Exploration of Antiproliferative Activity and Apoptosis Induction of New Nickel(II) Complexes Encompassing Carbazole Ligands

Abstract

To attest the effectiveness of nickel complexes as anticancer drug candidates with minimum side effects, the present investigation describes the facile synthesis and anticancer activities of nickel(II) complexes enriched with three derivatives of carbazolone-based benzhydrazone ligands(L) having a [Ni(L) 2 ] composition. Analytical and spectral techniques were used to characterize the synthesized Ni(II) complexes. The single-crystal X-ray diffraction performed for complex 4 confirmed the square planar geometry with a [Ni(κ 2 -N,O-L) 2 ] arrangement. The MTT assay was carried out for the complexes to determine in vitro cytotoxicity against cancerous human-cervical carcinoma, humancolon carcinoma, and non-cancerous L929 (fibroblast) cells. All three complexes exhibited good toxicity against the cancer cells with a low IC 50 concentration. Complex 4, containing −OCH 3 fragment, exhibits high lipophilicity and revealed exceptional cytotoxicity against cancer cells. AO-EB fluorescent staining indicated apoptosis-associated cell morphological changes after exposure to complex 4. The apoptosis induction was further confirmed by a HOECHST-33342 fluorescent staining technique via chromosomal condensation and nuclear fragmentation. Further, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) mechanistic studies revealed that complex 4 can raise ROS levels and reduce MMP and promote mitochondrial dysfunction-mediated apoptotic cell death. Further, stimulation of late apoptosis by complex 4 in cervical cancer cells was quantitatively differentiated through the staining of phosphatidylserine externalization by flow cytometry. Furthermore, the ELISA analysis confirmed that complex 4 induced apoptosis through caspase activation.

Anticancer activity of Ni(ii) and Zn(ii) complexes based on new unsymmetrical salophen-type ligands: synthesis, characterization and single-crystal X-ray diffraction

“…Previous studies have demonstrated that presence of a methoxy group (–OCH 3 ) in some molecules can significantly increase biological activity, particularly antiproliferative performance. 42,46,72,73 Unsubstituted Ni II -L 1 (with R = H) did not present antiproliferative activity in any of the tested cell lines (IC 50 > 100 μM). In contrast, its methoxy-containing derivative Ni II -L 2 (with R = –OCH 3 ) was the most potent anticancer agent (IC 50 = 3.4–11.3 μM).…”

“…Therefore, it was not possible to establish a clear correlation when including the methoxy group, in agreement with previous reports. 42,46,72,73 More salophen derivatives are required to assess the role played by substituents (R = H or -OCH 3 ) in the aromatic rings and further studies to examine the pathways of action through which these kinds of complexes act.…”

“…Moreover, many Ni(II) and Zn (II) compounds have anticancer activities via binding with proteins or DNA, leading to DNA injury in cancer cells, blocking cancer cell division, and cell death. 42,43 Although numerous symmetric N 2 O 2 complexes have been investigated, 28,32,[43][44][45][46] a relatively small number of studies on salen/salophen Ni(II) or Zn(II) complexes with asymmetric ligands have been reported. 47 To our knowledge, asymmetric N 2 O 2 Schiff base complexes have not been studied regarding their biological and antiproliferative properties.…”

“…Moreover, many Ni( ii ) and Zn( ii ) compounds have anticancer activities via binding with proteins or DNA, leading to DNA injury in cancer cells, blocking cancer cell division, and cell death. 42,43…”