Natural anticancer

Although data presented in the previous section illustrate the diversity of cycloaromatization reactions, most of the following discussion will concentrate on the Bergman cyclization - a reaction that has been studied intensively in recent decades due to its role in the mechanism of biological activity of natural anticancer antibiotics.8,9 We will take advantage of the large body of data produced by this... 

D. auricularia is a shell-less mollusk that, therefore, initially appears to lack defenses against predators however, this is only a preliminary supposition. Accumulated evidence supports the fact that Opisthobran-chia mollusks have developed very powerful chemical defenses (Pettit et ah, 1989). Pettit et al. (1981) were the first to isolate some of these compounds the pentapeptide dolastatin 10 (Fig. 5.1) was reported to be the most active natural anticancer substance at that time with an ED50 of 4.6x 10 5pg/mL against the P388 cell line (Pettit et al., 2008). Dolastatin 10 was also shown to inhibit tubulin polymerization and tubulin-dependent GTP hydrolysis (Bai et al., 1990). 

Since the 1950s, using a different approach, the U.S. National Cancer Institute, as well as agencies in other countries, has sought to find natural anticancer compounds in plants, fungi, microorganisms, and marine invertebrates. Among these are many antibiotics that intercalate into DNA helices, e.g.,... 

Lau, D.H. et al. (1989) Association of DNA cross-linking with potentiation of the morpholino derivative of doxorubicin by human liver microsomes, J. Nat. Cancer Inst. 81, 1034-1038. Rumyantseva, G.V. et al. (1989) Hydroxyl radical generation and DNA strand scission mediated by natural anticancer and synthetic quinones, FEBS letters 242, 397-400. 

However, in the skin, vitamin D is also activated by oxidation, and an excess of quenching of this oxidation, due to high concentrations of /3-carotene in the skin, may reduce the amount of vitamin D availability. This is not only important for bone construction, but also because vitamin D represents a powerful natural anticancer agent. This can be an explanation why an increase of lung cancer was found in Finland (country with relative lack of sun), where smoking people and subjects with asbestosis were treated with /3-Carotene and Retinol Efficacy Trial. Concomitantly in ATBC, ischemic episodes were more severe due to the very high dosage of /3-carotene, which can become pro-oxidant. 

Yang, H., Shi, G., Dou, Q. P. (2007). The tumor proteasome is a primary target for the natural anticancer compound withaferin A isolated from Indian winter cherry. Mol. Pharmacol., 71,426-437. 

After their discovery, the Vinca alkaloids became the first natural anticancer agents to be clinically used, and they are still an indispensable part of most curative regimens used in cancer chemotherapy nowadays. On the other hand, the plant producing these alkaloids, C. roseus, has become one of the most extensively studied medicinal plants. The levels of vincristine and vinblastine in the plant revealed to be extremely low and, for pharmaceutical production, approximately half a ton of dry leaves is needed to obtain 1 g of vinblastine [4]. This feet stimulated intense investigation in alternative methods for the production of vinblastine and vincristine, namely chemical synthesis and plant cell cultures. However, chemical synthesis showed not to be viable due to the high number of transformations involved, and the anticancer alkaloids were never detected in cell cultures, which express alkaloid metabolism very poorly [5, 6]. The biosynthetic pathway of terpenoid indole alkaloids in C. roseus has also been intensively studied with the objective of developing a manipulation strategy to improve the levels of the anticancer alkaloids in the leaves of the plant [5, 7-10]. 

In addition, formation of cancer cells in human body can be directly induced by free radicals and natural anticancer drugs as chemopreven-tive agents have gained a positive popularity in treatment of cancer. Therefore, marine algal radical scavenging compoimds such as phloro-taimins, sulfated polysaccharides, carotenoids, carbamol derivatives can be used indirectly to reduce cancer formation in the female body. 

Rifamycin - mode of action, resistance, and bios5mthesis 05CRV621. Studies on natural anticancer macrolactones cryptophycins and their mimetics 06CJO27. 

A. McLachlan, N. Kekre, J. MeNulty, and S. Pandey, Pancratistatin a natural anticancer compound that targets mitoehondria speeifieally in eaneer cells to induce apoptosis. Apoptosis, 10 (2005) 619-30. 

Iridium(lll) complexes, especially those with polypyridine ligands, as therapeutic and bioimaging reagents for cellular applications 12RCA12069. Isolation, biological activity and synthesis of the natural anticancer product eUipticine and related pyridocarbazoles 12RCA8883. 

Cyclizations of substructure type C (Figure 6.3) are also used in total synthesis of natural products bearing five-membered heterocycles, as shown by the example of (S)-camptothecin (83), a natural anticancer agent (Scheme 6.23) [71]. This pentacyclic alkaloid was synthesized in 10 steps, the last one being a 5-exo-intramolecular Mizoroki-Heck reaction. 

The (2i ,3i )-hydroxy-a-methyl ester was further converted into the expected natural anticancer agent, (2i ,3i )-dolaproine. 

Antimetabolite Metabolism and Natural Anticancer Agents, (ed. Powis, G.), Pergamon Press, 1994, 364 (rev)... 

During the last 60 years, unique classes of natural anticancer compounds have been isolated from plants. These plant products, represented by the Vinca and Colchicum alkaloids, as well as other plant-derived products such as paclitaxel (Taxol) and podophyUotoxin showed great promise for new drug discoveries based... 

The discovery of the novel diterpenoid anticancer agent taxol in 1971 by Monroe Wall and his collaborators ranks in retrospect as one of the most significant discoveries ever made in the field of naturally occurring anticancer agents. Although extensive researches have been done on natural anticancer agents, only a handful of plant-derived natural products have been found to show clinically useful activity, and taxol is clearly a member of this group. 

Lemeshko, V.V., Haridas, V., Quijano Perez, J.C., and Gutterman, J.U. (2006) Avicins, natural anticancer saponins, permeabilize mitochondrial membranes. Arch Biochem Biophys 454 114-122. 

The spiroacetal moiety is another frequently occurring structural element occurring in potent natural anticancer substances, such as spongistatin. The groups of Paterson [35,36] and Waldmann [37] have been the first to successfully synthesize Ubraries of this privileged structure using enantioselective aldol reactions—a reaction type which turned out to be difficult for implementation on sohd phase (Scheme 15). 

Rodriguez, 1. Kohler, B. and Metz, Y, Carhon-14 labeling of discodermolide, a natural anticancer product. Internal Report, 2001, Novartis Pharma AG. 

Howard, B.M., Clarkson, K., and Bernstein, R.L. (1979) Simple prenylated hydroquinone derivatives from the marine urochordate Aplidium califomicum natural anticancer and antimutagenic agents. Tetrahedron Lett., 46, 4449-4452. 

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