Oral Anticancer Heterobimetallic PtIV‐AuI Complexes Show High In Vivo Activity and Low Toxicity

AuI-carbene and PtIV-AuI-carbene prodrugs display low to sub-mM 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 cispPt (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.