Revisiting the anticancer properties of phosphane(9-ribosylpurine-6-thiolato)gold(I) complexes and their 9H-purine precursors

Abstract

New mono- and di-nuclear thio-purine and thio-purine nucleoside gold(I) complexes were synthesized, characterized, and evaluated in vitro for biological activities in comparison to related known purine complexes. By combining known anti-tumoral thio-purines with R3PAu moieties as present in auranofin, complexes with enhanced effects and selectivities were obtained, which not only act as cytostatics, but also disrupt tumor-specific processes. Their IC50 values in cytotoxicity test with tumor cell lines ranged from three-digit nanomolar to single-digit micromolar, revealing a tentative structure–activity relationship (SAR). Both the residues R2 of the phosphane ligand and R1 at C2 of the pyrimidine ring had a significant impact on the cytotoxicity. In most cases, the introduction of a ribo-furanosyl group at N9 of the purine led to a distinctly more cytotoxic complex. Most complexes were more active against multi-drug-resistant tumor cells or such lacking functional p53 when compared to the respective untreated wild type cell lines. Some nucleoside complexes displayed an interesting dose-dependent dual mode of action regarding cell cycle arrest and DNA repair mechanism. Some phosphane(purine-6-thiolato)gold (I) complexes had a stronger inhibitory effect on the thioredoxin reductase (TrxR) and on the reactive oxygen species (ROS) generation in cancer cells than is typical of other gold complexes. They also led to DNA fragmentation and showed anti-angiogenic effects. Their stability under test conditions was demonstrated by 77Se NMR monitoring of an exemplary selenopurine complex. Graphical abstract

New 4,5-Diarylimidazol-2-ylidene–iodidogold(I) Complexes with High Activity against Esophageal Adenocarcinoma Cells

“…FLO-1 cells are p53-mutant cells, and the gold complexes may take advantage of the absence of p53, the “guardian of the genome”, to kill the FLO-1 cells. Analogously, higher sensitivities of p53-knockout HCT-116 colon carcinoma cells, when compared with p53-wildtype HCT-116 cells, were observed only recently for various NHC–gold(I) complexes and phosphinogold(I) complexes [ 19 , 35 ].…”

“…Furthermore, derivatives of auranofin with improved anticancer properties were described [ 17 , 18 ]. Recent developments in the field of auranofin-derived gold compounds led to highly active thiolatopurine complexes showing strong DNA damaging effects aside from TrxR inhibition, apoptosis induction, ROS formation, and antiangiogenic effects [ 19 ]. Advances in the research of N -heterocyclic carbene (NHC) gold complexes established a prospering class of metal-based drugs, which showed eminent anticancer activities based on TrxR inhibition and DNA interaction, adding well to the currently available arsenal of anticancer platinum complexes and the leading gold(I) complex auranofin [ 20 , 21 , 22 , 23 , 24 ].…”

Palladium and Platinum Complexes of the Antimetabolite Fludarabine with Vastly Enhanced Selectivity for Tumour over Non-Malignant Cells

“…This “metal–drug synergism” may be used to improve an already active drug’s cytotoxicity, stability, solubility, and pharmacokinetics [ 17 ]. There are examples of metallodrugs with peculiar modes of action, reduced unwanted side effects, or enhanced anti-tumoural activity against cancer cell lines that were originally refractory to the metal-free organic drug [ 18 , 19 , 20 , 21 ]. For the approach we intended here, namely, the application of metal complexes of fludarabine itself, there has been previous research.…”