New binuclear dithiocarbamate complexes [M₂-µ²-bis-{(κ²S,S-S₂CN(R)CH₂CONHC₆H₄)₂CH₂}] (M=Ni^II, Cu^II, and Zn^II): 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 = Ni^II 1a, Cu^II 1b, Zn^II 1c; R=ⁱPr, M = Ni^II 2a, Cu^II 2b, Zn^II 2c; R=ⁿBu, M = Ni^II 3a, Cu^II 3b, Zn^II 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 Ni^II, Cu^II, or Zn^II 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.

GRAPHICAL ABSTRACT

Keywords:

• Dithiocarbamate
• binuclear macrocyclic
• electrochemistry
• density functional theory
• cytotoxic
• cell staining
• apoptosis

Acknowledgments

One of the authors, Vineeta Pillai, acknowledges UGC, New Delhi, India, for the UGC-BSR fellowship. Authors are grateful to Dr. Arun Das, CSMCRI, Bhavnagar for recording HRMS spectra.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

VKS acknowledges SERB-DST, New Delhi, India, for the financial support (Reference No. EMR/2016/003172).