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Synthetic Strategies towards Development of Stable Gold Based Anticancer Agents and their Mechanistic Insight.

Date:
Location:
CP 114
Speaker(s) / Presenter(s):
Adedamola Arojojoye

Despite notable advancements in the design and synthesis of novel chemotherapeutic drugs in recent years, cancer continues to be a leading cause of mortality in the United States. Metallodrugs, especially gold complexes, have played a prominent role in the search for the next generation chemotherapeutic agents. Herein, I report on the synthetic strategies proffered towards rational design of stable gold-based agents, studied their reactivity in biological environment and proffer insights into the cytotoxic mechanism of action in diseased and normal cells. Stable gold complexes exist mostly in +I or +III oxidation states. Research into Au(I) complexes has overshadowed Au(III) complexes due to the reemergence of auranofin for treatment of other conditions including cancer. 

Despite been isoelectronic to cisplatin, Au(III) complexes exhibit different chemistry, reactivity, and molecular target compared to their platinum counterpart. My work has developed synthetic tools exploring the use of chiral bisphosphine ligands (Quinox P*) to synthesize cytotoxic Au(III) bisphosphine enantiomers that show similar response when administered to cancer cells. Further studies on chiral bisphosphine ligands using R-DuPhos ligands (where R is methyl or isopropyl) identified for the first-time products from the speciation studies of chiral Au(III) complex with L-glutathione (L-GSH), a biological reductant in cells. Furthermore, I carried out structure activity relationship studies with bisphosphine ligands. Thus, reacting different bisphosphines with di-ยต-chlorido biphenyl digold(III), gold(III) bisphosphine complexes were obtained with the phosphine backbone or side chains dictating stability and reactivity. The complexes showed very high physiological stability in L-glutathione while also demonstrating serum stability for 24 h. Further mechanism studied showed that compared to cisplatin, these complexes act as mild mitochondria uncoupler comparable to other protonophores such as FCCP. This, to the best of my knowledge is the first Au(III) mitochondria uncoupling agent. Also, I studied the impact of degree of cyclometallation on two set of cyclometalated gold(III) complexes bearing either a phenylpyridine (C^N) or biphenyl (C^C) Au(III) backbone. While the neutral C^C complexes showed improved electrochemical and biological stability (in L-glutathione), they showed lower cellular responses in cancer cells when compared to the C^N counterpart. Furthermore, longer alkyl chain complexes were not soluble in biological media. To overcome physicochemical barriers encountered in long alkyl chain gold(III) dithiocarbamate, encapsulation with bovine serum albumen was carried out. This resulted in improved solubility, cytotoxicity, and cellular uptake of the drug into cancer cells