Combining aspects of the platinum anticancer drugs picoplatin and BBR3464 to synthesize a new family of sterically hindered dinuclear complexes; their synthesis, binding kinetics and cytotoxicity

摘要

Picoplatin is a sterically hindered mononuclear platinum drug undergoing clinical trials. The\ud2-methylpyridine ring provides steric hindrance to the drug, preventing attack from biological\udnucleophiles. BBR3464 is a trinuclear platinum drug which was recently in Phase II clinical trials, and is\udhighly cytotoxic both in vitro and in vivo; it derives this activity through the flexible adducts it forms with\udDNA. In this work we sought to combine the properties of both drugs to synthesise a family of sterically\udhindered, dinuclear platinum complexes as potential anticancer agents. The bis-pyridyl-based ligands\udwere synthesised through a peptide coupling reaction using diaminoalkanes of differing lengths (n = 2, 4\udor 8) and 4-carboxypyridine or 2-methyl-4-carboxypyridine. The resultant dinuclear platinum complexes\udwere synthesised by reacting two equivalents of transplatin or mono-aquated transplatin to each ligand,\udfollowed by purification by precipitation with acetone. The unprotected complexes react faster with\ud5′-guanosine monophosphate (drug to nucleotide ratio 1 : 2; t1/2 = 2 h), glutathione (1 : 10, t1/2 = 55 min)\udand human serum albumin (HSA) (1 : 1, t1/2 = 24 h) compared to their hindered, protected equivalents\ud(5′-guanosine monophosphate, t1/2 = 3.5 h; glutathione = 1.7 h; HSA, t1/2 = 110 h). The complexes were\udtested for in vitro cytotoxicity in the A2780 and A2780/cp70 ovarian cancer cell line. The unprotected\udplatinum complexes were more cytotoxic than their protected derivatives, but none of the complexes were\udable to overcome resistance. The results provide important proof-of-concept for the development of a\udlarger family of sterically hindered multinuclear-based platinum complexes