Development of Novel Platinum(IV) Anticancer Complexes with Nonclassical Action Mechanisms

Abstract

Platinum (Pt)-based drugs have been widely used for cancer therapy. However, problems such as cellular resistance and toxicity to normal cells impede their further applications. To solve these problems, developing novel platinum-based complexes with nonclassical action mechanisms is necessary. Besides, understanding the cellular resistance mechanisms will provide new insights into the development of new generation of drugs.

In the first chapter, the background of platinum drugs, from chemistry to cellular resistance, is reviewed. In addition, many novel small platinum complexes developed in the past five years are selectively discussed.

In the second chapter, aiming to break ground for developing platinum-based drugs, we designed and synthesized the first water-stable, reductant-tolerant, and substitutionally reactive Pt(IV) complex. This Pt(IV) monotrifluoromethyl complex is different from all current Pt(IV) complexes, which cannot directly react with other substrates. The chlorido ligand that locates at the opposite position of the trifluoromethyl ligand can be substituted by various substrates, including 5′-dGMP. Single-crystal X-ray diffraction analysis reveals that the Pt-Cl bond is the longest. The chlorido ligand is substituted by other ligand via the bimolecular nucleophilic substitution (S_N2) pathway, which differs from cisplatin. This Pt(IV) complex proves the possibility that Pt(IV) complex is directly used as drug without the prior reduction.

In the third chapter, we designed and synthesized several cisplatin-based dynamic constitutional frameworks (DCFs). DCF 2a and DCF2b demonstrated good cytotoxicity among all tested cell lines, while they did not exert better cellular uptake as well as genomic DNA binding level. These results challenge the believe that genomic DNA is the main target of platinum-based drugs. The subsequent cell death mechanism research discovered that cisplatin and III-2 could cause endoplasmic reticulum stress.

In the fourth chapter, a carboplatin-based photo-responsive Pt(IV) complex, in which a photosensitizer was attached to the equatorial position, was synthesized. Photo-responsive Pt(IV) prodrugs are receiving increasing attention due to their reduced side effects and controllability of drug release. However, two questions about these photo-responsive prodrugs still need to be answered: 1) how do the Pt(IV) prodrug transform to the Pt(II) complex; 2) why do we need to conjugate a well-established photosensitizer to Pt center. Conjugating a chromophore to Pt center via the equatorial ligand allows us to trace Pt species after the release of axial ligands from Pt(IV) complex through hydrolysis or reduction. We discovered that the chlorine anion, which is widely present in biological environments, played an important role in the photoreaction of Pt(IV) complex. If the reaction system did not contain chlorine anion, the main products were hydrolyzed Pt(IV) complexes, while they were Pt(II) complexes in the presence of chlorine anion. Furthermore, a chlorinated product was monitored using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) after irradiation. This chlorinated product was quenched by adding a radical quencher. The chlorine anion influence the reaction progress of Pt(IV) complex via substituting the axial ligand and making the homolysis of Pt-axial ligand bond easy. Since the generation of radicals during the transformation from Pt(IV) prodrug to the Pt(II) counterpart is not oxygen-dependent, the photocytotoxicity of Pt(IV) complex with a photosensitizer should also be oxygen-independent. This was demonstrated by MTT tests conducted under hypoxic conditions (0.5%-0.9% oxygen).

Date of Award	11 Sept 2024
Original language	English
Awarding Institution	City University of Hong Kong
Supervisor	Guangyu ZHU (Supervisor)