Browsing by Subject "Sulfonamides"
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Item Characterization of Ubiquitin Ligase Targeting by Anticancer Sulfonamides(2020-08-01T05:00:00.000Z) Ting, Tabitha Chung-Yan; De Martino, George; Nijhawan, Deepak; Yu, Hongtao; DeBose-Boyd, Russell A.Aryl sulfonamides are small molecules that are selectively toxic to a subset of human cancer cell lines. Clinical trials of the aryl sulfonamide indisulam have resulted in modest clinical activity against a subset of solid tumors. Recent work revealed that indisulam recruits the RNA binding protein RBM39 to DCAF15, a component of the CRL4-DCAF15 E3 ubiquitin ligase. This recruitment results in RBM39 ubiquitination and degradation, leading to splicing defects and cancer cell death (Han et al., 2017; Uehara et al., 2017). The mechanism of action of sulfonamides is similar to that of immunomodulatory drugs (IMiDs), which recruit substrates to the closely related CRL4-CRBN E3 ubiquitin ligase for ubiquitination. Known for their roles in inhibiting embryonic development and cancer cell growth, IMiDs exert their pleiotropic effects by targeting a variety of substrate proteins to the CRL4-CRBN E3. Despite major advances in our understanding of aryl sulfonamides, it is unclear whether sulfonamides also target multiple substrates or modulate the endogenous function of the CRL4-DCAF15 E3 ligase. This dissertation describes our efforts to define the requirements for RBM39 ubiquitination, identify other substrates that are recruited to the CRL4-DCAF15 E3 ligase, and further our understanding of the cellular consequences of indisulam treatment. In Chapters 2 and 3, we define the components required for RBM39 ubiquitination using a combination of in vitro and in vivo techniques. In Chapters 4 and 5, we identify putative endogenous substrates and a previously undescribed neo-substrate recruited to the CRL4-DCAF15 for ubiquitination. In Chapter 6, we characterize the cellular consequences of indisulam treatment and neo-substrate degradation. In aggregate, this work aims to contribute to our understanding of the sulfonamide mechanism of action and the field of targeted protein degradation.Item Studies Toward the Syntheses of Antiarrythmic, Anti-Virulence, and Anticancer Small Molecules(2015-11-23) Adebesin, Adeniyi Michael; Kürti, László; Falck, John R.; Chen, Chuo; Corey, David R.This work is comprised of three projects: a) the development of antiarrythmic analogs of 17(R),18(S)-epoxyeicosatetraenoic acid for the treatment of atrial fibrillation, b) the development of potent inhibitors of QseC mediated virulence gene expression, and c) studies toward a biomimetic total synthesis of nigricanoside A. Antiarrhythmic analogs of 17(R),18(S)-epoxyeicosatetraenoic acid (17(R),18(S)-EEQ): Arrhythmias such as atrial and ventricular fibrillation are a leading cause of death in the United States of America. However, the available drugs for the treatment of these deadly conditions can paradoxically induce proarrhythmic effects, amongst other side effects, and are individually insufficient for treatment. Through a neonatal rat cardiomyocyte assay, 17(R),18(S)-EEQ was found to possess negative chronotropic effects, a characteristic of antiarrhythmic activity. My work on this project led to the development of potent and metabolically robust analogs of 17(R),18(S)-EEQ, which are currently being developed by OMEICOS Therapeutics GmbH, an early stage drug development company, for the treatment of atrial fibrillation. Inhibitors of QseC mediated virulence gene expression: Quorum sensing E. coli regulator C (QseC), a membrane-bound histidine sensor kinase, mediates the expression of various virulence genes in Gram-negative bacteria such as Escherichia coli (EHEC), Salmonella typhimurium, and Francisella tularensis which are pathogenic to humans. Therefore, QseC is a potential target of anti-virulence antibacterial strategies. In collaboration with the Sperandio laboratory, my work on this project led to the development of novel inhibitors of QseC mediated virulence gene expression. Some of the analogs synthesized in this project are currently being investigated by GlaxoSmithKline as anti-virulence agents. Studies toward a biomimetic total synthesis of nigricanoside A: Nigricanoside A, a novel ether-linked glycoglycerolipid with 7 unassigned stereocenters, was reported to possess potent (IC50 ≈ 3 nM) antimitotic activity against MCF-7 and HCT-116 cancer cell lines. However, the rarity of the natural product precluded further structural and biological studies. With the aid of biomimetic hypotheses and literature precedents, the Falck laboratory reduced the stereochemical uncertainty associated with the structure elucidation of the nigricanosides. Furthermore, one of the biomimetic hypotheses inspired the development of a novel stereocontrolled distal epoxidation of conjugated dienols. Armed with this methodology, my work on this project led to the synthesis of the three major fragments of a nigricanoside.Item [UT News](1987-05-08) Rutherford, Susan