Palladium(II) compounds with potential antitumour properties and their platinum analogues: a comparative study of the reaction of some orotic acid derivatives with DNA in vitro.
Ethidium bromide was used to study perturbations induced in salmon sperm DNA complexed with a series of platinum and palladium compounds obtained from chloro and orotic acid derivatives as leaving ligands. The antitumoral activity of these compounds against Sarcoma 180 cells grafted intraperitoneally into mice is correlated with their capacity to interact with DNA in vitro and to perturb its secondary structure. Nevertheless, among these compounds, [Pt(Dach)(3-methyl-orot)] and [Pt(Dach)(5-fluoro-orot)] do not interact with DNA in vitro and are inactive against Sarcoma 180 cells. This lack of activity originates from the fact that strong chelating properties of the ligand prevent hydrolysis of the compounds which are unable to give rise to aquo species which are the reactive ones. On the other hand, the interaction with DNA is not the only prerequisite in order that a compound be active towards tumour cells. In fact, cis-[Pd(NH3)2Cl2] and cis[Pd(Dach)Cl2] are not antitumoral. It is well known that the former undergoes an inactive trans-conformation and that the two compounds hydrolyse very fast assuming that they interact in vivo with a lot of molecules particularly proteins preventing them to reach the DNA, their pharmacological target. By contrast, [Pd(Dach)(3-methyl-orot)] (T/C = 267%) and [Pd(Dach)(5-fluoro-orot)] (T/C = 270%) display significant antitumour activity.
Butour
J L
JL
Institut de Pharmacologie et de Biologie Structurale du CNRS, Toulouse, France.
Wimmer
S
S
Wimmer
F
F
Castan
P
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D017690:Cell Transplantation; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D006868:Hydrolysis; D007700:Kinetics; D008024:Ligands; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009963:Orotic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010165:Palladium / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017671:Platinum Compounds / Q000378:metabolism / Q000494:pharmacology*; D012474:Salmon; D012510:Sarcoma 180 / Q000401:mortality / Q000473:pathology; D013056:Spectrophotometry, Ultraviolet; D013094:Spermatozoa / Q000378:metabolism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D008024:Ligands; D017671:Platinum Compounds; D010165:Palladium; D009963:Orotic Acid