Improving Cytotoxicity by Changing a Linker from Diphenylether to Diphenylmethane and now to Phenylene in Binuclear Dithiocarbamate Complexes: Synthesis and Cytotoxicity Study

摘要

α-chloroamide 1,3-bis(2-chloroacetamido)phenylene (L') is se- lected as a lead compound to derive 1,3-bis(2-(alkylamino) acetamido)phenylene (L1 -L3 ). A programmed self-assembly involving L1 -L3 , CS2 and Ni II , CuII or ZnII ions affords access to a new series of 32-membered binuclear macrocyclic dithiocarba- mates [MII 2-μ2 -bis-{(k2 S,S-S2CN(R)CH2CONH)2C6H4}]{R=Cy, M= Ni II 1a, CuII 1b, ZnII 1c; R=i Pr, M=Ni II 2a, CuII 2b, ZnII 2c; R= n Bu, M=Ni II 3a, CuII 3b, ZnII 3c}. Compounds were charac- terized by spectroscopic ( 1 H, 13 C, DEPT 135, 1 H DOSYNMR, HRMS/ESI MS, UV-visible, Fluorescence, IR) and by the TGA. Evidently, L' forms a fascinating 2D infinite supramolecular molecular sheet. All the compounds were screened for their in vitro cytotoxic activity against malignant tumor Hep G2 (hepatoma) cell line by the MTT assay. A majority of com- pounds ca L', L1 , 1a, 1b, 1c, 2a, 2b, 2c, L3 ,3a, 3b, 3c display IC50 values lower than cisplatin and specificity for carcinoma Hep G2 over normal liver cell line (WRL-68). Evidently cytotoxic potentials of L1 -L3 improved tremendously upon formation of their corresponding bimetallic dithiocarbamate complexes. 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. Further, DFT level calculations have been per- formed on representative compounds to reinforce the exper- imental results.