Comparison of click-capable oxaliplatin and cisplatin derivatives to better understand Pt(ii)-induced nucleolar stress

Abstract

Pt(II) chemotherapeutic complexes have been used as predominant anticancer drugs for nearly fifty years. Currently there are three FDA-approved chemotherapeutic Pt(II) complexes: cisplatin, carboplatin, and oxaliplatin. Until recently, it was...

Click-Capable Phenanthriplatin Derivatives as Tools to Study Pt(II)-Induced Nucleolar Stress

“…This indicates that further studies with phenanthriplatin, and indeed 1 – 3 , are likely needed to fully elucidate the role of DDR in the nucleolar response of phenanthriplatin. , …”

“…This indicates that the small azide modification present in 1 – 3 does not prevent the complexes from binding to DNA in vitro . Following initial incubation of the complexes with HP-DNA, a strain-promoted azide–alkyne click reaction was carried out with the click-capable fluorophore, Alexa-647 DBCO. , Subsequent analysis by fluorescence imaging showed successful strain-promoted azide–alkyne click reaction in the case of each of 1 , 2 , and 3 , indicating the complexes can be successfully modified following reaction with biomolecules (Figure ). Taken together, these results indicate that 1 , 2 , and 3 are suitable click-mimics of phenanthriplatin and are suitable derivatives for studying Pt-modified biomolecules.…”

“…In line with previous results, treatment of A549 cells with the known DDR inducer, cisplatin, resulted in a strong γH2AX response indicating activation of DNA damage repair pathways (Figure ). , …”

“…(A) Structures of select previously reported azide-containing cisplatin click derivatives. , (B) Structures of previously reported azide-containing oxaliplatin click derivatives . (C) Structures of click-capable azide-containing phenanthriplatin derivatives reported in this study.…”

“…One approach that has previously shown great success in identifying the biological targets of Pt agents is the use of click-capable Pt complexes. , The use of cisplatin-like Pt-click complexes for instance has been successfully employed to identify a range of Pt-bound biomolecules such as P(II)-DNA, -RNA, and -protein adducts (Figure A). ,− Moreover, the design of Pt-click complexes allows for the assembly of more complex molecules such as Pt-click oligonucleotides for target enrichment or Pt-triplex-forming oligonucleotides (TFOs) for gene targeting applications. , Recently, our groups reported the first click-capable Pt complexes possessing azide derivatives of oxaliplatin’s 1,2-diaminocyclohexane (DACH) ligand, and demonstrated that one of these complexes could successfully induce nucleolar stress (Figure B) . To further expand the range of Pt-click complexes available and to generate a probe that can be used to study potential differences between oxaliplatin- and phenanthriplatin-induced nucleolar stress, we set out to design phenanthriplatin click complexes capable of inducing nucleolar stress responses.…”