**2. Cytotoxic activity of metal thiosemicarbazone complexes**

#### **2.1 Pd (II) and Pt(II) complexes**

Recently many authors were reported the anticancer activity of thiosemicarbazones and their palladium and platinum complexes. Nguyena et al. [6] reported the anticancer activities of Pd(II) and Pt(II) complexes of 1-picolinoyl-4-substituted Thiosemicarbazones against MCF7 and HepG2 cancer cell lines. Anti-proliferative activity of N-Substituted Indole thiosemicarbazones and its Pd(II) complexes against HeLa S3 cancer cell lines was reported by [7]. Nyawade et al. [8] reported cytotoxic activity of 2-acetyl-5-methyl thiophene and cinnamaldehyde thiosemicarbazones and their palladium(II) complexes cytotoxic activity on human cancer cell lines, Caco-2(Colon), HeLa(Cervical), Hept-G2 (hepatocellular) and PC-3 (Prostate)

cell lines. Complexes shows excellent activity than ligands. Matesanz et al. [9] studied anticancer activity of Pd(II) and Pt(II) complexes of pyrrol-2-carbaldehyde N-p-chlorophenylthiosemicarbazone.

The palladium complexes of N-Substituted isatin thiosemicarbazones shows significant *in vitro* cytotoxicity against human breast (MCF) and lung (A549) cell lines [10] cancer cell lines (A549) than the ligand and cisplatin [11]. Pd(II) and Pt(II) complexes of Chlorophenyl substituted thiosemicarbazones were studied and performed the in-vitro anti-cancer activity of the ligand and complexes against T-47D, A2780 and A2780cus R human cell lines. The results indicate that the ligand has more activity than the complexes [12].

Isatin thiosemicarbazone derivatives and its complexes of Pt(II) shows potent activity against human colorectal carcinoma cell line (HCT 116) [13]. 2,6-Diacetylpyridine bis(4 N-tolylthiosemicarbazone) complexes of Pd(II) and Pt(II) show the activity against cisplatin resistant A2780cisR tumor cells. These were shows high antiproliferative activity against breast cancer cell MCR-F-7 cells [14]. 2-Oxo-1,2-dihydroquinoline-3-carbaldehyde thiosemicarbazones complexes of Pd(II) shows a good cytotoxic activity against human cancer cell lines such as HeLa, KEp-2, Hep G2, and A431. It was evaluated and found the relationship between the structure and the activity of palladium complexes [15].

6-Methoxy-2-oxo-1,2-dihydro quinoline-3-carbaldehyde <sup>4</sup> N-substituted thiosemicarbazones and its complexes of Pd(II) shows better cytotoxic activity against human lung cancer cell line A549 than other complexes and even cisplatin. All the complexes had strong anti-oxidant property [16]. Pd(II), Ni(II), Pt(II) complexes of 5-Acetylbarbituric-<sup>4</sup> N-dimethylthiosemicarbazones studies show that one of the complex had sufficient cytotoxicity against HeLa cells [17]. 3,5-Diacetyl-1,2,4 triazol bis(4 N-substituted thiosemicarbazone) and its complexes of Pd(II) were tested for antiproliferative activity against NCI-H460, A2780 and A2780cisR human cancer cell lines and found that they exhibit low toxicity on kidney cells with respect to cisplatin [18].

Pt(II) complexes of Bis(thiosemicarbazones) of the 3,5-diacetyl-1,2,4-triazol series were tested cytotoxic activity against NCI-H460, A2780, and A2780cisR cancer cell lines and the results indicates that they were active against those cell lines and had high activity against NCI-H460 cell line [19]. 5-Substitutedthiophene-2-Carboxaldehyde thiosemicarbazones and its complexes of Pt(II), Pd(II) shows better cytotoxic activity than free ligand, but palladium complexes shows lesser activity than free ligands [20]. Pt(II) complexes of 3,5-Diacetyl-1,2,4-triazol bis(4,4-dimethylthiosemicarbazone) Anti-proliferative activity of ligand and its complexes was tested against NCI-H460, A2780 and A2780cisR human cancer cell lines. The results show that the compounds exhibits better activity against A2780cisR cell line than cisplatin [21].

2-Acetylpyridine-*N*(4)-methyl-thiosemicarbazone and 2-Acetylpyridine-*N*(4) phenyl-thiosemicarbazone and its palladium complexes were act as cytotoxic agents similar to cisplatin. All the compounds show better activity against *Mycobacterium tuberculosis* [22]. Cytotoxic activity of the ligands (3,5-Diacetyl-1,2,4-triazol bis(4 substituted) thiosemicarbazones) and their Pd(II) and Pt(II) complexes was tested against human A2780 and A2780cisR epithelial ovarian carcinoma cell lines. The results show that the activity of these compounds were in the range similar to cisplatin drug [23]. Anti-proliferative activity was studied on Phenanthrenequinone thiosemicarbazone and its complexes of Pd(II). The palladium complex had cytotoxic activity against breast cancer cell lines and nontoxic towards the normal mammary epithelial cells [24].

2-Acetyl Pyridine N(4)-Ethyl-thiosemicarbazones, 2-Acetyl Pyridine N(4)-1-(2 pyridyl)-piperazinyl TSC, 2-Formyl Pyridine N(4)-1-(2-pyridyl)-piperazinyl TSC and its complexes of Pt(II), Pd(II) shows antiproliferative activity against gram +ve bacteria but not on gram –ve bacteria. Some of the complexes overcome the cisplatin resistance of A2780/Cp8 cells [25]. 2-Acetylpridine thiosemicarbazone and Platinum complexes were effective on gram + bacteria. They were also effective on yeast. Few of the complexes were exhibits antitumor activity [26]. 2-Acetylpyridine and pyridine-2-carbaldehyde N(4)-ethyl thiosemicarbazones and Platinum complexes were found to be overcome the cisplatin resistant tumor cells, A2780/Cp8 [27].

Pyridine-2-carbaldehyde thiosemicarbazone and its complexes of Pd(II) and Pt(II) exhibits the higher in vivo antitumor activity [28]. Pd(II) and its complexes of 3,5-Diacyl-1,2,4-triazole bis(thiosemicarbazone); 2,6-diacylpyridine bis(TSC); benzyl bis(TSC) shows better antitumor activity against several human, monkey and murine cell lines [29]. *p*-Isopropylbenzaldehyde thiosemicarbazone and its Pd(II) and Pt(II) complexes show cytotoxic activity of the complexes reported against cisplatin resistant tumor cell lines (**Figure 2**) [30].

Isopropylbenzaldehyde thiosemicarbazone and its complexes of Pd(II) and Pt(II) show anticancer activity against several human and murine cell lines were reported by [31]. Phenylacetaldehyde thiosemicarbazone and its complexes of Pd(II) and Pt(II) cytotoxic activity was studied and observed that Cis-DDP-resistant tumor cells has high activity [32].

*Cytotoxic Activity of Schiff Bases and Their Complexes DOI: http://dx.doi.org/10.5772/intechopen.108570*

3,5-Diacyl-1,2,4-triazole bis(thiosemicarbazone); 2,6-diacylpyridine bis(TSC); benzyl bis(TSC) and its Pd(II) complexes shows better antitumor activity against several human, monkey and murine cell lines [29]. *p*-Isopropylbenzaldehyde thiosemicarbazone and its complexes of Pd(II) Pt(II) Cytotoxic activity reported against cisplatin resistant tumor cell lines [30]. *p*-Isopropylbenzaldehyde thiosemicarbazone and its complexes of Pd(II) and Pt(II) show anticancer activity against several human and murine cell lines [31].

Cytotoxic activity of phenylacetaldehyde thiosemicarbazone and its Pd(II) and Pt(II) complexes were studied and it was reported that cis-DDP-resistant tumor cells has reacted highly [32]. 2-Acetylpyridine N(4)-methyl, N(4)-ethyl and N(4)-phenyl thiosemicarbazones and its complexes of Pd(II) Antitumor studies indicates that all the palladium complexes were active in the inhibition of DNA synthesis on P388 and L1210 cell cultures (mice bearing tumors) [33]. 2-Acetylpyridine N(4)-propyl, N(4)-dipropyl- and 3-hexamethyleneiminyl thiosemicarbazones and its Palladium complexes does not had antifungal activity against the tested species. But they had significant anti-tumor activity against P388 and L1212 cell cultures [34].

#### **2.2 Copper complexes**

Thiosemicarbazone and its copper (II) complexes exhibits high anticancer activity due its highest stability and membrane permeability [35]. 2-Picoline and 5,5-dimethylbipyridine and its Cu(II) complexes cytotoxic activity was reported on MDA-MB-231 breast cancer cell line [36]. Chitosan-functionalized pyridine-based Thiosemicarbazones and their Cu(II) complexes shows antiproliferative activity against MCDK and MCF-7 cancer cell lines and their complexes shows high cytotoxic activity than ligands [37]. *N*-substitution in isatin thiosemicarbazones and its Cu(II) complexes MTT assays were done on A549,HeLa S3, Jurkat and IMR90 cells, its complexes exhibits more cytotoxic activity on HeLa S3 and Jurkat cell lines than cisplatin and morphological changes were observed [38]. Series of thiosemicarbazones and their Cu(II) complexes cytotoxic activity was studied and was noted that ligands chelation with Cu(II) enhances its antitumor activity well [39]. Copper(II) complexes of pyridoxal dithiocarbazate and thiosemicarbazone ligands are prone to study antitumor activities (Ehrlich and S-180 cells) and it was observed that these complexes were very active towards the cell death and they will act as excellent drug against cancer in future [40]. Copper(II) complexes bearing 2-hydroxynaphthaldehyde-based thiosemicarbazones shows cytotoxic activity against lung cancer (A549) cell line and human kidney (HEK-293 T) cell lines and it was observed that these complexes are active in cell death and it was showing excellent medical properties [41].

6-Methyl-2-oxo-quinoline-3-carbaldehydethiosemicarbazone and its Cu(II) complexes Cytotoxic activities were evaluated for both the ligand and three complexes. In vitro anti-tumor studies revealed that copper complex shows better activity towards SK-OV-3 and MGC80-3 tumor cell lines than the commercial anticancer drug, cisplatin. But all the complexes show lower activity against human liver cell lines than cisplatin [42]. 3-Phenyl (substituted)-1-pyridin-2-ylprop-2-en-1-one thiosemicarbazone and its Cu(II) Cytotoxic activity were tested against human cancer cell lines such as HL60, MDA-MB 231, and HCT-116. The results indicate that coordination of copper increases the cytotoxic activity of the compounds [43].

Glyoxal-bis(4-methyl-4-phenyl-3-thiosemicarbazone) and its Copper complex has better cytotoxic activity against various human cancer cell lines than the Adriamycin, a commercial drug. The copper complex significantly inhibits the growth of tumor HCT 116 xenografts in nude mice [44]. Cu(II) and its complexes of 2-Oxo-1,2-dihydroquinoline-3-carbaldehyde4(*N,N*)-dimethylthiosemicarbazone Cytotoxic activity of the complex and ligand was tested against HeLa, Hep G2, and HEp-2 cancer cell lines and found that the copper complex has significant activity on HeLa cell line than others [45]. N-substituted-2-oxo-1,2-dihydroquinoline-3 carbaldehyde thiosemicarbazones and its complexes of Cu(II) antiproliferative activities were studied the substituent at terminal nitrogen atom was observed. The ethyl and phenyl substituted complexes shows better activity against NIH 3 T3 and HeLa cell lines [46].

α-Heterocyclic-N4-substituted thiosemicarbazones and its Cu(II) complex Antiproliferative activity were tested against breast cancer cell line SK-BR-3. The ligands shows better catalytic inhibition property of topoisomerase-Iiα than complexes [47]. Cu(II) complexes of 2-Acetylpyridine-4,4-dimethyl-3-thiosemicarbazone, di-2-pyridyl ketone-4,4-dimethyl-3-TSC shows better anti-proliferative activity than ligand [48]. 2-Hydroxy-8-R-tricyclo [7.3.1.0.2,7] tridecane-13-one thiosemicarbazone and its complexes of Cu(II), Pd(II) shows Anti-microbial activities and cytotoxic activities of the compounds were reported [49]. Salicylaldehyde semi−/thiosemicarbazones and its complexes of Cu(II) were tested for cytotoxic activity against MCF-7 human breast cancer cell lines. The results revealed that ligands were inactive but copper complex of thiosemicarbazone was more active than others [50].

5-Formyluracil thiosemicarbazone derivatives and its Cu(II) Complexes were exhibits DNA interaction by electrostatic and groove binding. But these were no activity against human leukemic cell line U937 [51]. α-Ketoglutaric acid thiosemicarbazone and its Cu(II) Copper complexes has antiproliferative activity against human cell line U937 and no effect on the K562 cell line [52]. 10-Deacetylbaccatin thiosemicarbazone and its Cu(II) Cytotoxic activity of the ligand and its complex was tested against human breast cancer cell line MCF-7 [53].

Ref. [54] reported the cytotoxic activity of Cu(II) and its complexes of 2-Acetylpyrazone-N-substituted thiosemicarbazones. Ref. [55] studied the anticancer activity of 5-Formyluracil thiosemicarbazone and its Cu(II) complexes against human leukemic cell lines K562 and CEM (**Figure 3**).
