An investigation of the therapeutic potential of phenylaminoalkyl selenides through mechanistic and biological studies and an exploration of ciber: the center of innovative biomaterial education and research

Thioselenurane;Stopped-flow;Antioxidant;Phenlyaminoalkyl selenides

Cowan, Elizabeth Alice ; Chemistry and Biochemistry

University:Georgia Institute of Technology

Department:Chemistry and Biochemistry

关键词: Thioselenurane;    Stopped-flow;    Antioxidant;    Phenlyaminoalkyl selenides;   

Others  :  https://smartech.gatech.edu/bitstream/1853/42937/1/Cowan_Elizabeth_A_201112_phd.pdf

美国|英语

来源: SMARTech Repository

【 摘 要 】

The overproduction of reactive oxygen species (ROS) have been linked todiseases and other pathologies. As therapeutic agents, antioxidants have been tested andsome shown to attenuate these diseases by relieving oxidative stress. The May laboratoryhas previously developed a family of phenylaminoalkyl selenides and has demonstratedthe antihypertensive and antioxidant properties of these compounds.To further understand the antioxidant property of these selenide compounds, thetwo step mechanism of the reaction between the selenoxide form and glutathione wasinvestigated by stopped-flow and mass spectrometry, leading to the detection andcharacterization of a novel thioselenurane intermediate. Mass spectrometry studiessupported the redox cycle of the selenide compounds as a straightforward cycle with nobyproducts or side reactions and was the first evidence reported of a thioselenuraneintermediate present in a reduction reaction of a selenoxide.The therapeutic potential of these compounds was further supported by cell andhistological studies demonstrating their ability to alleviate the cardiotoxic effect ofanthracyclines without affecting the anti-cancer property of the drugs. Codosage of aphenylaminoethyl selenide with Doxorubicin decreased the infiltration of inflammationcells in the myocardium of mice. Phenylaminoethyl selenides were also able to maintainthe body weight of mice treated with Doxorubicin, compared to mice treated withDoxorubicin alone.In order to make the possibility of using Phenylaminoalkyl selenides astherapeutic agents or supplements with other agents, delivery of the compounds wasinvestigated. N acetyl phenylaminoethyl selenides were successfully encapsulated intopoly(lactic-co-glycolic) (PLGA) nanoparticles using the nanoprecipitation technique. Anattempt was made to demonstrate the ability of these selenide- nanoparticles to reducecellular oxidative stress caused by incubation with LPS. Future studies are needed tooptimize the loading of the selenide compounds into nanocarriers and to demonstrate theability of the encapsulated drug to work as the free drug. The long term goal of thisresearch is to fully understand the potential of phenylaminoalkyl selenides as an efficienttherapeutic agent for ailments derived from increased levels of ROS and a state ofoxidative stress.As a supplemental project funded by the National Science Foundation, the Centerfor Innovative Biomaterial Education and Research (CIBER) was created. Enzymaticallycatalyzed reaction and polymerizations were investigated using Candida antarcticaLipase B (CALB). Several CALB catalyzed Michael addition reactions were successfuland yielded compounds that could be used as future reactants and monomers. As aneducation requirement of the project a website was created in order to educate the publicof the importance, sources and uses of biomaterials. The website provides informationfor all levels of students and educators. This center has allowed The Georgia Institute ofTechnology to form relationships and exchange programs with leading universitiesaround the world allowing the exchange of knowledge and research in biomaterials.