title: Modulation of drug activation profiles through carboxylate ligand modification in cytotoxic trans-platinum planar amine compounds.
abstract: Transplatinum planaramine (TPA) compounds possessing carboxylate ligands in the trans position have been shown to be potential antitumor drugs in a variety of cell types, including cisplatin and oxaliplatin-resistant cell lines. In this work, we ask whether the nature and stability of the carboxylate ligand can be tuned in an attempt to manipulate the extent of serum protein binding; and consequently influence cytotoxicity, cellular drug accumulation and DNA adduct formation. Monitoring the interactions of selected TPAs with N-acetyl-methionine (NAM) by (1)H and (195)Pt NMR spectroscopy shows significant differences in the rate of sulfur binding. TPA-containing acetate ligands show a much lower sulfur binding rate than those possessing formate leaving groups. The same trend was seen when acetate and formate TPA compounds were incubated with human serum albumin and the reaction monitored for 24 h. To understand whether these results could be translated into a cellular medium, MTT cytotoxicity assays were conducted for each compound, before and after incubation with whole serum. Both the formate and acetate compounds, t-[Pt(4-pic)NH(3)(OFm)(2)] and t-[Pt(4-pic)NH(3)(OAc)(2)], showed minimal losses in cytotoxic efficacy and outperformed cisplatin after pre-incubation with serum. The same trends were seen when monitoring the effects of protein binding on cellular uptake and DNA platination. The rate of protein binding/drug deactivation was shown to be directly related to the stability of the leaving group (OAc(-) > OFm(-) > Cl(-)). Thus, our results suggest that utilization of the 'carboxylate strategy' substantially enhances the cellular efficacy of TPA compounds over cisplatin by allowing for an optimal balance between cytotoxic and metabolic efficiency.
authors.affiliation: Department of Chemistry and Massey Cancer Center, Virginia Commonwealth University, 1001 W. Main St., Richmond, VA 23284, USA.
authors.forename: Brad T
authors.initials: BT
authors.lastname: Benedetti
authors.forename: Susana
authors.initials: S
authors.lastname: Quintal
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Farrell
mesh_terms: D000588:Amines / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity; D002264:Carboxylic Acids / Q000737:chemistry*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry / Q000633:toxicity; D056831:Coordination Complexes / Q000737:chemistry* / Q000633:toxicity; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D008024:Ligands; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000633:toxicity; D000077150:Oxaliplatin; D010984:Platinum / Q000737:chemistry*; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D056831:Coordination Complexes; D008024:Ligands; D009944:Organoplatinum Compounds; D012709:Serum Albumin; D000077150:Oxaliplatin; D010984:Platinum; D004247:DNA; D002945:Cisplatin