ABSTRACT
A series of complexes of the general formula trans-[PtCl2(Am)(pip-pip)] x HCl where pip-pip is 4-piperidinopiperidine and Am is NH3, methylamine (MA), dimethylamine (DMA), n-propylamine (NPA), isopropylamine (IPA), n-butylamine (NBA), or cyclohexylamine (CHA) were prepared and characterized, and their cytotoxic properties against ovarian and colon cancer cells were evaluated. The trans-[PtCl2(NH3)(pip-pip)] x HCl was significantly more potent than cisplatin in all the cisplatin-resistant ovarian cancer cell lines and was nearly as cytotoxic as cisplatin against colon cancer cells. In vivo studies in mice showed that the pip-pip complexes are significantly less toxic than cisplatin. Cisplatin was more efficacious than both trans-[PtCl2(NH3)(pip-pip)] x HCl and trans-[PtCl2(NBA)(pip-pip)] x HCl in the A2780 and A2780cisR tumor xenograft models, consistent with its lower IC50 values in A2780 cells but contrary to the higher IC50 values in A2780cisR cells. In the colon cancer cell studies, trans-[PtCl2(NH3)(pip-pip)] x HCl was slightly less potent than cisplatin in the in vitro studies but had efficacy comparable to that of cisplatin in the in vivo xenograft model.
Subject(s)
Antineoplastic Agents/chemical synthesis , Organoplatinum Compounds/chemical synthesis , Piperidines/chemical synthesis , Amines/chemistry , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/toxicity , Cell Line, Tumor , Cell Nucleus/genetics , Colonic Neoplasms , DNA/metabolism , Drug Screening Assays, Antitumor , Female , Glucose/pharmacology , Humans , Ligands , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Nude , Organoplatinum Compounds/pharmacokinetics , Organoplatinum Compounds/pharmacology , Organoplatinum Compounds/toxicity , Ovarian Neoplasms , Piperidines/pharmacokinetics , Piperidines/pharmacology , Piperidines/toxicity , Sodium Chloride/pharmacology , Solubility , Solvents , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
The determination of the structures and DNA interactions and the reactions with GSH and ubiquitin of complexes of the general formula trans-[PtCl2(Am)(pip-pip)] x HCl, where pip-pip is 4-piperidinopiperidine and Am is NH3, methylamine (MA), dimethylamine (DMA), n-propylamine (NPA), isopropylamine (IPA), n-butylamine (NBA), or cyclohexylamine (CHA), were performed. X-ray structures and NMR studies of the NH3 and MA complexes showed that both pip rings were in the chair conformation and that the second pip ring is fluxional. The DNA binding studies showed that these complexes bind to calf thymus DNA nearly an order of magnitude more quickly than cisplatin and form covalent adducts that stabilize the double helix. The binding of the pip-pip complexes to DNA results in high unwinding angles (approximately 30 degrees) and in the formation of approximately 25% interstrand cross-links. The pip-pip complexes reacted with GSH more quickly than cisplatin and transplatin, and the rate of reaction decreased with increasing steric bulk of the ligand trans to the pip-pip. The reactions with ubiquitin resulted in monofunctional binding to Met1. Only the NH3, MA, and DMA complexes reacted with ubiquitin in a slower and less efficient fashion than cisplatin.
Subject(s)
Antineoplastic Agents/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Organoplatinum Compounds/chemistry , Piperidines/chemistry , Amines/chemistry , Cations , Circular Dichroism , Crystallography, X-Ray , DNA/chemistry , Glutathione/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Transition Temperature , Ubiquitin/chemistryABSTRACT
Three isomeric complexes, trans-[PtCl2(NH3)(2-methylpiperidine)], trans-[PtCl2(NH3)(3-methylpiperidine)] and trans-[PtCl2(NH3)(4-methylpiperidine)], were prepared and their cytotoxicities against six ovarian cancer cell lines, three sensitive and three resistant to cisplatin, were measured. There were no significant differences in the cytotoxicities of the three isomers against these cell lines. The interactions of the three complexes with reduced glutathione (GSH) and with ubiquitin (Ub), as a model protein, were studied. The trans-[PtCl2(NH3)(2-methylpiperidine)] reacted approximately twice as slowly with GSH as did the other two isomers. In the 1:1 interactions of the three complexes with ubiquitin (Mr = 8565 amu), trans-[PtCl2(NH3)(3-methylpiperidine)] and trans-[PtCl2(NH3)(4-methylpiperidine)] attained 100% modification while trans-[PtCl2(NH3)(2-methylpiperidine)] reached only less than 50% modification. Trans-[PtCl2(NH3)(2-methylpiperidine)] reacts significantly less efficiently with GSH and proteins than the other two isomers yet this is not reflected in the cytotoxicity values. These results indicate that for these complexes, in these cell lines, cytosolic detoxification probably does not play a dominant role in determining the cytotoxicity of the complexes.
