Organogold(III)-dithiocarbamate compounds and their coordination analogues as anti-tumor and anti-leishmanial metallodrugs

Abstract

The limited chemical stability of gold(III)-based compounds in physiological environment has been a challenge in drug discovery, and organometallic chemistry might provide the solution to overcome this issue. In this work, four novel cationic organogold(III)-dithiocarbamate complexes of general structure [(C^N)Au^IIIDTC]PF₆ (C1a - C4a, DTC = dithiocarbamate, L1 - L4, C^N = 2-anilinopyridine) are presented, and compared to their coordination gold(III)-dithiocarbamate analogues [Au^IIIDTCCl₂] (C1b - C4b), as potential anti-cancer and anti-leishmanial drugs. Most of the complexes effectively inhibited cancer cell growth, notably C3a presented anti-proliferative effect in the nanomolar range against breast cancer (MCF-7 and MDA-MB-231 cells with moderate selectivity. Pro-apoptotic studies on treated MCF-7 cells showed a high population of cells in early apoptosis. Reactivity studies of C3a towards model thiols (N-acetyl-L-cysteine) refer to a possible mode of action involving bonding between the organogold(III)-core and the thiolate. In the scope of neglected diseases, gold complexes are emerging as promising therapeutic alternatives against leishmaniasis. In this regard, all gold(III)-dithiocarbamate complexes presented anti-leishmanial activity against at least one Leishmania species. Complexes C1a, C4a, C1b, C4b were active against all tested parasites with IC₅₀ values varying between 0.12 and 42 μM, and, overall, organometallic compounds presented more intriguing inhibition profiles. For C4a selectivity over 500-fold for L. braziliensis; even higher than the reference anti-leishmanial drug amphotericin B. Overall, our findings revealed that the organogold(III) moiety significantly amplified the anti-cancer and anti-leishmanial effects with respect to the coordination analogues; thus, showing the great potential of organometallic chemistry in metallodrug-based chemotherapy for cancer and leishmaniasis.

Keywords: Amastigotes; Anticancer; Dithiocarbamate ligands; Gold complexes; Organometallic drugs.