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COMBATING CANCER AND ALZHEIMER'S DISEASE: SYNTHESIS OF NOVEL, CHEMOTHERAPEUTIC REXINOIDS

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The FDA-approved drug bexarotene has been predominantly utilized for the treatment of cutaneous T-cell lymphoma (CTLC), but has shown promise as an off label treatment for various other cancers as well as Alzheimer's disease (AD). However, harmful side effects such as hypothyroidism have catalyzed a search for alternative rexinoids which…

The FDA-approved drug bexarotene has been predominantly utilized for the treatment of cutaneous T-cell lymphoma (CTLC), but has shown promise as an off label treatment for various other cancers as well as Alzheimer's disease (AD). However, harmful side effects such as hypothyroidism have catalyzed a search for alternative rexinoids which retain similar levels of RXR agonism while reducing the undesirable effects incurred by bexarotene. This honors thesis outlines the steps taken to design and synthesize novel analogues of the selective retinoid-X-receptor (RXR) agonist 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene). Corresponding NMR spectra indicates the successful construction of four novel compounds which are structurally similar to known, biologically-evaluated rexinoids that have induced fewer side effects while stimulating greater levels of RXR selectivity as compared to bexarotene. Future In vitro analyses of these four analogues coupled with the recognized efficacy of their parent compounds demonstrate the chemotherapeutic potential of structurally modified bexarotene analogues
ContributorsDavidson, Jesse Raymond (Author) / Wagner, Carl (Thesis director) / Ball, Rebecca (Committee member) / School of Mathematical and Natural Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
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Synthesis of Novel Rexinoids for Use in Preclinical Trials of Cancer Models

Description
Rexinoids such as Bexarotene have been developed as effective treatments of different diseases including lymphoma, breast cancer, lung cancer, Alzheimer’s disease, and diabetes. This is due to the widespread nature of the retinoid X receptor, which is the target of these drugs, throughout the body. However, Bexarotene is not infallible…

Rexinoids such as Bexarotene have been developed as effective treatments of different diseases including lymphoma, breast cancer, lung cancer, Alzheimer’s disease, and diabetes. This is due to the widespread nature of the retinoid X receptor, which is the target of these drugs, throughout the body. However, Bexarotene is not infallible and has many negative side effects which limit the use of the drug to only a short period of time. This may be fine for chemotherapy, but rexinoids have been proposed to also be effective at preventing cancer as well. This is not currently possible with the side effects seen with approved rexinoids. Due to this, six novel rexinoids were created in hopes of reducing the side effect profile of rexinoids. The idea of dual agonism was also explored with two of the compounds created as well. All six of these compounds, after creation and purification, were sent off for in vitro and in vivo testing to confirm side effect profile and efficacy.
ContributorsFrazier, Madison S (Author) / Wagner, Carl (Thesis director) / Marshall, Pamela (Committee member) / School of Mathematical and Natural Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05