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| author | Danielle Daly Millick |
| title |
Investigation of Stereochemical Structural Changes to Inhibit the Human In Vitro Metabolic Rate of Chemical Mutant p53 Reactivators as a Potential Oncology Therapy
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| abstract | Even if a drug candidate has high biological activity, selectivity and decent drug-like properties, without a reasonable metabolic
rate, it will not have much success. Previously quinolone and benzimidazole class compounds have been synthesized and shown to reactivate mutated forms of the
transcription factor protein, p53, which is a reoccurring mutation motif in cancer cells. Additionally a metabolism assay has been designed and employed using human liver
microsomes, containing Cytochrome P450 enzymes, and the cofactor NADPH in order to determine human clearance and half-life of these compounds. Previous findings in this
study indicate that the presence of an electron-withdrawing group on the side of the benzimidazole derivatives where metabolism is taking place, inhibited metabolism and
produced a larger in vitro human half-life (in minutes). The aim of the current study was to determine whether not only the electronegativity but also the size of
the electron-withdrawing group being added (F, Cl, Br, and I) had an effect on the metabolic rate. The concentration of our parent compound and metabolites were monitored
via quantitative liquid chromatography mass spectrometry, throughout the duration of the assay. This approach allowed us to establish metabolic profiles for our
benzamidazole derivatives, and make structural modifications in order to achieve in vitro human clearance rates similar to those of marketed drugs Midazolam:
t1/2 = 49.6 min., and Propranolol: t1/2 = 20.5 min. In this study, Chloro-, Bromo-, and Iodo- compounds demonstrated smaller half-lives (68.6/19.3
min, 25.2 min, and <<15 min, respectively) compared to the Fluoro- compound (half-life of 30 min). We found that electronegativity of the substituent added had a
greater effect on the inhibition of metabolism versus the size of the substituent, when added at that indicated position of the ring. |
| school | The College of Liberal Arts, Drew University |
| degree | B.A. (2017) |
| advisor | Dr. Ronald Doll |
| committee | Dr. Adam Cassano
Dr. Joanna Miller |
| full text | DDMillick.pdf |
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