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Dissertation_Neha Malik.pdf (6.37 MB)

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Total Synthesis of Natural Product Pterocarpans Useful as Selective Estrogen Receptor Modulators

Malik, Neha
http://rave.ohiolink.edu/etdc/view?acc_num=mco1384344530

Abstract Details

2013, Doctor of Philosophy in Medicinal Chemistry (Ph.D.), University of Toledo, College of Pharmacy.
Breast cancer is one of the leading causes of cancer deaths in women worldwide. Inhibition of estrogen receptors is an important strategy for the treatment of estrogen dependent breast cancer. Estrogen mimicking plant compounds called 'phytoestrogens' can bind to estrogen receptors and exert estrogenic effects. They also serve to block the effects of the normal estrogens present in humans. Thus, these phytoestrogens have the ability to act as natural, selective estrogen receptor modulators or SERMs. Soy glyceollins (GLYs) have been recently identified as estrogen mimics or phytoestrogens and represent novel natural SERMs. The GLYs are 6a-hydroxypterocarpans that are elicited as phytoalexins or plant defensive agents when soybean plants or seeds are stressed. They are produced in trace quantities as a mixture of three isomers glyceollin I, II and III. Despite their promising therapeutic potential, complete pharmacological characterization of such 6a-hydroxypterocarpans remains hampered by limited access to these systems either from natural or synthetic sources. Most notable is the lack of methodology to establish the 6a-hydroxy group for which only a few practical routes have been made available by reported syntheses. The most common route deploys a Sharpless dihydroxylation that requires osmium tetroxide to produce a benzopyran-diol that can subsequently be closed to the benzofuran cis-fused system. A drawback for the latter, however, becomes the toxicity associated with osmium tetroxide that diminishes enthusiasm for its use on large scale. This dissertation involves the development of novel approaches for the synthesis of 6a-hydroxypterocarpans which do not require osmium tetroxide. These routes are centered on an intramolecular benzoin condensation to install the key 6a-hydroxy center present in these systems. The practicality of this chemical route has been demonstrated by the novel synthesis of glycinol (GLO) in its racemic form. GLO is the key biosynthetic precursor to the GLYs and has interesting biological properties which are similar to the parent GLYs. This phytoalexin is known for its estrogen-like effects and hence it's potential to be developed as a SERM for use during hormone replacement therapy. A one-pot method was developed that facilitated intramolecular cyclization leading to assembly of the benzofuran and direct production of GLO. The chemistry developed to obtain racemic GLO was then utilized for the total syntheses of glyceollin II and III in their racemic forms. This project also involves medicinal chemistry efforts directed toward further defining the unique SERM activity observed for this novel family of phytoalexin natural products. In that regard, molecular modeling and receptor docking studies were performed to further define the interactions of these molecules with their cellular targets, namely, the estrogen receptors. Lastly, because a new chemical route was developed, certain key synthetic steps have been devised. These steps have general applicability as new methods that are useful for future process chemistry initiatives that may be undertaken within the context of this interesting class of novel SERM compounds and 6a-hydroxypterocarpans in general.
Paul Erhardt (Committee Chair)
Viranga Tillekeratne (Committee Member)
Ronald Viola (Committee Member)
Amanda Bryant-Friedrich (Committee Member)
Jeffrey Sarver (Committee Member)
226 p.
Chemistry; Pharmaceuticals; Pharmacy Sciences
Breast cancer, Selective estrogen receptor modulators, Pterocarpans, Glyceollins, Glycinol, Benzoin condensation

Recommended Citations

Citations

  • Malik, N. (2013). Total Synthesis of Natural Product Pterocarpans Useful as Selective Estrogen Receptor Modulators [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1384344530

    APA Style (7th edition)

  • Malik, Neha. Total Synthesis of Natural Product Pterocarpans Useful as Selective Estrogen Receptor Modulators. 2013. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1384344530.

    MLA Style (8th edition)

  • Malik, Neha. "Total Synthesis of Natural Product Pterocarpans Useful as Selective Estrogen Receptor Modulators." Doctoral dissertation, University of Toledo, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=mco1384344530

    Chicago Manual of Style (17th edition)

mco1384344530
904
© 2013, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.