Sponsor
Portland State University. Department of Chemistry
First Advisor
Reuben H. Simoyi
Date of Publication
1-1-2012
Document Type
Dissertation
Degree Name
Doctor of Philosophy (Ph.D.) in Chemistry
Department
Chemistry
Language
English
Subjects
Metastasis inhibitor, Kinetics, Mechanism, Transition metal complexes -- Research, Tumor suppressor proteins -- Research, Metastasis -- Research, Thiols -- Research
DOI
10.15760/etd.378
Physical Description
1 online resource (xvii, 164 pages)
Abstract
Imidazolium trans-[tetrachloro (dimethyl sulfoxide)(imidazole)ruthenate(III)], NAMI-A, is an experimental metastasis inhibitor whose specific mechanism of activation and action remains to be elucidated. In the nucleophilic and reducing physiological environment; it is anticipated that the most relevant and available reductants upon introduction of NAMI-A as a therapeutic agent will be the biologically-relevant free thiols. The kinetics and mechanisms of interaction of NAMI-A with biologically-active thiols cysteamine, glutathione, cysteine and a popular chemoprotectant, 2-mercaptoethane sulfonate (MESNA) have been studied spectrophotometrically under physiologically-relevant conditions. The reactions are characterized by initial reduction of NAMI-A with simultaneous formation of dimeric thiol and subsequent ligand exchange with water to various degrees as evidenced by Electospray Ionization Mass Spectrometry. Stoichiometry of reactions shows that one molecule of NAMI-A reacted with one mole of thiol to form corresponding disulfide cystamine, dimeric MESNA, oxidized glutathione and cystine. Observed rate constants, ko, for the reaction of NAMI-A with cysteamine, MESNA, GSH and cysteine were deduced to be 6.85 + 0.3 x 10-1, 9.4 + 0.5 x 10-2 , 7.42 + 0.4 x 10-3 and 3.63 + 0.3 x 10-2 s-1 respectively. Activation parameters determined from Arrhenius plots are indicative of formation of associative intermediates prior to formation of products. A negative correlation was obtained from the Brønsted plot derived from observed rate constants and the pKa of the different thiols demonstrating significant contribution of thiolate species towards the rate. In conclusion, interactions of NAMI-A with biologically-active thiols are kinetically and thermodynamically favored and should play significant roles in in vivo metabolism of NAMI-A.
Rights
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Persistent Identifier
http://archives.pdx.edu/ds/psu/7986
Recommended Citation
Adigun, Risikat Ajibola, "Insight into the Reactivity of Metastasis Inhibitor, Imidazolium trans-[tetrachloro (dimethyl sulfoxide)(imidazole)ruthenate(III)], with Biologically-active Thiols" (2012). Dissertations and Theses. Paper 378.
https://doi.org/10.15760/etd.378
Comments
Portland State University. Dept. of Chemistry