Annonaceous acetogenins as antineoplastic leads from the leaves of Rollinia mucosa: New methods for the structural characterization of annonaceous acetogenins
Abstract
The objective of this project has been to find the active principles in the medicinal plant, Rollinia mucosa (Jacq.) Baill., a tropical Annonaceous fruit tree that has been used for the primitive medical treatment of tumors in the West Indies and Indonesia. The phytochemistry of the Annonaceae suggested that acetogenins were likely to be the most important anticancer agents behind this folklore. Indeed, the brine shrimp lethality test (BST), in activity-directed investigation of the leaves of R. mucosa, revealed a total of twenty structurally diverse bioactive Annonaceous acetogenins (1-20), of which fifteen (1, 2, 4, 7, 10-20) were new to the literature and five (3, 5, 6, 8, 9) were known but were isolated from this species for the first time. New subclasses of acetogenins which bear tetrahydropyran (THP) as well as tetrahydrofuran (THF) and hydroxylated THF rings were discovered. All of the new compounds have been tested for their in vitro antitumor activities in a panel of six human solid tumor cell lines, and some of them showed ED$\sb{50}$ values that are not only potent but are selective as well. This potent selectivity in different cancerous cell lines suggests that these compounds do not kill tumor cells through general cytotoxicity. The small quantity of the starting plant material used in this project stimulated our efforts to explore new, more efficient, detection and chemical characterization methods. As a result, the following advances were achieved: (1) the sensitive technique of LC/MS has been successfully used, for the first time, to detect acetogenins in the crude extract and some chromatographic fractions; the work quickly led to the isolation of two new acetogenins; (2) a novel perspective of Mosher's method was systematically explored to determine quickly the absolute configurations of epimeric carbinols; (3) a new procedure using the pattern recognition of NOESY spectra was established to determine unambiguously the relative stereochemistries of 1,4-diols; the method should be generally valuable for analyzing 1,n-diols, where n = 2-5.
Degree
Ph.D.
Advisors
McLaughlin, Purdue University.
Subject Area
Pharmacology|Organic chemistry|Analytical chemistry
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