Iron(III) and nickel(II) complexes of tetradentate thiosemicarbazones: Synthesis, structure, cytotoxicity, and lipophilicity

Abstract

Eighteen of the iron(III) and nickel(II) complexes with tetradentate thiosemicarbazidato ligands were synthesized and described, by analytical and spectroscopic methods. Two complexes as an example to the iron and nickel centered ones were crystallographically analyzed to confirm the molecular structures. Cytotoxic effects of the complexes on K562 chronic myeloid leukemia cells were determined by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay. For comparison, human umbilical vein endothelial cells (HUVECs) was used as a noncancerous cell line. While four of the iron(III) complexes exhibited the antileukemic effect with 50% inhibition of cell growth (IC50) values in the 3.4 to 6.9 μg/mL range on K562 cell line, the nickel(II) complexes showed no significant effect on both cell lines. The complexes Fe4, Fe5, and Fe6, bearing 4‐methoxy substituent exhibited relatively high antiproliferative activity on both cell lines. Complex Fe3 with 3‐methoxy and S‐allyl groups exhibited a selectivity between K562 and HUVEC cells by IC50 values of 6.9 and >10 μg/mL, respectively. Lipophilicity, a key parameter for bioavailability and oral administration, was found in the range of −0.3 and +1.3 that desired for drug active ingredients. The results were discussed in the context of a structure‐activity relationship.

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.…”

Iron(III) complexes based on tetradentate thiosemicarbazones: Synthesis, characterization, radical scavenging activity andin vitrocytotoxicity on K562, P3HR1 and JURKAT cells

“…However, complex Fe7 bearing 3-methoxy showed remarkable activity against K562 and P3HR1 cells, arising from allyl group (CH 2 -CH CH 2 ) in the sulfur atom like in similar molecules. [59] The 3,5-dichloro substituents did not contribute positively to cytotoxicity.…”

“…In brief, an easily noticeable change was observed in the backbone of the thiosemicarbazone after complex formation as seen in analogous iron centered structures. [41,59,60] The calculated nominal mass for expected structures of Fe7 and Fe8 having the same molecular formula, C 17 H 19 ClFeN 3 O 3 S, is 436 Da; Fe4 bearing propyl group instead of allyl group on Fe7,8 structures is 438 Da. When compared the masses of picked peaks with those of the possible molecular ions for Fe7, Fe8, and Fe4, it was seen that the expected molecular mass peak [M] was recorded at m/z 454.0, 454.9 (for Fe7); 454.1, 454.6 (for Fe8) and 455.4, 457.9 (for Fe4) with NH 4 adduction, [M+NH 4 ], at lowest intensity (relative abundance <5%).…”

“…These results are consistent with the antiproliferation effects of similar complexes determined in previous studies. For instance, two series of the iron(III) complexes with diarylidene-thiosemicarbazidato ligands exhibited meaningful cytotoxic effects on the leukemic cell line (K562) with the IC 50 values 6.8-13.8 [59] and 0.02-9.64 μM range. [67] Two of them metabolized by cytochrome P450 (CYP) enzymes are cytotoxic in IC 50 values of 1.34-5.13 μM range against Caco2, HCT116, Hep3B, HepG2 cancerous cell lines from different origins.…”