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Novel G2 cell cycle checkpoint inhibitors and antimitotic agents isolated through two new HTS bioassays Xu, Lin

Abstract

The search for new pharmacologically active agents by screening natural sources such as microbial fermentations and plant extracts has led to the discovery of many clinically useful drugs that play a major role in the treatment of human diseases. Analogous to the investigation of terrestrial products, some recent studies of marine natural products have focused on their potential applications, particularly the treatment of human diseases, such as cancer. The goal of my thesis research was to discover structurally novel G2 cell cycle checkpoint inhibitors and antimitotic agents in natural product extracts. Active crude extracts were identified via high throughput bioassays for G2 checkpoint inhibitors and antimitotic agents. The assays were developed by our collaborator Michel Roberge and the details of the assays are introduced in the thesis. Several G2 checkpoint inhibitors were isolated and identified from extracts of marine organisms and plants. A new inhibitor pachyclavularolide F (18) was isolated from the soft coral Pachyclavularia violacea. Several inactive analogs including pachyclavulariolides A (43), B (44), C (45), D (46), E (47), and G (48) were also isolated from P. violacea. The previous known inhibitor staurosporine (10) and its new semisynthetic oxazolidone derivative (17) were discovered from a marine microorganism. The known metabolites aaptamine (12), isolated from the sponge Aaptos auberitoides and the diterpene lactones (19, 54, 55) from the tropical bush Parinari curatellifolia were found to show the G2 checkpoint inhibition. Using Dr. Roberge's high throughput antimitotic assay, the paclitaxel derivatives 10-deacetyltaxuyunnanine A (71) and 7-(β-xylosyl)-10-deacetyltaxol C (72) were isolated from the Southern American plant Ilex macrophylla. This work resulted in the discover of a new natural source for paclitaxel derivatives, and it also validated the accuracy and efficiency of the new antimitotic assay. My research on new metabolites from a marine sponge Xestospongia ingens guided by a traditional cytotoxicity bioassay led to several new ingenamine alkaloid derivatives, including ingenamines H (56), I (57), J (58), K (59), and L (60).

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