title: Chiral cyclopalladated complexes derived from N,N-dimethyl-1-phenethylamine with bridging bis(diphenylphosphine)ferrocene ligand as inhibitors of the cathepsin B activity and as antitumoral agents.
abstract: Chiral cyclopalladated complexes derived from N,N-dimethyl-1-phenethylamine and the coordinating ligand 1,1'-bis(diphenylphosphine)ferrocene were synthesized and studied as Cathepsin B inhibitors and antitumoral agents against solid tumors. Our results revealed that the palladium compound [Pd2(C2,N-S(-)dmpa)2(mu-dppf)Cl2] (2) was able to inhibit Cathepsin B activity in a reversible fashion. This palladacycle compound binds to free cathepsin B (E) as well as to the enzyme-substrate complex (ES) with dissociation constants of KH=12+/-1 microM and alphaKH=2.4+/-0.3 microM, respectively. The application of this complex, in Walker tumor-bearing rats, resulted in 90% inhibition of the tumor growth. Subcutaneous inoculations of 10(6) tumoral cells produced solid tumors with a mass of 4.0+/-1.0 g in 12 days Walker tumor-bearing rats. However, when these animals were treated with one dose of the palladacycle compound (2.0 mg/kg), the tumoral mass was reduced to 0.3+/-0.1 g. On the other hand, the same complex (2) did not afford any protection to mice bearing the non-metastatic Ehrlich Ascites tumor treated with doses of 0.5, 5.0, and 30 mg/kg for a period of four, three and one day, respectively, beginning 72 h after tumor inoculation. Toxicological studies using mice treated with one high dose of the complex (2) (100 mg/kg) did not show any alterations in red and white blood cell morphology 14 days after the drug administration. Similar results were obtained with hepatic, kidney, and spleen tissues. The results presented in this work introduce the title cyclopalladated complexes as promising antitumoral drugs with reduced toxicity in experimental studies.
authors.affiliation: Centro Interdisciplinar de Investigação Bioquímica-CIIB, Universidade de Mogi das Cruzes, Av. Cândido Xavier de Almeida Souza, 200-CEP: 08701-970, CP: 411, Mogi das Cruzes-SP, Brazil.
authors.forename: Cláudia
authors.initials: C
authors.lastname: Bincoletto
authors.forename: Ivarne L S
authors.initials: IL
authors.lastname: Tersariol
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Oliveira
authors.forename: Simone
authors.initials: S
authors.lastname: Dreher
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Fausto
authors.forename: Marco Antonio
authors.initials: MA
authors.lastname: Soufen
authors.forename: Fábio D
authors.initials: FD
authors.lastname: Nascimento
authors.forename: Antonio C F
authors.initials: AC
authors.lastname: Caires
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005296:Ferrous Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D008024:Ligands; D008297:Male; D000075163:Metallocenes; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D010165:Palladium / Q000737:chemistry*; D010627:Phenethylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010720:Phosphines / Q000138:chemical synthesis / Q000737:chemistry*; D051381:Rats; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005296:Ferrous Compounds; D008024:Ligands; D000075163:Metallocenes; C503776:N,N-dimethyl-1-phenethylamine; D009942:Organometallic Compounds; D010627:Phenethylamines; D010720:Phosphines; D010165:Palladium; D002401:Cathepsin B; C004998:ferrocene