Preclinical testing of novel natural, synthetic, and semi-synthetic compounds as anti-cancer agents

Abstract

Cancers and their resistance to therapy have led to an extensive search for a curative agent. We have systematically evaluated the responses of cancer cells to various anti-cancer agents, including synthetic, semi-synthetic, and natural products, using in vitro techniques.
With the emergence of cisplatin resistance and toxicity in patients, we designed new ruthenium metal complexes. Our ruthenium(II) anti-cancer complexes were found to be selectively cytotoxic between cancer cells (e.g., DU145 prostate cancer cells) and PTN1A normal prostate cells. From structure-activity relationship (SAR) studies, we found that possession of a 1,10-phenanthroline ancillary ligand by our ruthenium(II) arene complex significantly increased its anti-cancer activity compared to the complex with a 1,4,5,8-tetraazaphenanthrene ancillary ligand. Furthermore, the addition of heterocyclic substituents (VNK-572 and POW-12) to the intercalating ligand of our ruthenium(II) bis-phenanthroline dipyridoquinoline polypyridyl complex (VNK-754) enhanced its anti-proliferative activity. These ruthenium complexes were able to reduce cell migration (ENB-01), intercalate DNA (VNK-572 and POW-12A), cause DNA fragmentation, and induce apoptotic cell death.
Optimisation of terpenes by the addition of a para-substituted fluoro-isoxazoline substituent was also done and led to a 2-fold increase in the anti-cancer activity of some of the terpenes against MDA-MB-231 cells. Here, the fluoro-isoxazoline derivative of the terpenoid, caryophyllene oxide, was the most cytotoxic. We observed that hydrogen bonding could play a role in the cytotoxic activity of the caryophyllene oxide derivatives, as esterification attenuated this effect.
Finally, we screened donepezil and it’s regio-isomeric fluorine analogues. The results showed higher anti-cancer activity for the isomer with a para-fluorine substituent compared to those with ortho- and meta-fluorine substituents respectively.

Date of Award	22 May 2025
Original language	English
Awarding Institution	Northumbria University
Supervisor	Stephany Veuger (Supervisor) & Valery Kozhevnikov (Supervisor)