Studies of palladacycle compounds derived from functionalized triazoles as antitumoral agents

Abstract

One of our research interest has been the synthesis and development of new antitumoral drugs derived from palladacycle compounds having the N,N-dimethyl-1-phenethylamine as cyclometallation agent. [1-4]. One of our results revealed that the palladium compound [Pd2(C2,N-S(-)dmpa)2(m-dppf)Cl2 ] was able to inhibit the Cathepsin-B activity in a reversible fashion being efficient antitumoral agent with low toxicity [1]. In another study we conclude that the suppressive effects of ionic palladacycle compound [Pd(C2,N-S(-)dmpa) (dppf)]Cl on haematopoiesis could be attributed, at least in part, due to the inhibitory effects of this drug on ACE activity, which probably results in AcSDKP increased levels [2]. We have reported also that the binuclear palladacycle complex [Pd2(C2,N-S(-)dmpa)2(m-dppe)Cl2] as most active complexes against melanoma B16F10-Nex2 cell line where this complex induces the cellular apoptosis [3]. Finally, we recently observe by confocal microscopy studies that the complex [Pd(C2,N-S(-)dmpa) (dppf)]Cl promotes cellular apoptosis by lysosomal way [4]. In this last work, based on the evidences that programmed cell death in tumour cells is of generous benefit for cancer chemotherapy and results of biological assays performed with leukaemia cells, allowed us to conclude that the palladacycle compound may have an important cytotoxic effect. In all mentioned cases, the fine structure dependence represented by a chiral carbon in the cyclometallation ring (C2,N-dmpa) for a functional response in vivo and for toxicity is remarkable. These complexes showed a significant enantioselective activity in vitro, with the S(-) enantiomers being more active than the R(+) enantiomers. To increase our knowledge remains these drugs and contributing to better elucidate the structural features of these complexes and its biological relevance, in this project we propose the synthesis and the study of new palladacycle compounds derived from functionalized triazoles as antitumoral agents. References: [1] Bincoletto C, Tersariol ILS, Oliveira CR, Dreher S, Soufen MA, Nascimento FD, Caires ACF (2005) Bioorg. Med. Chem.13, 3047 [2] Caires ACF, Oliveira CR, Smith MCM, Hemerly JP, Juliano MA, Bincoletto C (2004) Immunopharmacology and Immunotoxicology 26,487-500[3] Rodrigues EG, Silva LS, Fausto DM, Hayashi MS, Dreher SD, Santos EL, Pesquero JB, Travassos LR, Caires ACF (2003) Int J Cancer 107: 498-504[4] BARBOSA, Christiano M V, OLIVEIRA, Carlos R, NASCIMENTO, Fábio D, SMITH, Mickaela C M, FAUSTO, Daniela M, SOUFEN, Marco Antonio, SENA, Eliana, ARAÚJO, Ronaldo C, TERSARIOL, Ivarne L S, BINCOLETTO, Cláudia, CAIRES, A. C. F. European Journal of Pharmacology, 542, 2006, p. 37 - 47. (AU)