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Investigation into the biologically active metabolites of Coccoloba acuminata and Minquartia guianensis Nelson, Jim

Abstract

The comprehension of cellular processes remains central to the development of novel techniques for the treatment of disease. The use of small molecule protein inhibitors can aid in better understanding these processes and potentially be used therapeutically. The G2 checkpoint allows for cells to pause and repair DNA damage. In conjunction with radiation therapy, the use of G2 checkpoint inhibitors has demonstrated (in vitro) a greater mortality for cancer cells over healthy cells. The bioassay guided fractionation of Coccoloba acuminata afforded the G2 checkpoint inhibitor enf-kaur-16-en-15-oxo-18-oic acid (7). [diagram not included] At an optimal concentration of 12 μg/ml, diterpene 7 exhibited a maximum release of cells from G2 → M of 48%. A biotinylated linker was attached to 7 to form an affinity probe 14. [diagram not included] At an optimal concentration of 7 μg/ml, compound 14 released 39-41% of cells from G2 to M phase. The binding of Pin1 to phosphorylated tau plays a role in the formation of paired helical filaments, a hallmark of Alzheimer's disease. Therefore, inhibitors of the binding of Pin1 to phosphorylated tau could be used as a potential therapeutic for Alzheimer's disease. The bioassay guided fractionation of M. guianensis yielded the cytotoxic polyacetylene minquartynoic acid 8 [diagram not included] and two inhibitors of Pin1 binding 4-O-(α-rhamnopyranosyl)ellagic acid 9 [diagram not included] and 4-O-(β-xylopyranosyl)ellagic acid 10 [diagram not included]. The IC₅₀ is 0.7 μ/mL for 4-O-(β-xylopyranosyl)ellagic acid 10 [diagram not included] and 0.6 μ/mL for 4-O-(α-rhamnopyranosyl)ellagic acid 9 for inhibition of Pin1 binding to phosphorylated tau.

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