Synthesis, characterization and anti-tumor activity of Pd(II) complexes with 4,5-benzo-3H-1,2-dithiole-3-thione

Abstract

Reaction of Na-2[PdCl4] with two equivalents of 4,5-benzo-3H-1,2-dithiole-3-thione (btt) affords cis-[PdCl2(kappa(1)-btt)(2)] (1), which provides a convenient entry into mixed-ligand btt complexes. Addition of one equivalent of a range of diamines or diphosphines gives the salts [Pd(kappa(1)-btt)(2)(kappa(2)-diamine)]Cl-2 (2a-d) (diamine = en, dap, bipy, phen) and [Pd(btt)(2)(kappa(2)-diphosphine)]Cl-2 (3a-c) (diphosphine = dppe, dppp, dppf) in good yields. In contrast, two equivalents of dppm result in [Pd(kappa(1)-btt)(2)(kappa(1)-dppm)(2)]Cl-2 (4), where the diphosphine binds in a monodentate fashion. Two equivalents of PPh3 result in a mixture of cis- and trans-isomers of [Pd(kappa(1)-btt)(2)(PPh3)(2)]Cl-2 (5a-b) (ca. 1:5 ratio); the pure trans-isomer 5b was isolated by ion-exchange chromatography. The cis-isomer 5a could be synthesized independently from the reaction of cis-[PdCl2(PPh3)(2)] with two equivalents of btt. In all of these complexes, the btt ligand binds in a monodentate manner through the exocyclic thione sulfur. The anti-tumor activities of representative examples, cis-[PdCl2(kappa(1)-btt)(2)] (1), cis-[Pd(kappa(1)-btt)(2)(kappa(1)-dppm)(2)]Cl-2 (4) and cis-[Pd(kappa(1)-btt)(2)(PPh3)(2)] (5a), were evaluated by cell proliferation assays and phase-contrast microscopy against prostate cancer cell lines PC3, DU145 and LNCaP, with complexes 1 and 4 showing potent anti-proliferative effects (TGI values of 19.2 and 21.1 mu g/mL, respectively) against LnCaP cells.