Derivatives of 4, 4′-Oxydianiline Show Distinct In Vitro Cytotoxicity, Apoptosis Induction, and Selectivity against HepG2 Cancer Cells

Gathering of number of pharmacophore on a single molecular platform evidently lead to improved therapeutic efficiencies and reduced side effects of conventional chemotherapy drugs. Three diamino precursors 4,4'-bis(2-(alkylamino)acetamido)di-phenylether (L-1-L-3) was selected to derive new series of metallomacrocyclic dithiocarbamate complexes [M-2-mu(2)-bis-{( kappa S-2,S-S2CN(R)CH2CONHC6H4)(2)O}] {R = Cy, M = Ni(II)1a, Cu-II 1b, Zn(II)1c; R = Pr-i, M = Ni(II)2a, Cu-II 2b, Zn(II)2c; R = Bu-n, M = Ni(II)3a, Cu(II)3b, Zn(II)3c}. These were characterized by standard spectroscopic and thermogravimetric methods. MTT assay was carried out on these compounds to explore their in vitro cytotoxicity against HepG2 (hepatoma) cell line. The diamino derivatives (L-1-L-3) in their metal-free form and metallomacrocyclic complexes, 1a, 1c, 2a, 2b, 2c, 3a, 3b and 3c exhibit improved cytotoxicity than Cisplatin and selectivity against HepG2 over normal cells. Remarkably, complexes 2c (3.55 +/- 0.06 mu M) and 3c (2.19 +/- 0.04 mu M) demonstrate 21 folds to 34 folds better cytotoxic activity whereas L-3 (5.49 +/- 0.04 mu M), 1a (7.27 +/- 0.16 mu M) and 3a (4.42 +/- 0.06 mu M) showed more than 10 fold better cytotoxic activity against HepG2 cell line as compared to the reference drug Cisplatin. Morphological evidences like shrinking of cells indicates the induction of apoptosis as part of the mechanism of action of these compounds which is further supported by the distinct staining of the cells by acridine orange/ethidium bromide (AO/EB).