A study of the properties, reactivity and anticancer activity of novel N-methylated-3-thiazolyl or 3-thienyl carbazoles and their Pd(II) and Pt(II) complexes

Abstract

The synthesis and characterization of two hybrid N-methylated carbazole derivatives containing a thiazolyl or a thienyl ring is reported. The thiazolyl derivative has been also characterised by X-ray diffraction analysis. The study of its reactivity in front of [MCl2(dmso)2] (M = Pd or Pt) or Na2[PdCl4] in methanol has allowed us to isolate and characterize its complexes. However, for the thienyl analogue, the formation of any Pd(II) or Pt(II) complex was not detected, indicating that it is less prone to bind to the M(II) ions than its thiazolyl analogue. Density Functional Theory (DFT) and Time-Dependent Density Functional Theory (TD-DFT) calculations have also been carried out in order to rationalize the influence of the nature of the thiazolyl or thienyl group on the electronic delocalization. Molecular mechanics calculations show that the free rotation of the thiazolyl in relation to the carbazole requires a greater energy income than for its thienyl analogue. Studies of the cytotoxic activity of the new compounds on colon (HCT116) and breast (MDA-MB231 and MCF7) cancer cell lines show that the thiazolyl carbazole ligand and its Pt(II) complex are the most active agents of the series and in the MCF7 line their potency is higher than that of cisplatin. In the non-tumoral human skin fibroblast BJ cell line, all the compounds were less toxic than cisplatin. Their potential ability to modify the electrophoretic mobility of pBluescript SK+ plasmid DNA and to act as inhibitors of Topoisomerases I and IIα or cathepsin B has also been investigated.