Topoisomerases properties

The most important aspect of coralyne is its ability to inhibit DNA relaxation in a fashion significantly similar to the most potent antitumour alkaloid camptothecin, which is known to exert this property [242], Presumably, the most notable biological action of these alkaloids appears to be topoisomerase inhibition [238-242], which has direct relevance to their DNA intercalating property. In this context. Pilch et al. [167] described a mixed binding mode model (Fig. 16) in which the protoberberine structure constitutes portions that can intercalate or bind to the minor groove of DNA. Wang et al. [240] demonstrated that coralyne (Ci) and several of its derivatives (Ce to Ch) (Scheme 5), including the partial saturated... 

The potential properties of A. suaveolens Bl. has a source of topoisomerase II inhibitor is open for exploration. The plant probably elaborates aporphine alkaloids because aporphines are known to occur in the genus Artabotrys (2,3), Liriodenine and athero-spermidine from Artabotrys undnatus and artabotrine from Artabotrys zeylanicus abrogated the survival of cancer cells cultured in vitro (4). 

The molecules with distinct topological properties are not a mere curiosity, since they can be found in Nature. Circular DNA schematically presented as 42 are sometimes found in living organisms in the form of catenanes and knots [38], and special enzymes topoisomerases take part in their formation and transformations [39]. Circular DNA molecules can even form nets of catenated structures like that schematically presented in Figure 2.7 [40]. A discussion of biological topological structures falls outside the scope of this monograph it should be stressed, however, that their role in Nature is not understood and warrants an explanation. 

DNA supercoiling is a precisely regulated process that influences many aspects of DNA metabolism. Every cell has enzymes with the sole function of underwinding and/or relaxing DNA. The enzymes that increase or decrease the extent of DNA underwinding are topoisomerases the property of DNA that they change is the linking number. These enzymes play an especially im-... 

Moreau P, Gaillard N, Marminon C, Anizon F, Dias N, Baldeyrou B, Bailly C, Pierre A, Hickman J, Pfeiffer B, Renard P, Prudhomme M (2003) Semi-Synthesis, Topoisomerase I and Kinase Inhibitory Properties, and Antiproliferative Activities of New Rebeccamycin Derivatives. Bioorg Med Chem 11 4871... 

Kanai Y, Ishiyama D, Senda H, Iwatani W, Takahashi H, Konno H, Iwatani W, Takahashi H, Konno H, Tokumasu S, Kanazawa S (2000) Novel Human Topoisomerase I Inhibitors, Topopyrones A, B, C and DI. Producing Strain, Fermentation, Isolation, Physico-Chemical Properties and Biological Activity. J Antibiot 53 863... 

Oxidative stress reduces the rate of cell proliferation, and that occurring during chemotherapy may interfere with the cytotoxic effects of antineoplastic drugs, which depend on rapid proliferation of cancer cells for optimal activity. Antioxidants detoxify ROS and may enhance the anticancer effects of chemotherapy. For some supplements, activities beyond their antioxidant properties, such as inhibition of topoisomerase II or protein tyrosine kinases, may also contribute. ROS cause or contribute to certain side effects that are common to many anticancer drugs, such as gastrointestinal toxicity and muagenesis. ROS also contribute to side effects that occur only with individual agents, such as doxorubicin-induced cardiotoxicity, cisplatin-induced nephrotoxicity, and bleomycin-induced pulmonary fibrosis. Antioxidants can reduce or prevent many of these side effects, and for some supplements the protective effect results from activities other than their antioxidant properties. Certain side effects, however, such as alopecia and myelosuppression, are not prevented... 

Dietary supplementation with antioxidants may provide a safe and effective means of enhancing the response to cancer chemotherapy. Vitamin E may prove to be an important nutrient for enhancing antineoplastic activity because of its role in preventing lipid peroxidation, thus maintaining the rapid rate of proliferation of cancer cells. Other antioxidants may be important because of their antioxidant properties, as well as for activities such as inhibition of topoisomerase II and PTKs. 

Some saponins from plants are quite phytotoxic,36 but little is known of their mode(s) of action. Some of these compounds have effects on membrane properties, due to their detergent-like activity. However, all membrane effects are apparently not due to nonspecific effects on membrane lipids. Kauss and Jeblick23 provided indirect evidence that digitonin effects on plant cell Ca2+ uptake are due to effects on membrane protein phosphorylation/dephosphorylation processes. Betulin (Fig. 10.1), a phytotoxic saponin,22 is known for its pharmaceutical activity. It is an inhibitor of DNA topoisomerase.45 The natural product-based DNA topoisomerase inhibitor drug podophyllotoxin is also phytotoxic.37... 

In addition, benzene metabolites appear to be able to inhibit enzymes involved with DNA replication and repair, specifically the topoisomerase enzymes (Chen and Eastmond 1995). Singh et al. (1994) have studied the prooxidant and antioxidant properties of iron-hydroquinone and iron-1,2,4-ben-... 

Disturbances of the cytoskeleton, DNA replication, and DNA topoisomerase, or DNA alkylation and intercalation usually lead to cell death by apoptosis [18] (Table 1.2). The cytotoxic properties are usually not specific for animals but also affect bacteria, fungi, other plants, and even viruses. Alkaloids thus defend plants against a wide diversity of enemies. They have the disadvantage that a producing plant could theoretically kill itself by its own poison. Compartmentation, target-site insensitivity, and other mechanisms (which are largely unknown) must have evolved to overcome such problems. 

---