Synthesis and Anticancer Activity of Bis-Thiosemicarbazone Complexes
Muhammad Hamza Ashfaq
Department of Chemistry, School of Science, University of Management and Technology, Lahore, Pakistan.
*Corresponding Author E-mail: hamzaashfaqchaudhary@gmail.com
ABSTRACT:
In a present review article, relationships were identified between the structure and activity of the bis-thiosemicarbazone ligands and their zinc and copper complexes. These compounds have different substituents at the diimine point and terminal nitrogen of the backbone. All the copper complexes showed distortion in geometry from square planar while all the zinc complexes showed distortion in geometry from square pyramidal. In electrochemistry determination by cyclic voltammetry, all the copper complexes were found quasi-reversible. When the antiproliferative activity was checked against tumor cells, copper complexes showed the greatest activity. It was seen that antiproliferative activity was decreased when hydrophobic moieties were present at diimine points and terminal nitrogen. Zinc complexes showed the lowest antiproliferative activity because they were failed in ligand delivery intracellularly as they were not chaperone. But cobalt showed good activity by successfully delivering the ligand acting as chaperone1. Copper complexes showed more antiproliferative activity as compared to the ligand. In the environment of the tumor, hypoxia was found which decreased the antiproliferative activity of the ligand and its copper complexes. In the present study, it was concluded that this relationship could be helpful in the synthesis of antitumor agents such as bis-thiosemicarbazone and its complexes.
INTRODUCTION:
Excellent in vivo and in vitro anticancer activity2 was shown by bis-thiosemicarbazones and monomeric thiosemicarbazones3-8. Complexes of the thiosemicarbazone ligand with transition metals are attaining the attention of research because they show antiviral and anticancer therapeutic uses5,6,9. Metal complexes of bis-thiosemicarbazones showed the greatest anticancer activities10. Dimeric structures are present in di-thiosemicarbazones and bis-thiosemicarbazones because they contain two entities of thiosemicarbazones. Swearingen and West reported that there are two entities of monomeric thiosemicarbazone which have amide nitrogen atoms connected to the spacer of aromatic and aliphatic moieties shown in Figure 111.
Moreover, bis-thiosemicarbazones have two connected thiosemicarbazone entities through imine N atoms shown in Figure 111.
Figure 1: Chemical structure
In Swiss mice, glyoxal bis-thiosemicarbazone was used to inhibit the growth of sarcoma – 180 tumors12. When bis-thiosemicarbazone was chelated with Copper (II) metal, it was noted that in vivo anticancer activity13 was increased. But drawbacks like loss of weight and toxicity related to the liver were also observed in rats and mice 14. These drawbacks helped in the development of that types of ligands that show less cytotoxicity, and which have more selectivity for tumor cells instead of normal cells15.
Different biological activities were shown by bis-thiosemicarbazones either they were present in the form of free ligands or the form of metal complexes8,16. When Thiosemicarbazides were condensed with diketone or dialdehyde then the ligands were derived.
Figure 2: Chemical Structure
Figure 3: Chemical Structures
The ligands thus produced can form complexes on reaction with transition metals. As a result, lipophilic and stable complexes can be formed which can be neutral also showing increased biological activities when compared with ligands17. The lipophilic copper complexes shown below in Figure 2 and 3, were neutral and can be used to treat different cancers and neural diseases8,18.
Some bis-thiosemicarbazones5,6,19 shown above in figure 3 can form copper complexes which are redox-active can form species that have reactive oxygen in them, and show cytotoxicity of tumor cell through permeabilization of the lysosomal membrane20. When copper is chelated with Cu(GTSM), the anticancer activity can be inhibited by the use of tetra thiomolybdate20,21. Cu(GTSM) which are copper ionophores can be used for elevation of intracellularly available copper, they show therapeutic activity22 against cancer cells of prostate8,23. The potential of anticancer activity of bis-thiosemicarbazone is based on the intrinsic ability of the compound to release copper which is coordinated to a compound present in an intracellular reductive environment20,24. Cu(ASTM) also has the potential to target tumor hypoxia selectively, because hypoxic cells have less oxygen tension which helps in stabilization of Copper (I) charged complex and as a result intracellular accumulation takes place and hypoxia selectivity also occur25,26.
In this review, preparation, characterization and complex formation with zinc and copper metal and their activities have been studied. The relationship between structures and their activities due to different substituents at diimine and terminal nitrogen positions has also been studied3, 27. These compounds are shown below in Figure 4 exhibit anticancer activity due to two substitutions at the 4th nitrogen atom3,4,28,29.
di – 2 – pyridylketone 4 – cyclohexyl – 4 – chyclohexyl – 4 – methyl- 3 – thisemicarbazone (DpC), and iron chelator, desferrioxamine
Figure 4: Chemical Structure
Different substitutions at diimine and terminal nitrogen position increase the biological activity of the compounds shown in Figure 5 20, 25.
Figure 5: Chemical structures
DISCUSSION:
BIS-THIOSEMICARBAZONE COMPLEXES:
Glyoxaldehyde copper and nickel complexes were prepared and characterized spectroscopically. Melting point technique, electronic and proton NMR were used to characterize the bis-thiosemicarbazones. These complexes are then coordinated to tetradentate di-anionic ligands30,31.
Alkyl substitution in the backbone of copper complexes of bis-thiosemicarbazones showed biological properties due to different redox changes. For the determination of the cause of these changes, an x-ray analysis was performed. Hypoxia tracer was also present in these complexes. These complexes showed slight distortion from planar structures which was due to the molecular interactions. As a result, complexes became cross-linked flat.
Figure 6: Structures for compounds characterised in this study
Hydrogen bonding was interrupted due to the substitution of alkyl groups at the terminal N atoms, resulted in planar geometry of complexes but no effect on the coordination sphere. Carbon-carbon bond length increased because of substitution at backbone with alkyl groups. This thing enabled the better fitting of metal in the cavity of the ligand with tiny Cu-S bonds32.
Hypoxia, the flow of blood, and radiolabel cells were imaged with positron emission tomography. In this technique, bis-thiosemicarbazone copper complexes were used. The applications mentioned were based on controlled lipophilicity and redox potentials of complexes. Adjustments could be made by alteration of ligand substituents. Copper acetate was used for the preparation of copper complexes through the trans-metalation of zinc complexes. Relationships between the structure and activity of linked ligand alkyls were determined33.
Biological, physical, and chemical properties of zinc bis-thiosemicarbazone complexes were studied. Respiration is inhibited in ascites cells of Ehrlich by zinc complexes. Bis-thiosemicarbazone ligand first stimulated and then depressed the Oxygen uptake. Zinc ion behavior of different zinc bis-thiosemicarbazone complexes with tumor cells was interpreted by partition coefficients and constants34.
Phenylglyoxal nickel and copper complexes were synthesized and characterized spectroscopically. Melting point technique, IR, electronic, and proton NMR were also used for characterization. These complexes are then coordinated to tetradentate di-anionic ligands35.
Copper (II) is reduced to Copper (I) through the reduction mediated by thiol, as a result, reactive oxygen containing species are produced. In this study, the anticancer activity36-38 of Triapine copper complexes was compared and it was concluded that redox cycling based on reducing agents occurs at the outside of the cells, resulting in superoxide radical’s generation and their dismutation. As a result, hydrogen peroxide is produced in cytotoxic amounts. It was assumed that thiosemicarbazone copper complexes can generate thiol-induced ROS but this factor cannot be considered determined39.
Stefani et al. reported the anti-neoplastic activities of bis-thiosemicarbazones and their copper complexes. No doubt, the mechanism was not understood. The relationship between structure and activity of bis-thiosemicarbazones was examined and its anti-cancer activity was also evaluated. It was concluded that permeabilization of the lysosomal membrane of bis-thiosemicarbazone copper complex plays role in anti-cancer activity evaluated by fluorescence microscopy. In this study, it was highlighted that species that have reactive oxygen and permeabilization of lysosomal membrane plays role in the anticancer activity of bis-thiosemicarbazone complexes20.
For cancer treatment, iron chelators have also developed. In this present study, different thiosemicarbazone ligands with different substituents and their derivatives were prepared as they show remarkable and selective anticancer activity. These compounds were concluded as the effective antiproliferative agents showing remarkable lipophilicity, neutral pH and allow access to Fe pools intracellularly 40.
Figure 7: Structure of di – 2 – pyridyl ketone 4,4 – dimethyl – 3 – thiosemicarbazone
Baker et al. reported the preparation of iron chelator of hydrazine with pyridoxal iso-nicotinoyl and its activity was checked in the reduction of hepatocyte iron. Aromatic aldehydes were condensed for the synthesis of 45 compounds. Some derivatives were more active than the parent compound. All the compounds showed potential activity in the reduction of hepatocyte iron41.
Thiosemicarbazone chelators having di-2-pyridyl ketone were synthesized showing selective and remarkable anticancer activity. Then their manganese, copper, nickel, cobalt, and zinc complexes were prepared to evaluate their biological activities. Four metals formed divalent complexes and iron formed trivalent complex. Lipophilic vehicle character was assumed for the complexes which help in the facilitation of the delivery of ligand intracellularly through metal dissociation42.
The role of copper in the promotion of angiogenesis was studied. Angiogenic tumors entered the phase of extreme growth and their metastatic potential was also increased. Tetra-thiomolybdate caused copper deficiency which resulted in the growth of the tumor and angiogenesis. Formation of vessel network was inhibited, and nuclear factor was suppressed by tetra-thiomolybdate43.
CONCLUSION:
The present study focused on the relationships between the structures and activities of bis-thiosemicarbazone ligands having different substituents and their zinc and copper complexes. Antiproliferative activity of these compounds and their complexes were also evaluated, and copper complexes resulted in the greatest activity. Zinc complexes showed the lowest antiproliferative activity because they were failed in ligand delivery intracellularly as they were not chaperone. In the present study, it was concluded that this relationship could be helpful in the synthesis of antitumor agents such as bis-thiosemicarbazone and its complexes.
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Received on 10.02.2022 Modified on 23.07.2022
Accepted on 14.12.2022 ©Asian Pharma Press All Right Reserved
Asian J. Pharm. Res. 2023; 13(3):181-185.
DOI: 10.52711/2231-5691.2023.00034