Matching Items (9)

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Analysis of differential secondary effects of novel rexinoids: select rexinoid X receptor ligands demonstrate differentiated side effect profiles

Description

In order to determine the feasibility of utilizing novel rexinoids for chemotherapeutics and as potential treatments for neurological conditions, we undertook an assessment of the side effect profile of select

In order to determine the feasibility of utilizing novel rexinoids for chemotherapeutics and as potential treatments for neurological conditions, we undertook an assessment of the side effect profile of select rexinoid X receptor (RXR) analogs that we reported previously. We assessed pharmacokinetic profiles, lipid and thyroid-stimulating hormone (TSH) levels in rats, and cell culture activity of rexinoids in sterol regulatory element-binding protein (SREBP) induction and thyroid hormone inhibition assays. We also performed RNA sequencing of the brain tissues of rats that had been dosed with the compounds. We show here for the first time that potent rexinoid activity can be uncoupled from drastic lipid changes and thyroid axis variations, and we propose that rexinoids can be developed with improved side effect profiles than the parent compound, bexarotene (1).

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Date Created
  • 2015-03-16

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Treatment for T-Cell Lymphoma Cancer: Synthesis of Analog Compound of Bexarotene

Description

Cancer, a disease which affects many lives, has been the topic of interest for this research. Treatment options are often available to help lessen the effects of the disease and

Cancer, a disease which affects many lives, has been the topic of interest for this research. Treatment options are often available to help lessen the effects of the disease and in regards to cutaneous T-cell lymphoma (CTCL), no cure currently exists. An FDA approved drug by the name of Bexarotene has been developed to provide chemotherapeutic effects within CTCL. Bexarotene has also been used in trials of breast cancer, lung cancer, glioblastoma multiforme and various neurodegenerative diseases. Yet the medication often causes serious side effects including hyperthyroidism, raised triglyceride levels and cutaneous toxicity. The focus of this research is to synthesize a hydroxylated analog compound of Bexarotene in efforts to produce a molecule that provides better chemotherapeutic effects while also lessening the various side effects caused. Synthesis of the molecule followed various organic chemistry techniques and reactions to create the final product. Melting point analysis, NMR and other various characterization data helped to confirm the synthesis of the intended molecule. Preliminary bioassay data results of the analog compound showed similar potency to that of Bexarotene. Further testing, however, will be required to determine the full pharmacokinetic profile of the molecule. Future direction of the research focuses on both further testing of the hydroxylated analog as well synthesizing newer analog compounds to find a molecule that can provide the best effects within cutaneous T-cell lymphoma and the various other diseases as well.

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Date Created
  • 2018-05

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Characterization of Second and Third Generation, Novel RXR Selction Agonists for the Treatment of Cutaneous T-Cell Lymphoma

Description

Bexarotene is a commercially produced drug commonly known as Targetin presecribed to treat cutaneous T-cell lymphoma (CTCL). Bex mimics the actions of natural 9-cis retinoic acid in the body, which

Bexarotene is a commercially produced drug commonly known as Targetin presecribed to treat cutaneous T-cell lymphoma (CTCL). Bex mimics the actions of natural 9-cis retinoic acid in the body, which are derived from Vitamin A in the diet and boost the immune system. Bex has been shown to be effective in the treatment of multiple types of cancer, including lung cancer. However, the disadvantages of using Bex include increased instances of hypothyroidism and excessive concentrations of blood triglycerides. If an analog of Bex can be developed which retains high affinity RXR binding similar to the 9-cis retinoic acid while exhibiting less interference for heterodimerization pathways, it would be of great clinical significance in improving the quality of life for patients with CTCL. This thesis will detail the biological profiling of additional novel (Generation Two) analogs, which are currently in submission for publication, as well as that of Generation Three analogs. The results from these studies reveal that specific alterations in the core structure of the Bex "parent" compound structure can have dramatic effects in modifying the biological activity of RXR agonists.

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Date Created
  • 2012-05

Bite Force Analysis of Leucoraja erinacea Skates to Understand Morphological Evolution of Different Cartilaginous Fish

Description

By studying organismal performance, one can gain insight regarding the evolutionary and developmental processes that shape the adult organism. Bite force is an important trait that can be linked to

By studying organismal performance, one can gain insight regarding the evolutionary and developmental processes that shape the adult organism. Bite force is an important trait that can be linked to performance, and therefore survival, of the entire organism. In order for an animal to successfully feed upon its prey, the components of the jaw, such as the skeleton and attached muscles, must be strong enough to withstand the forces required for capturing and then processing (masticating) the prey. Because sharks and skates have a fully cartilaginous skeleton, they theoretically bite off more than deemed biologically possible, these organisms, therefore, are excellent models for study when trying to understand bite performance. The goal was to measure the bite force of Leucoraja erinacea. Dissections were completed for 14 individuals, in order to expose the muscles beneath the skin. The muscles were then removed, and the mass was recorded. Calculations derived from the literature were used to determine total bite force. Linear regression was used to determine the relationship between bite force and size of the organism. The average maximum bite force of Leucoraja erinacea was determined to be roughly 23.3 Newtons (N). There was a positive relationship between bite force and size. This skate produces a much smaller bite force than many other organisms, providing insight into its ecological role in food webs. Many of the shells of commercially important prey were also much stronger than the bite forces estimated for these skates, suggesting that either the skates were not mature or large enough to feed on these prey, or, perhaps this species is unable to feed on these organisms entirely.

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Date Created
  • 2018-05

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Treatment of Type II Diabetes: Synthesis and Analysis of Five Analogs of Compound NEt-4IB that Target the Retinoid-X-Receptor

Description

This project details the synthesis and analysis of five analogs of model compound NEt-4IB (6-[ethyl(4-isobutoxy-3-isopropylphenyl)amino]nicotinic acid), that target the retinoid-X-receptor (RXR). These molecules were synthesized by substituting, adding, or removing

This project details the synthesis and analysis of five analogs of model compound NEt-4IB (6-[ethyl(4-isobutoxy-3-isopropylphenyl)amino]nicotinic acid), that target the retinoid-X-receptor (RXR). These molecules were synthesized by substituting, adding, or removing substituents in the nitrogen-containing ring of NEt-4IB. The parent compound is a RXR partial agonist and has proven to be effective in the treatment of type II diabetes without the unwanted side effects seen with full agonists. Many of the current drugs used to treat type II diabetes are accompanied by adverse effects including increased triglyceride levels, weight gain, and hypoglycemia. Biological evaluation with KK-Ay (obese diabetic) model mice indicates that NEt-4IB may even be more effective than current drugs on the market, like pioglitazone. As a result, it is predicted that due to such structural similarity, the analogs synthesized for this work will perform equally, if not better than, NEt-4IB.

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Date Created
  • 2016-05

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Analysis of Retinoid X Receptor (RXR) Homodimerization Driven by RXR Ligands Using Yeast Two-Hybrid

Description

Bexarotene (Targretin®) is an FDA approved drug used to treat cutaneous T-cell lymphoma (CTCL), as well as off-label treatments for various cancers and neurodegenerative diseases. Previous research has indicated

Bexarotene (Targretin®) is an FDA approved drug used to treat cutaneous T-cell lymphoma (CTCL), as well as off-label treatments for various cancers and neurodegenerative diseases. Previous research has indicated that bexarotene has a specific affinity for retinoid X receptors (RXR), which allows bexarotene to act as a ligand-activated-transcription factor and in return control cell differentiation and proliferation. Bexarotene targets RXR homodimerization to drive transcription of tumor suppressing genes; however, adverse reactions occur simultaneously when bound to other nuclear receptors. In this study, we used novel bexarotene analogs throughout 5 iterations synthesized in the laboratory of Dr. Wagner to test for their potency and ability to bind RXR. The aim of our study is to quantitatively measure RXR homodimerization driven by bexarotene analogs using a yeast two-hybrid system. Our results suggests there to be several compounds with higher protein activity than bexarotene, particularly in generations 3.0 and 5.0. This higher affinity for RXR homodimers may help scientists identify a compound that will minimize adverse effects and toxicity of bexarotene and serve as a better cancer treatment alternative.

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Created

Date Created
  • 2015-05

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

Description

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

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

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Created

Date Created
  • 2016-05

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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

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.

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Created

Date Created
  • 2020-05

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Synthesis of Bexarotene Analogs for the Treatment of Breast Cancer

Description

Bexarotene is a synthetic analog of 9-cis-retinoic acid and ligand for the retinoid X receptor which has a history of clinical success in the treatment of T-cell lymphoma. Bexarotene has

Bexarotene is a synthetic analog of 9-cis-retinoic acid and ligand for the retinoid X receptor which has a history of clinical success in the treatment of T-cell lymphoma. Bexarotene has also shown potential for treating a variety of other cancers, which we seek to explore in this project. The potential of bexarotene lies in its unique mechanisms and wide application, however, it has shown limited effectiveness thus far in the treatment of breast and lung cancer, with moderate levels of efficacy and symptoms such as cutaneous toxicity, hyperlipidemia, and hypothyroidism. For this project several analogs of bexarotene were synthesized with the intentions of making a more potent ligand that can be used to treat these carcinomas while minimizing harmful side effects. We were successful in synthesizing a large variety of analogs over the span of roughly two years, including iso-chroman derivatives of bexarotene and NEt-TMN, in addition to a new series of analogs of the reported NEt-TMN derivative. These analogs were analyzed via melting point determination and nuclear magnetic resonance (NMR) spectroscopy to confirm the molecular structure and determine purity, and it is our intent to continue with further testing of these compounds to determine their effectiveness as well as the side effects they are likely to cause with levels of toxicity. Recent studies suggest that continuing the analysis of these compounds and other rexinoids like the ones described herein is a worthwhile endeavor as similar rexinoids have shown in numerous assays to be more potent and less toxic in the treatment of cancers when compared with bexarotene.

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Created

Date Created
  • 2019-05