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.