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Dissertation Information for Rhonda L. Moore

NAME:
- Rhonda L. Moore

DEGREE:
- Ph.D.

DISCIPLINE:
- Chemistry

SCHOOL:
- Emory University (USA) (2006)

ADVISORS:
- Dennis C. Liotta

COMMITTEE MEMBERS:
- Albert Padwa
- Lanny S. Liebeskind

MPACT Status: Fully Complete

Title: Part 1: Synthesis and biological evaluation of novel phenyl epothilone analog. Part 2: Oxazolidinone directed diastereoselective synthesis of beta-amino carbonyl derivatives. Part 3: Synthesis of novel sphingolipid analogs

Abstract: Part 1 of this dissertation describes the synthesis of a novel phenyl epothilone analog and biological evaluation as an anticancer agent. The synthetic strategy to construct the analog featured three key steps involving a suzuki cross coupling reaction, an aldol reaction and subsequent macrolactionation. The final product was submitted for biological testing and the IC 50 value in A2780 human ovarian cancer cells was 16 [mu]g/mL. Although compared to known microtubule stabilizing agents such as taxol the bioactivity was moderate the result provided significant structure-activity relationship (SAR) information. Part 2 of the dissertation focused on the diastereoselective addition of chlorotitanium enolates of N-acylated oxazolidinones to various oxime ethers to form azetines and pyrimidinones with syn stereochemistry. Both enolizable and nonenolizable oxime ethers were applicable. The azetine and pyrimidinone rings were opened under hydrolytic conditions leading to [beta] 2,3 amino acid precursors. The pyrimidinones opened with high diastereoselectivity while the azetines were less selective but offered an excellent opportunity to extend the methodology. The azetines were alkylated with various alkyl halides leading to the stereoselective synthesis of quaternary centers. The highly strained rings were opened to provide [beta] 2,2,3 amino acid precursors and in some cases the [beta]-lactams. Part 3 of the dissertation describes the synthesis of novel sphingolipid analogs. L-proline was used because the pyrrolidine ring can rigidify the backbone of the structure. In addition the hydroxyl group was moved from the primary position to prevent phosphorylation. The free amines, ceramides and synthetic intermediates were subjected to biological evaluation. The IC 50 values in HT29 and DU145 cancer cell lines were similar to that of endogenous sphingolipids, sphingosine and sphinganine.

MPACT Scores for Rhonda L. Moore

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calculated 2008-03-16 16:00:39

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