Annonaceous acetogenins from the seeds of Annona muricata
Abstract
This project involved the biological activity-directed isolation and characterization of a number of the cytotoxic and potentially pesticidal agents from the seeds of Annona muricata L. (Annonaceae). Ethanol extraction, partition, and repeated chromatographic separations, with brine shrimp toxicity directing the fractionation, resulted in the isolation of sixteen compounds: annonacin (1), annonacin-10-one (2), goniothalamicin (3), isoannonacin (4), isoannonacin-l0-one (5), annonmontacin (6), muricatacin (7), muricatetrocin A (8), muricatetrocin B (9), gigantetrocin B (10), gigantetrocin A (11), cis-annonacin (12), cis-annonacin-10-one (13), cis-goniothalamicin (14), arianacin (15) and javoricin (16). Fifteen are Annonaceous acetogenins and one (7) is a related product. Nine of these compounds (7, 8-10, 12-16) are new to the literature, and four of these (12-16) are the first cis mono-tetrahydrofuran ring acetogenins to be reported. A refined method for the isolation and structural elucidation of the Annonaceous acetogenins is presented. Once a bioactive compound was isolated from the plant matrix, proton and carbon nuclear magnetic resonance (NMR) spectroscopy were used to determine the functionalities present and the purity of the isolated compound. Mass spectrometry (MS) of the trimethylsilyl (TMSi) derivatives was used to provide mass fragmentation information, which permitted placement of functionalities along the carbon skeleton. High resolution MS of both the parent compound and its derivatives confirmed the molecular weight and the composition of selected diagnostic fragments. Model synthetic compounds that are published in the literature allowed assignment of the relative ring stereochemistry. Aliphatic chain alcohols were derivatized to yield cyclized structures whose relative conformations were deduced through symmetry considerations. The final step in the structural elucidation of these compounds was the determination of absolute stereochemistry of the carbinol centers by Mosher ester studies. Bioassays of the pure compounds in the brine shrimp test, the inhibition of crown gall tumors, and in a panel of human tumor cell lines for cytotoxicity evaluated relative potencies.
Degree
Ph.D.
Advisors
McLaughlin, Purdue University.
Subject Area
Pharmacology
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