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PART 1. SYNTHESIS OF STABLE-ISOTOPE LABELED AMINO ACIDS PART 2. SYNTHESIS OF MECHANISTIC PROBES OF RETINOID ACTION

Barnett, Derek W.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1038951598

Abstract Details

2002, Doctor of Philosophy, Ohio State University, Pharmacy.
Stable-isotope labeled amino acids are used in nuclear magnetic resonance (NMR) spectroscopy to facilitate protein structure determination with the use of isotope edited or filtered experiments. We are currently developing synthetic routes to 15N containing amino acids that have been stereoselectively deuterated at the beta-carbon. Once incorporated into a protein of interest, these molecules can be used to obtain stereospecific assignments of the prochiral beta-methylene protons. These assignments greatly increase the precision of the structure determination process and are critical to accurately establishing the orientation of amino acid side-chains within the protein. The utility of this strategy has been demonstrated by the synthesis of the (2S, 3R)-[3-2H,15N]-phenylalanine and (2S, 3S)-[3-2H,15N]-tyrosine derivatives. The key step in the syntheses is the alkylation of a chiral lithium enolate derived from 15N-(-)-8-phenylmenthylhippurate with an enantiotopically deuterated benzylic electrophile. A prominent feature of this strategy is its versatility. By selecting the appropriate protecting groups and electrophile, any of the four possible diastereomers can be synthesized. In addition, the method is amenable to the incorporation of various isotope labeling patterns owing to the commercial availability of different isotopomers of glycine. The details of the phenylalanine and tyrosine syntheses are presented as well as a summary of the efforts to optimize the strategy and extend the methodology to the production of several other labeled beta-methylene unit containing amino acids. N-(4-Hydroxyphenyl)retinamide (4-HPR) is a synthetic amide analog of retinoic acid that has been studied extensively as a cancer chemopreventive and chemotherapeutic agent. However, the mechanism through which 4-HPR exerts its antiproliferative effects remains unclear. It has been demonstrated that 4-HPR induces apoptosis in many tumor cell lines despite having virtually no affinity to the nuclear retinoid receptors. This is in direct contrast to retinoic acid, which possesses very high affinity for the retinoic acid receptors and induces differentiation in tumor cell lines. This data suggests that 4-HPR and retinoic acid may act at different cellular targets. In an effort to identify possible targets of 4-HPR binding, we have synthesized a series of electrophilic and photo affinity label analogs of 4-HPR. The details of the syntheses and preliminary chemical reactivity are presented.
Robert Curley Jr. (Advisor)
240 p.
amino acids; stable-isotope labeling; nuclear magnetic resonance spectroscopy (NMR spectroscopy); chlorination; affinity labeling; retinoid

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Citations

  • Barnett, D. W. (2002). PART 1. SYNTHESIS OF STABLE-ISOTOPE LABELED AMINO ACIDS PART 2. SYNTHESIS OF MECHANISTIC PROBES OF RETINOID ACTION [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1038951598

    APA Style (7th edition)

  • Barnett, Derek. PART 1. SYNTHESIS OF STABLE-ISOTOPE LABELED AMINO ACIDS PART 2. SYNTHESIS OF MECHANISTIC PROBES OF RETINOID ACTION. 2002. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1038951598.

    MLA Style (8th edition)

  • Barnett, Derek. "PART 1. SYNTHESIS OF STABLE-ISOTOPE LABELED AMINO ACIDS PART 2. SYNTHESIS OF MECHANISTIC PROBES OF RETINOID ACTION." Doctoral dissertation, Ohio State University, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=osu1038951598

    Chicago Manual of Style (17th edition)

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© 2002, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.