Thiocarbazole-based gold nanoparticles: synthesis, characterization and anti-proliferative activity evalutation

Carbazoles are aromatic heterocyclic compounds derived from the fusion of a benzene ring with an indole nucleus in position 2,3. Today, many carbazole derivatives are widely used as antioxidants, anti-fungal, photoconductor, anti-bacterial, antimalarials, anti-tuberculosis, anti-HIV agents and for obesity's treatment. Some of them, differently substituted, have been synthetized and their biological activity have been evaluated. Ellipticine, a vegetable alkaloid with a carbazole backbone , isolated from the leaves of Elliptica Ochrosia, is well-known for its marked antitumor activity, exerted through different mechanisms, including inhibition of the topoisomerases. However, the presence of side effects limits its use, as well as for some of its derivatives, in clinic therapy. Thus, over the years new carbazole derivatives were synthesized with the aim to cut down side effects and improving their biologic activities. The aim of this work is the study of and the biological evaluation of a new series of carbazoles in which the carbazole nitrogen has been functionalized with alkyl-thiol chains. This work is focused on the creation of new N-tioalchilcarbazole derivatives bearing on the nitrogen of the carbazolic core long alkyl chains up to seven, eight and nine carbon atoms, linked to a terminal thiol group, and various substituents on the carbons in position 1, 4 and 6. Some of the synthesized compounds have shown anti-proliferative activity, due to the induction of the intrinsic apoptotic pathway, also known as mitochondrial pathway, in mammary MCF-7 and MDA and, to a greater extent, in uterine HeLa and Ishikawa tumor cell lines. The main advantage of these compounds may be ascribed to the absence of cytotoxic effect on non-tumoral cell lines MCF-10a and 3T3-L1, making them promising compounds in anti-cancer therapy. These derivatives have been used as binders for gold nanoparticles synthesized in an organic solvent. The bond between the ligand and the nanoparticle exploits the known affinity of the terminal functional -SH group, suitable to act as capping agents for the stabilization of gold nanoparticles with the formation of dynamic covalent bonds. In this way, the formation of self-assembled monolayers of these ligands is obtained on the spherical surface of gold nanoparticles, with a stabilizing effect against aggregation. These systems might present a double innovative function, combining an antitumoral activity common of carbazoles, with the photothermal effects of gold nanoparticles.