycetes with anti-tumor activity. Quinonedi-azide ( 4-diazo-2,5-cyclohexadien-1 -one) and phenyl-diazonium salts [ 4-(hydroxymethyl)benzenediazo-nium ion] have been detected in the ffuitbodies of the mushroom genus Agaricus. Further biologically active... 

In the initial study we completed the total synthesis of (+)goniofufurone (3) (eq. 14) (30), the key component of styryl lactones which showed anti-tumor activities. As a first generation synthesis, we felt that even though it uses water as a solvent, it was still too long. Presently, we are developing a second generation synthesis in which only three steps are involved (Scheme 2). With this method, a variety of structurally related natural products, such as papulacandin D (9) andchactiacandin... 

MCF-7 and A-549 [1]. However, neither analogue displayed any significant anti-tumoral activity when compared to the natural product. The IC50 values are summarized in Table 3.1 and compared to the ED50 values of the natural product [1]. The most active compound was found to he (+)-8-muricatacin lb against a colon carcinoma cell line (HT-29). 

In the first chapter of this volume the wide variety of bioactive macrocyclic natural products is explored, including examples of those with clinically validated anti-infective and anti-tumor activity. Many of these natural products have been the subject of drug discoveiy efforts that have leveraged semi-synthesis, biosynthesis and total synthesis in order to investigate or optimize their pharmacological effects and viability as drugs. The medicinal... 

Due to its extraordinary anti-tumor activity, the antitubulin marine natural product halichondrin B (Figure 1.9, 81) was chosen for preclinical development in 1992 by the Developmental Therapeutics Program (DTP) at the NCI. However, clinical development was severely impeded due to the limited amounts of compound available from natural sources. 

C-H activation remains an important topic for catalysis even after thirty years of intensive research. The potential shortcuts it offers for many present routes to a wide variety of chemicals that are produced will continue to inspire industrial and academic research [32], An interesting example involves the enantiospecific, coordination-directed C-H bond functionalisation in the synthesis of a natural product, rhazinilam, an anti-tumor agent. The resulting vinyl moiety obtained in the dehydrogenation was subsequently carbonylated to form a cyclic amide [33],... 

The acridone alkaloids constitute a small group of natural products found exclusively in the Rutaceae family of higher plants. A sustained interest in this field has been due to the reported activity of acronycine a constituent of Acronnychia baueri and Vepris amphody as an anti-tumor agent. 

Encelin from Montanoa speciosa is inhibitory to growth and development of fungal cells of Mucor rouxii. Other cytotoxic sesquiterpene lactones from Montanoa tomentosa ssp. microcephala have been reported.45,46 A number of kaurane diterpenes and e/tf-kauranoids have been reported that are potentially useful because of their cytotoxicity against human tumor cells, anti-HIV activity, and trypanosomicidal activity.47 56 New structures are frequently discovered, and probably we will learn new effects in humans and animals in the future.57,58 Paradoxically, these plant natural products probably have specific and important effects in the plants, but we are still ignorant of these roles. 

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