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Novel 2-substituted isoflavones: A privileged structure approach to new agents for hormone-dependent breast cancer

Kim, Young-Woo
http://rave.ohiolink.edu/etdc/view?acc_num=osu1061576906

Abstract Details

2003, Doctor of Philosophy, Ohio State University, Pharmacy.
Natural isoflavones are well known as phytoestrogens due to their biological activities that mimic endogenous estrogens. For this reason, we recognized the isoflavone nucleus as a promising privileged structure for the development of new therapeutics for hormone-dependent breast cancer, in which estrogens play a key role in growth and development of tumor. We envisioned that a specific activity could be achieved by introducing proper functional groups into the isoflavone nucleus, and we designed a library of novel 2-substituted isoflavones. For the library synthesis, we developed efficient synthetic routes, in which alpha-oxoketene dithioacetals are employed as key intermediates. Various 2-(alkylthio)isoflavones were obtained directly from readily available deoxybenzoins and electrophiles using a phase transfer catalysis procedure. Alternatively, 2-substituted isoflavones were prepared through a 1,4-conjugate addition-elimination reaction of 2-(methylsulfonyl)isoflavones using a variety of commercially available nucleophiles. With efficient synthetic routes developed, we examined the potential utility of this approach for the discovery of new leads towards specific molecular targets in the breast cancer. Initially, we have focused on two major classes of therapeutic agents, aromatase inhibitors and selective estrogen receptor modulators (SERMs). As potential aromatase inhibitors, we prepared various isoflavones possessing a nitrogen-containing heterocycle, which may interfere with aromatase activity by coordinating with its heme iron. Several compounds were identified with potent aromatase inhibitory activities. As potential SERMs, we prepared a series of isoflavones containing an amine-bearing side chain, which is known to be essential for the tissue selectivity of many known SERMs. Several compounds in this series were highly potent in inhibiting proliferation of human breast cancer cells. However, their low binding affinities for estrogen receptors suggest that these compounds may not be SERMs. Currently, extended studies are underway to elucidate their mechanisms of action. Consequently, our approach using isoflavone as a privileged structure proved useful to identify new leads for breast cancer treatment. In addition, with a growing number of newly identified proteins in this post-genome era, the number of potential targets for therapeutic intervention has also increased. Therefore, our approach could also be useful in identifying new chemical probes that can provide insight into biological problems presented by breast cancer.
Robert Brueggemeier (Advisor)
249 p.
hormone-dependent breast cancer; estrogens; isoflavones; aromatase inhibitors; selective estrogen receptor modulators; 2-substituted isoflavones; privileged structure

Recommended Citations

Citations

  • Kim, Y.-W. (2003). Novel 2-substituted isoflavones: A privileged structure approach to new agents for hormone-dependent breast cancer [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1061576906

    APA Style (7th edition)

  • Kim, Young-Woo. Novel 2-substituted isoflavones: A privileged structure approach to new agents for hormone-dependent breast cancer. 2003. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1061576906.

    MLA Style (8th edition)

  • Kim, Young-Woo. "Novel 2-substituted isoflavones: A privileged structure approach to new agents for hormone-dependent breast cancer." Doctoral dissertation, Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1061576906

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.