Synthesis of a DNA-targeting nickel (II) complex with testosterone thiosemicarbazone which exhibits selective cytotoxicity towards human prostate cancer cells (LNCaP)

Abstract

Testosterone thiosemicarbazone, L and its nickel (II) complex 1 were synthesized and characterized by using FTIR, CHN, (1)H NMR, and X-ray crystallography. X-ray diffraction study confirmed the formation of L from condensation of testosterone and thiosemicarbazide. Mononuclear complex 1 is coordinated to two Schiff base ligands via two imine nitrogens and two tautomeric thiol sulfurs. The cytotoxicity of both compounds was investigated via MTT assay with cisplatin as positive reference standard. L is more potent towards androgen-dependent LNCaP (prostate) and HCT 116 (colon). On the other hand, complex 1, which is in a distorted square planar environment with L acting as a bidentate NS-donor ligand, is capable of inhibiting the growth of all the cancer cell lines tested, including PC-3 (prostate). It is noteworthy that both compounds are less toxic towards human colon cell CCD-18Co. The intrinsic DNA binding constant (Kb) of both compounds were evaluated via UV-Vis spectrophotometry. Both compounds showed Kb values which are comparable to the reported Kb value of typical classical intercalator such as ethidium bromide. The binding constant of the complex is almost double compared with ligand L. Both compounds were unable to inhibit the action topoisomerase I, which is the common target in cancer treatment (especially colon cancer). This suggest a topoisomerase I independent-cell death mechanism.

Synthesis, electronic structure and molecular docking of new organometallic palladium (II) complexes with intercalator ligands: The influence of bridged ligands on enhanced DNA/serum protein binding and in vitro antitumoral activity

“…As revealed in Table 3, SI values of both complexes were found to be higher than 2, which in term of SI definition [48], are imputed as the selective. Our results are also in good correlation with the previous studies in which more cytotoxic activity to cancer cells than the normal cells [90,93,94,95,96,97] was found, owing to the sensitivity of cancer cells towards the death complexes. Consequently, both complexes, 2 being more active than 3, exhibited significant selective dose-dependent inhibition on proliferation and viability of both cancer cells.…”

“…According to the result of docking study, the distance between the Trp213 residue and the complex 3 is 5.9Å and the residues involved in the interaction of the complex 3 with BSA are Ala290, Glu291, Arg194, Lys221, Arg217, Lys439, Glu443 and Cys447. [90,91,92]. As illustrated in Figure 12, the dose-dependent reduction in the survivability of JURKAT and SKOV3 cancer cells treated by complex 2 ranged from 14 to 84% and 45 to 93%, and for complex 3, it ranged from 8 to 71% and 32 to 84%, respectively.…”

Evaluation of DNA Binding and Topoisomerase I Inhibitory Activities of 16’‐Decarbomethoxydihydrovoacamine from Tabernaemontana corymbosa

“…The E. coli topo1 inhibition assay was thus carried out to determine whether 1 inhibits topo1 activity which is manifested as inhibition of the relaxation of supercoiled plasmid DNA pBR322. As depicted in Figure 5, 0.25 unit of E. coli topo1 was able to convert all the supercoiled pBR322 (L2, Form III) into two types of relaxed topoisomers (L4, Form I and Form II) and there was no observable difference between the untreated (L4) and treated (L5‐12) DNA‐topo1 complexes, suggesting that 1 did not affect the activity of topo1 [6a] . Bisindole 1 therefore exerts its cytotoxicity against colorectal cancer cells independent of topo1.…”

Synthesis and Spectroscopic Characterizations of Ni(II) Thiosemicarbazone Bearing Anthracene

“…Nonetheless, many Ni(II) thiosemicarbazone complexes with cis geometries were reported. Indeed, weak interactions such as π-π stackings among the thiosemicarbazone ligands are needed to sustain the cis arrangements [4,5]. Our group also reported anthracene-based and pyrenebased Ni(II) thiosemicarbazone complexes which showed cis geometries cemented by intramolecular π-π interactions [6,7].…”

“…The N (2) -H signal (11.67 ppm) in HL are not found in the spectrum of NiL, hinting the tautomerization of the ligand upon complexation with Ni(II). Moreover, N (4) substituted methyl groups in HL and NiL give rise to doublet signal at 3.02 ppm and 2.41 ppm, respectively. A quartet at 6.78 ppm arising from N (4) H in NiL is largely upfield shifted from that in HL (8.32 ppm).…”