DNA-damaging natural products

DNA - Damaging Natural Products with Potential Anticancer Activity... 

The methodologies involved in our search for DNA-damaging natural products with potential ariticancer activity include extraction, bioassay, bioactivity-guided fractionation, dereplication, structure elucidation and structure-activity relationship (SAR) studies. In this section the general methodologies used by us for extraction, mechanism-based yeast bioassay and bioactivity-guided fractionation will be... 

Isolation of potential anticancer compounds from bioactive extracts involves bioactivity-guided fractionation. The DNA-damaging natural products encountered in our studies were extracted by MEK and/or methanol, and the general methodology which we have employed in our bioassay-directed fractionation of these extracts is schematically presented in Fig. 7. These fractionations involved solvent-solvent partition, Sephadex LH-20 gel filtration, normal phase and reversed-phase (RP) column, preparative thin-layer and high pressure liquid chromatography (HPLC). Silica gel chromatography was employed only if bioactive compounds were found to be stable under these mildly acidic conditions. 

A wide variety of unique DNA-damaging natural products are in clinical development, including ET-743 derived from a marine tunicate, HMAF (MGl-114) derived from mushrooms, and the bacterium-derived rebeccamycin analog, all of which are nonclassical inhibitors of topoisomerase 11. How natural products achieve this task is unknown. From numerous previous studies, it is very clear that grape seed OPCs show prolific anti-DNA damaging activity in normal cells and promote DNA-damaging activity in cancerous cells. Future studies will umavel the underlying mechanisms. 

Dairy foods present a unique opportunity from a nutrigenomics perspective, given the nature of mammalian milk as a complete source of nutrition which has been adapted over time to meet the needs of particular animals (German, 2009). The potential for dairy products to prevent DNA damage was reported by Fenech et ah (2005), who identified a reduced... 

The camptothecins are natural products that are derived from the Camptotheca acuminata tree, and they inhibit the activity of topoisomerase I, the key enzyme responsible for cutting and religating single DNA strands. Inhibition of the enzyme results in DNA damage. Topotecan is indicated in the treatment of patients with advanced ovarian cancer who have failed platinum-based chemotherapy and is also approved as second-line therapy of small cell lung cancer. The main route of elimination is renal excretion, and for this reason caution must be exercised in patients with abnormal renal function, with dosage reduction being required. 

Fig. 15.7 The DNA damage-response pathway. DNA damage is sensed by protein kinases. In mammals and in yeast the activation of the ATM kinase and of the DUNl kinase, respectively, is oontrolled by a phosphorylation oasoade, responsive to DNA-damage signals. (ATM is a kinase and the product of the AT gene, the ataxia teiangiectasia gene). p53 is phosphorylated and in humans and yeast p53-P removes the blook at promoters of RNR genes and the nuclear p53R2 IS expressed. (Reproduced from Fig. 2 in ref. 37 with permission of the authors and Nature.)...

The question of oxidative cyclization versus a polyepoxide cascade in the biosynthesis of polyether natural products has been reviewed <1995AGE298>. Enzymatic domino reactions involving epoxide intermediates have been reviewed <2001CSR332>. The DNA-damaging activity of epoxides and other oxidized species has been examined using chemical models <1995ACR289>. 

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