Exploring the Anti-Cancer Activity of Novel Thiosemicarbazones Generated through the Combination of Retro-Fragments: Dissection of Critical Structure-Activity Relationships

Abstract

Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized “soft” donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination.

Synthesis, characterization and biological activities of semicarbazones and their copper complexes

“…Therefore, we conclude that semicarbazones are generally non-active compared to thiosemicarbazones. This is consistent with literature reports [26] We do not have the crystal structure details for the L2 and L3 copper complexes, which possess similar structural features except that the oxygen is replaced with the sulphur (thiosemicarbazones) but on our intuition is that a similar behaviour for copper coordination is seen in these compounds.…”

“…The anticancer activity of several thiosemicarbazones have been previously examined and showed extremely high anti-proliferative activity, typically falling between 4.7-30 µM for the colon, lymphoma, cervical carcinoma, and neuroepithelioma cancer cell lines [26]. However, our interest was to find out the anti-proliferative effect in prostate cancer cell lines.…”

“…In the recent years attention has focussed on the biological applications of these compounds. In this regard, it has been found that some thiosemicarbazones have potent anticancer activity [4][5][6][7][8][9][10][11][12][13][14] The use of iron chelators containing thiosemicarbazones has also been extensively studied [15][16][17][18][19][20][21][22][23][24][25][26] as has the anticancer activity of novel thiosemicarbazones generated through the combination of retro fragments. Some thiosemicarbazones have been found to have antibacterial and antifungal activity [27][28][29] and the pharmacological profile of thiosemicarbazones attached to a heterocyclic core has been reported by Singhal et al [30] The biological profile exhibited by these thiosemicarbazone and semicarbazone derivatives has led to work in which these compounds have been complexed with positron emitting isotopes (e.g.…”

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

“…Cytotoxic activity is primarily related to the metal ion and ligand structure for these N 2 O 2 chelate complexes but it should be taken into account that the lipophilic and hydrophilic properties of test samples may be a parameter for the proposed activity mechanism of thiosemicarbazones …”

Cytotoxic effect of palladium (II) inclusion compounds in beta-cyclodextrin

“…De hecho, las tiosemicarbazonas y sus complejos metálicos son de gran interés por su amplio rango de efectos biológicos (13,14), ya que tanto los ligandos derivados de ellas como los complejos metálicos de transición tienen otras propiedades farmacológicas antivirales, antibacterianas, antifún-gicas, antiparasitarias y antitumorales (3,10,(15)(16)(17)(18).…”