Novel Platinum(II) and Platinum(IV) Anticancer Agents: Synthesis, Stability, Activation, and Mechanism of Action

Abstract

Non-conventional Pt(II) complexes bearing phosphine ligands have been reported over the past decades. Some of these Pt(II) complexes are cytotoxic against cisplatin-resistant cancer cells, while the detailed mechanisms of action remain unclear. Moreover, phosphine-Pt(II) complexes are primarily synthesized by ligand exchange reactions, which restricts the conjugation of carboxylate or carbamate ligands and often compromises stereoselectivity. In Chapter II, a reductive ligand exchange reaction between Pt(IV) complexes and phosphines was extended to synthesize a series of phosphine-Pt(II) complexes bearing carbamate ligands. The most potent Pt(II) complexes are selected through cytotoxicity screening, and their biological activities to kill cancer cells are evaluated. Most of these phosphine-Pt(II) complexes exhibit comparable cytotoxicity to cisplatin against various cancer cells and resistance factors ranging from 0.5 to 1.5, demonstrating their ability to overcome drug resistance. The lead complex 2-1b majorly accumulates in the endoplasmic reticulum (ER), triggers paraptosis by the ER stress pathway, and arrests the cell cycle in the G0/G1 phase. In contrast, the tetra-P-coordinated complex 2-16 arrests the cell cycle in the S phase and induces a combined cell death mode of autophagy and paraptosis. This chapter highlights the therapeutic potential of non-conventional phosphine-coordinated Pt(II) complexes and introduces promising drug candidates for anticancer research.

Recently, multitargeted Pt(IV) anticancer prodrugs have demonstrated significant activity in reducing drug resistance associated with conventional Pt(II) drugs. However, the types of bioactive ligands and drugs that can be conjugated to the Pt center remain limited to O-donors. In Chapter III, the synthesis of Pt(IV) complexes featuring axial pyridines via ligand exchange reactions is reported. The quick release of axial pyridines after reduction indicates their utility as axial leaving groups. These pyridinyl Pt(IV) complexes are effective in killing platinum-resistant cancer cells. Furthermore, two multitargeted Pt(IV) prodrugs are developed, containing bioactive pyridinyl ligands: a PARP inhibitor and an EGFR tyrosine kinase inhibitor; these conjugates also exhibit great potential for overcoming drug resistance, and the latter conjugate inhibits the growth of Pt-resistant tumors in vivo. This research adds to the array of conjugating bioactive axial ligands to Pt(IV) prodrugs.

Photoactivation of Pt(IV) prodrugs has been reported as a controllable method to release Pt(II) anticancer drugs and enhance the selectivity to kill cancer cells. However, due to the limited penetration depth of UV/visible light, many studies attempted to extend the activation wavelength to enable the in vivo application of photoactivable Pt(IV) complexes. In Chapter IV, a series of green-light activable Pt(IV) anticancer prodrugs incorporating ER-targeting groups is presented. Photosensitive ligands derived from flavonoids are coordinated to Pt(IV) through their pyridinyl moieties by utilizing the ligand exchange reaction described in the previous chapter. The ligand-to-metal charge transfer of N-coordination significantly red-shifts the maximum absorption wavelength of these Pt(IV) complexes. Under green light irradiation, these Pt(IV) complexes are quickly reduced to carboplatin in the buffered solution and release the de-ethylated flavone ligands. Flavoplatins-3a and 3b, which contain sulfonated ligands, display at least 27-fold greater cytotoxicity than carboplatin under green light irradiation, with the resistance factor as low as 0.8. Both complexes efficiently accumulate in the ER and quickly trigger pyroptosis through the NLRP3/caspase-1/GSDMD pathway. This chapter introduces a novel class of triple-action Pt(IV) prodrugs that eliminate cancer cells by non-conventional mechanisms, providing a promising strategy for developing novel platinum-based anticancer agents.

Date of Award	28 Aug 2025
Original language	English
Awarding Institution	City University of Hong Kong
Supervisor	Guangyu ZHU (Supervisor)