59 research outputs found
Development of imidazotetrazines for the treatment of glioblastoma & as synthetic precursors to diazo species
No full textGlioblastoma multiforme (GBM), a grade IV astrocytoma, is the most prevalent, aggressive, and deadly form of malignant brain tumor with only 10% of patients surviving five years. The current standard treatment for GBM patients is bulk surgical resection and radiotherapy with concomitant and adjuvant temozolomide (TMZ), a small molecule DNA alkylating agent. The antitumor effect of TMZ is ultimately mediated through methylation of the O6-position of guanine and subsequent mismatch repair (MMR)-dependent cell death. Although TMZ was first synthesized in 1984 and has been FDA approved for two decades, certain key derivatives have been inaccessible due to synthetic challenges, precluding a broad exploration of the link between imidazotetrazine structure and biological activity. Novel synthetic strategies provided access to several new classes of C8-substituted imidazotetrazines and an evaluation of their aqueous stabilities enabled the derivation of a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent. Promising compounds modified at the C8 position were identified and found to have appropriate hydrolytic stability, enhanced blood-brain barrier permeability, lower hematological toxicity profiles, and superior activity relative to TMZ in a mouse model of GBM.
Despite its widespread use, certain GBM patient populations do not respond to TMZ therapy. Expression of O6-methylguanine DNA methyltransferase (MGMT) and loss of MMR function are the primary clinical modes of resistance to TMZ. Imidazotetrazine analogs modified at the N3 position were designed to deliver alternative DNA adducts that were irremovable by MGMT. An analog bearing a propargyl group at N3 demonstrated MGMT-independent activity in GBM cells in culture. Tuning the stability with an electron-donating chloro substituent at the C8 position produced novel dual-substituted imidazotetrazine CPZ, which displayed anticancer activity irrespective of MGMT expression and MMR status.
Imidazotetrazines such as TMZ are precursors to alkyl diazoniums, used therapeutically to alkylate DNA and elicit an anticancer effect. Given their stability as prodrugs and the reactivity of the species released, imidazotetrazines were repurposed into synthetic surrogates for diazomethane and other diazoalkanes. TMZ was employed to conduct esterifications and metal-catalyzed cyclopropanations, with methyl ester formation from a wide variety of substrates proving efficient and operationally simple. As a commercially available solid that is non-explosive and non-toxic, TMZ should find broad utility as a synthetic replacement for diazomethane.Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2022-05-01The student, Riley Svec, accepted the attached license on 2020-04-14 at 17:59.The student, Riley Svec, submitted this Dissertation for approval on 2020-04-14 at 18:07.This Dissertation was approved for publication on 2020-04-16 at 13:46.DSpace SAF Submission Ingestion Package generated from Vireo submission #14980 on 2020-08-25 at 17:40:15Made available in DSpace on 2020-08-27T00:49:56Z (GMT). No. of bitstreams: 3
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Previous issue date: 2020-04-16Embargo set by: Seth Robbins for item 115864
Lift date: 2022-08-27T00:50:22Z
Reason: Author requested closed access (OA after 2yrs) in Vireo ETD systemEmbargo set by: Seth Robbins for item 115864
Lift date: 2022-08-27T00:51:40Z
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Utilizing Knowledge of Physics in Safety Engineering
No full textAny technician working in safety engineering needs certain knowledge of physics. This knowledge includes physical quantities and units of measurement, physical properties of substances, various formulae and equations, etc. It is also very important to possess knowledge enabling general - and often highly complex - processes to be simplified. This paper discusses two such possibilities for simplification
Impact of Financial Crisis on the Profitability of Capital Structure Arbitrage in Australia
No full textWe evaluate the performance of a convergence style capital structure arbitrage trading strategy using Australian CDS spreads estimated by the Credit Grades model. By comparing a number of volatility inputs, we find that although option-implied volatility inputs produce biased spreads compared to historical measures, their correlation with medium-term changes in market spreads generate significantly more profitable trades during the financial crisis, even after the inclusion of transaction costs. While the strategy is risky at both the individual obligor and the iTraxx Index level, combining positions into an equally-weighted index of arbitrage trades reduces risk.
 
Formal Specification in “Z” Language by Software Z/EVES
No full textThe paper shows a short overview of representation formalisms, which can be used for specification of technical system functional requirements. Some basic model schemas of function called User Identification of ITS are presented by formal specification “Z” language and software Z/EVES
Impact of Financial Crisis on the Profitability of Capital Structure Arbitrage in Australia
No full textWe evaluate the performance of a convergence style capital structure arbitrage trading strategy using Australian CDS spreads estimated by the Credit Grades model. By comparing a number of volatility inputs, we find that although option-implied volatility inputs produce biased spreads compared to historical measures, their correlation with medium-term changes in market spreads generate significantly more profitable trades during the financial crisis, even after the inclusion of transaction costs. While the strategy is risky at both the individual obligor and the iTraxx Index level, combining positions into an equally-weighted index of arbitrage trades reduces risk
The Game Changer: Regulatory Reform and Multiple Credit Ratings
No full textThis paper examines the change in the regulatory use of multiple credit ratings after the Dodd-Frank Act (Dodd-Frank). We find that post Dodd-Frank reform, firms are less likely to demand a third rating (typically from Fitch) for ratings near the high yield (HY) - investment grade (IG) boundary to support their new corporate bond issues. Third ratings also become less informative post Dodd-Frank, with a much weaker market impact on credit spreads for firms with S&P and Moody’s ratings on opposite sides of the HY-IG rating boundary. We provide new evidence on the effect of Dodd-Frank in curbing corporate borrowers’ strategic use of multiple credit ratings near this boundary
Do Firms Adjust Their Acquisition Strategies and Payment Options in Response to Changes in Financial Reporting Incentives?
No full textA monolithic lipase reactor for biodiesel production by transesterification of triacylglycerides into fatty acid methyl esters
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