Oral Anticancer Heterobimetallic Pt^IV−Au^IComplexes Show High In Vivo Activity and Low Toxicity

Abstract

AuI‐carbene and PtIV−AuI‐carbene prodrugs display low to sub‐μM activity against several cancer cell lines and overcome cisplatin (cisPt) resistance. Linking a cisPt‐derived PtIV(phenylbutyrate) complex to a AuI‐phenylimidazolylidene complex 2, yielded the most potent prodrug. While in vivo tests against Lewis Lung Carcinoma showed that the prodrug PtIV(phenylbutyrate)‐AuI‐carbene (7) and the 1 : 1 : 1 co‐administration of cisPt: phenylbutyrate:2 efficiently inhibited tumor growth (≈95 %), much better than 2 (75 %) or cisPt (84 %), 7 exhibited only 5 % body weight loss compared to 14 % for 2, 20 % for cisPt and >30 % for the co‐administration. 7 was much more efficient than 2 at inhibiting TrxR activity in the isolated enzyme, in cells and in the tumor, even though it was much less efficient than 2 at binding to selenocysteine peptides modeling the active site of TrxR. Organ distribution and laser‐ablation (LA)‐ICP‐TOFMS imaging suggest that 7 arrives intact at the tumor and is activated there.

A hydrolytically stable oxo-rhenium(v) antitumor agent for synergistic combination therapy with cisplatin: from synthesis and mechanistic studies to toxicity assessment in zebrafish

“…5–8 These shortcomings have prompted researchers and clinicians to search for more effective strategies. 9 Extensive investigations on the antitumor potential of non-Pt metal complexes of ruthenium (Ru), 10–12 iridium (Ir), 13,14 titanium (Ti), 15 gold (Au) 16–18 etc ., with distinct mechanisms of action than DNA-targeting Pt drugs, have led to the identification of several promising candidates which are in preclinical or advanced clinical trials. 19,20 Alternatively, combination therapy comprising a Pt drug and other drugs with a distinct mechanism of action ( e.g.…”