Date of Award

5-23-2010

Document Type

Honors Thesis

Department

Chemistry

First Advisor

Kristi Humphreys

Language

English

Abstract

NAMI-A is a ruthenium based anti-metastatic agent currently in phase II clinical trials. Two derivatives, using 1-methyimidazole and 1-ethylimidazole, were synthesized and compared to NAMI-A to determine the effects of the ring substituents on the activation of the compounds. Hydrolysis at pH 4.0 and pH 7.4 and reduction potential were the main points of study. The hydrolysis reaction follows zero-order kinetics for both compounds in sodium phosphate buffer (pH 7.4). The average value of the rate constant k was 2.20 x 10-8 M/s for both the Me-Im derivative and the Et-Im derivative (±1.44 x 10-9 M/s, ±1.99 x 10-9 M/s respectively). The average half-life was 40.3 minutes (±4.6 minutes) for the Me-Im derivative and 42.4 minutes (±5.9 minutes) for the Et-Im derivative. The hydrolysis reaction follows first-order kinetics in sodium acetate buffer (pH 4.0) for both compounds. The average value of the rate constant k was 6.11 x 10-6 s-1 (±1.14 x 10-7 s-1) for the Me-Im derivative and 7.07 x 10-6 s-1 (±2.07 x 10-7 s-1) for the Et-Im derivative. The average half-life was 31.5 hours (±0.58 hours) for the Me-Im derivative and 27.3 hours (±0.78 hours) for the Et-Im derivative. Reduction potentials were 256 mV for the Me-Im derivative and 255 mV for the Et-Im derivative. Hydrolysis as compared to NAMI-A is slower at physiological pH and faster at acidic pH, while reduction potential is slightly higher than NAMI-A. Overall, these compounds may be more effective than NAMI-A at treating metastatic tumors because they can undergo the second aquation step (leading to the biologically active species) sooner. Future experiments testing the compounds' performances against cancer cells at physiological temperature and studies of the second aquation step would be of use in making a final determination of the effectiveness of the compounds in comparison to NAMI-A.

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