New binuclear dithiocarbamate complexes [M2-µ2-bis-{(κ2S,S-S2CN(R)CH2CONHC6H4)2CH2}] (M=NiII, CuII, and ZnII): synthesis, characterization, DFT, and in vitro cytotoxic study

Abstract

A new series of binuclear dithiocarbamate macrocyclic complexes [M2-µ2-bis-{(κ2S,S-S2CN(R)CH2CONHC6H4)2CH2}] {R=Cy, M = NiII 1a, CuII 1b, ZnII 1c; R=iPr, M = NiII 2a, CuII 2b, ZnII 2c; R=nBu, M = NiII 3a, CuII 3b, ZnII 3c} have been efficiently synthesized by using a self-assembly process involving diamino precursor 4,4’-bis(2-(alkylamino)acetamido) diphenylmethane (L1, L2, or L3), CS2 and NiII, CuII, or ZnII ion. Compounds are suitably characterized by 1H, 13C, DEPT135, 1H DOSY NMR, HRMS, ESI MS, UV–Visible absorption, IR, and TGA/DTA methods. The experimental results are further supported by DFT level calculations. Compounds have been screened for their in vitro cytotoxicity against HepG2 (hepatoma) cell line by the MTT assay. The results showed much better activity of all the newly synthesized derivatives than clinically used drug cisplatin and specificity (except L’) for cancer cells over normal liver cells. Exceptionally, macrocyclic dithiocarbamate complexes 1b (IC50: 6.91 µM ± 0.22 µM) and 1c (IC50: 5 µM ± 0.16 µM) holding N–Cy substituents showed nearly 10–15 fold better cytotoxic activity against HepG2 cell lines compared to the reference drug cisplatin (IC50: 75.67 µM ± 0.25 µM). The shrinking of cells can be clearly visualized by acridine orange/ethidium bromide (AO/EB) staining, indicating the induction of apoptosis as part of the mechanism of action of these compounds.