Fluorinated amino prodrugs of natural products containing enone functionality and the development of a novel imino-aldol reaction using difluoroenolates

James Ryan Woods, Purdue University

Abstract

The sesquiterpene lactone class of natural products possesses a variety of biological activities including antitumor, antimicrobial, anti-inflammatory, antiulcer and antiviral activities. These activities are all due to the presence of the α-methylene-γ-lactone motif. However, this motif is a double-edged sword as it also hampers the clinical translation of these compounds because of its non-selective binding as a Michael acceptor. In addition, clinical translations of these compounds have been hindered by the lack of aqueous solubility inherent in this class of natural products. To overcome these problems, a prodrug approach was developed in which an amine is added to alpha-methylene-gamma-lactone to mask this group from undesired nucleophilic partners and to increase the aqueous solubility. Our group, on the other hand, has used this same prodrug approach to gather mechanism of action data. Fluorinated amino adducts of the sesquiterpene lactone parthenolide were prepared and evaluated in HL-60 cells. A fluorinated aminoparthenolide with biological activity similar to the parent compound was assayed in the presence and absence of the key thiol nucleophile glutathione. By monitioring the assay using 19F NMR, we discovered that the fluorinated aminoparthenolide eliminates faster in the presence of glutathione than in the absence of glutathione. This mechanistic data suggest that this action may contribute to the cellular selectivity of the compound for glutathione-rich cancer cells over non-malignant cells. The structure of the fluorinated amines proved to be critical for maintaining a similar biological profile to that of the parent compound. Therefore, a method of constructing fluorinated amines with a diverse molecular architecture was clearly needed. By expanding the recently developed trifluoractetate- release methodology published by Colby and co-workers, a novel imino-aldol reaction was developed. Difluoenolates, generated in situ by the release of trifluoracetate from pentafluoro gem-diols, were readily reacted with both activated and unactiviated imines. Reaction conditions were mild and yields were typically moderate to good. This methodolgy provides an intriguing opportunity to quickly assemble fluorinated amines with diverse structures.

Degree

Ph.D.

Advisors

Colby, Purdue University.

Subject Area

Organic chemistry

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