Date on Master's Thesis/Doctoral Dissertation

8-2022

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Chemistry

Degree Program

Chemistry, PhD

Committee Chair

Grapperhaus, Craig

Committee Co-Chair (if applicable)

Buchanan, Robert

Committee Member

Nantz, Michael

Committee Member

Bates, Paula

Author's Keywords

metal complexes; bisthiosemicarbazones; alkylthiocarbamates; copper; cancer; hypoxia

Abstract

Bis(thiosemicarbazones) (BTSCs) and their metal complexes have been extensively studied for various applications including catalysis for hydrogen evolution reactions, treatment of neurodegenerative diseases, hypoxia imaging, and a wide range of pharmacological purposes including antitumor, antiviral, antibacterial, and antifungal agents. The paramount property that makes BTSC metal complexes interesting for their use in these applications is the reduction potential of the coordinated metal, which can be selectively tuned by varying the substituents present on the ligand framework. Although the BTSCs have shown a great deal of success as potential cancer therapeutic agents, they lack selectivity towards cancer cells. For this matter, there has been a reoccurring need for the development of new molecular libraries that can not only show good potency towards cancer but also are more selective towards cancer cells, displaying minimal side effects. In this dissertation, we have developed two different derivatives of BTSCs and their metal complexes that are fully characterized using NMR, FT-IR, UV-Visible spectroscopy, EPR, and single crystal X-ray crystallography. The reduction potential of the metal complexes can be determined using electrochemical tools like cyclic voltammetry and the purity of the compounds is assessed using square wave voltammetry. The metal complexes have been explored for their antiproliferation activity against lung adenocarcinoma cell line (A549) and non-malignant lung fibroblast cell line (IMR-90) using (4,5-dimethylthiazol-2-yl)-2,5-diphenyltatrazolium bromide (MTT) assay. The first class of metal complexes (ML1-3; M = Cu, Ni, Zn) contains a hybrid ligand system (H2L1-3) constituting of components of a BTSC and an alkylthiocarbamate (ATCB). The hybrid vi compounds offer both polar and nonpolar domains as another way to tune the properties of the metal complexes. The effect of electronic structure on the activity of these compounds was assessed. The constitutional isomers (H2L3 and H2L4) of these hybrid systems were synthesized and complexes with copper (CuL3-4) to evaluate the role of physical structure on the antiproliferation activity of these compounds. The second class of compounds contain linkage isomers (CuL7, CuL7' and CuL8, CuL8') synthesized from ATCB ligand system via different chemical routes. The linkage isomers possess different electronic and physical structures and provide an interesting way to explore its effects on the antiproliferation activity. In the end, we have synthesized four complexes (CuL10, CuL10' and CuL11, CuL11') that provide a unique opportunity to study the effect of linkage isomers and constitutional isomers on biological activity as the complexes have the same composition but differ in their electronic and physical structures.

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