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- All Subjects: Antineoplastic agents
- All Subjects: Quinone
- Creators: Skibo, Edward
Description
It has been well established that mitochondria play a critical role in the pathology of Friedreich's Ataxia. This disease is believed to be caused by a deficiency of frataxin, which research suggests is responsible for iron sulfur cluster assembly. This incomplete assembly of iron sulfur clusters is believed to be linked with dysfunctional complexes in the mitochondrial respiratory chain, increased oxidative stress, and potential cell death. Increased understanding of the pathophysiology of this disease has enabled the development of various therapeutic strategies aimed at restoring mitochondrial respiration. This thesis contains an analysis of the biological activity of several classes of antioxidants against oxidative stress induced by diethyl maleate in Friedreich's Ataxia lymphocytes and CEM leukemia cells. Analogues of vitamin E α-tocopherol have been shown to protect cells under oxidative stress. However, these same analogues show various levels of inhibition towards the electron transport chain complex I. Bicyclic pyridinols containing a ten carbon substituent provided favorable cytoprotection. N-hydroxy-4-pyridone compounds were observed to provide little protection. Similarly, analogues of CoQ10 in the form of pyridinol and pyrimidinol compounds also preserved cell viability at low concentrations.
ContributorsJaruvangsanti, Jennifer (Author) / Hecht, Sidney (Thesis advisor) / Woodbury, Neal (Committee member) / Skibo, Edward (Committee member) / Arizona State University (Publisher)
Created2012
Description
Combretastatin A-4 (CA-4) represents one of the most promising antineoplastic and cancer vascular targeting stilbenes that have been isolated from the South African bush willow, Combretum Caffrum Kuntze. In order to further explore the bioactivity of this molecule, a diiodo derivative of CA-4, as well as its phosphate prodrug, was synthesized and analyzed for its biological activity; although only a scale up synthesis of this compound was performed herein for ongoing analysis. In general, no increased specificity was noted for the human cancer cell lines. Antiangiogenic properties were similar to the untreated control. The diiodocombstatin was active against M. luteus, and its phosphate prodrugs were very active against N. gonorrhoeae. Combretastain A-2 is another biologically active stilbene isolated from Combretum Caffrum Kuntze. In an attempt to increase biological activity of this molecule both mono-iodo and diiodo derivatives have been partially synthesized. The initial step involving the iodination of piperonal utilizes a novel, cost effective and mild reaction. The iodo stilbenes were obtained via a Wittig reaction using phosphonium salts 25 and 27 along with 2,3-Bis-[tert-butyldimethylsiloxy]-4-methoxy benzaldehyde 29. Deprotection of the subsequent z-stilbenes, non-isolated mono-iodo stilbene and the diiodo 30 produced two synthetic objective z-stilbenes 16 and 17. Synthesis as well as biological analysis is ongoing.
ContributorsTrickey-Platt, Brindi Brooks (Author) / Pettit, George R. (Thesis advisor) / Moore, Ana (Committee member) / Skibo, Edward (Committee member) / Arizona State University (Publisher)
Created2011
Description
A potential new class of cancer chemotherapeutic agents has been synthesized by varying the 2 position of a benzimidazole based extended amidine. Compounds 6-amino-2-chloromethyl-4-imino-1-(2-methansulfonoxyethyl)-5-methyl-1H-benzimidazole-7-one (1A) and 6-amino-2-hydroxypropyl-4-imino-1-(2-methansulfonoxyethyl)-5-methyl-1H-benzimidazole-7-one (1B) were assayed at the National Cancer Institute's (NCI) Developmental Therapeutic Program (DTP) and found to be cytotoxic at sub-micromolar concentrations, and have shown between a 100 and a 1000-fold increase in specificity towards lung, colon, CNS, and melanoma cell lines. These ATP mimics have been found to correlate with sequestosome 1 (SQSTM1), a protein implicated in drug resistance and cell survival in various cancer cell lines. Using the DTP COMPARE algorithm, compounds 1A and 1B were shown to correlate to each other at 77%, but failed to correlate with other benzimidazole based extended amidines previously synthesized in this laboratory suggesting they operate through a different biological mechanism.
ContributorsDarzi, Evan (Author) / Skibo, Edward (Thesis advisor) / Gould, Ian (Committee member) / Francisco, Wilson (Committee member) / Arizona State University (Publisher)
Created2011