Date of Award

12-2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Chemistry

Major Professor

David C. Baker

Committee Members

Shawn Campagna, Ben Xue, Elizabeth Howell

Abstract

Hydramycin is an antitumor antibiotic isolated from Streptomyces violaceus. It is a pyranoanthraquinone-type antitumor agent that has shown broad-spectrum activity against a variety of human-derived cancer cell lines. Among tumors evaluated at the National Cancer Institute (lung, colon, melanoma, breast and prostate), GI50s were <10−10 M in the NCI's 60-cell-line panel. We embarked on the synthesis and evaluation of a simplified congener 2-(1-hydroxy-1-(oxiran-2-yl)ethyl)-4H-naphtho[2,3-h]chromene-4,7,12-trione(17), which would facilitate synthesis while retaining the potent activity. Hydramycin has two chiral centers, and our goal is to design and synthesize all the possible enantiomers (four in total) for the congener of hydramycin 17 in order to ascertain which of the enantiomers is responsible for the observed antitumor activity. The use of enantiospecific techniques such as the Sharpless epoxidation was initially tried to introduce the chiral centers at a later stage during the multi-step synthesis and obtain the required pure enantiomers. Due to some limitations observed with this technique and many other asymmetric epoxidation techniques which utilize very substrate-specific ligands, we then modified the synthetic scheme to use another procedure, the Sharpless asymmetric dihydroxylation in order to obtain two of the pure enantiomers of this congener of hydramycin. The other two enantiomers are selectively obtained using the Sharpless asymmetric dihydroxylation procedure via cyclic sulfate intermediates, followed by a modified irreversible Payne rearrangement procedure. These routes then allowed us to obtain separately all four stereoisomers, each having more than 90% ee as determined on chiral columns with HPLC. The four stereoisomers have been fully characterized and will then be tested separately to ascertain which of the isomers is responsible for the observed antitumor activity.

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