Publication Date

Summer 2021

Advisor(s) - Committee Chair

Dr. Blairanne Williams (Director), Dr. Kevin Williams, and Dr. Moon-Soo Kim

Degree Program

Department of Chemistry

Degree Type

Master of Science

Abstract

Platinum(II) compounds including the three FDA approved drugs, cisplatin, carboplatin, and oxaliplatin, are composed of two structural components, a leaving ligand, and a non-leaving ligand, each attached to a central platinum(II) atom. All bifunctional platinum compounds studied have similar mechanisms of initiating cell death. However, their efficacy as chemotherapeutics depends on the tissues in which the cancer originates. No model has explained these tissue-specific efficacies. We hypothesized that the efficacies of these platinum compounds vary due to structural differences in the leaving ligands. To test the influence of the leaving ligand on cellular survival, novel platinum compounds were synthesized, and toxicological profiles were created in cellular models of cancer from various tissues. The novel platinum compounds used here: malonato(ethylenediamine)platinum(II) (Pt(en)mal), 1,1- cyclobutanedicarboxylato(ethylenediamine)platinum(II) (Pt(en)CBDCA), and dichloro(ethylenediamine)platinum(II) (Pt(en)Cl2). Cellular models were exposed to the toxicants individually in a dose-dependent manner and then 24 hours after exposure, cell viability was examined by MTT (3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Based on our data, Pt(en)mal survival response was higher in the A549 (IC50 = 350 μM ± 3.32), HT-29 (IC50 = 300 μM ± 8.77), and HT-1197 (IC50 = 200 μM ± 1.78) cells compared to the MCF7 (IC50 = 80 μM ± 5.38), HEK293 (IC50 = 60 μM ± 11.68), SK-MEL-5 (IC50 = 60 μM ± 4.01), and NTERA2 (IC50 = 20 μM ± 5.61) cell lines. Pt(en)CBDCA survival response was higher in the HT-29 (IC50 = 400 μM ± 6.50), and MCF7 (IC50 = 200 μM ± 0.98) cells compared to the SK-MEL-5 (IC50 = 100 μM ± 8.08), A549 (IC50 = 75 μM ± 2.78), and HEK293 (IC50 = 50 μM ± 5.74) cell lines. Pt(en)Cl2 survival response was also higher in the HT-29 (IC50 = 250 μM ± 4.72), and A549 (IC50 = 200 μM ± 7.70) compared to the HT-1197 (IC50 = 50 μM ± 4.20), MCF7 (IC50 = 50 μM ± 1.85), HEK 293 (IC50 = 40 μM), SK-MEL-5 (IC50 between 30 μM ± 13.63 and 40 μM ± 3.60) cell line. Given the differences in IC50 based on our data, we conclude that leaving ligand structure influences cell survival of platinum(II) compounds.

Disciplines

Biochemistry | Cancer Biology | Cell and Developmental Biology | Structural Biology | Toxicology

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