ABSTRACT
Two new Schiff base ligands (TE and TF) were prepared from conjugation of testosterone with 4-(4-ethylphenyl)-3-thiosemicarbazide and 4-(4-fluorophenyl)-3-thiosemicarbazide, respectively. Their nickel (NE and NF) and zinc (ZE and ZF) complexes were reported. X-ray crystallography revealed a distorted square planar geometry was adopted by NE. The compounds demonstrated excellent selectivity towards the colorectal carcinoma cell line HCT 116 despite their weak preferences towards the prostate cancer cell lines (PC-3 and LNCaP). Against HCT 116, all these compounds were able to arrest cell cycle at G0/G1 phase and induce apoptosis via mitochondria-dependent (TE, NE, and TF) and extrinsic apoptotic pathway (ZE, NF, and ZF). Moreover, only ZE was able to act as topoisomease I poison and halt its enzymatic reactions although all compounds presented excellent affinity towards DNA.
Subject(s)
Colorectal Neoplasms , Coordination Complexes , Nickel , Testosterone , Thiosemicarbazones , Zinc , Cell Death/drug effects , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Coordination Complexes/pharmacokinetics , Coordination Complexes/pharmacology , HCT116 Cells , Humans , Nickel/chemistry , Nickel/pharmacokinetics , Nickel/pharmacology , Testosterone/chemistry , Testosterone/pharmacokinetics , Testosterone/pharmacology , Thiosemicarbazones/chemistry , Thiosemicarbazones/pharmacokinetics , Thiosemicarbazones/pharmacology , Zinc/chemistry , Zinc/pharmacokinetics , Zinc/pharmacologyABSTRACT
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.
Subject(s)
Cytotoxins/chemistry , Cytotoxins/pharmacology , DNA, Neoplasm/metabolism , Nickel/pharmacology , Prostatic Neoplasms/pathology , Testosterone/pharmacology , Thiosemicarbazones/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Death/drug effects , Cell Line, Tumor , Crystallography, X-Ray , DNA, Neoplasm/chemistry , Drug Delivery Systems/methods , Humans , Ligands , Magnetic Resonance Spectroscopy , Male , Molecular Structure , Nickel/chemistry , Schiff Bases/chemistry , Schiff Bases/pharmacology , Substrate Specificity , Testosterone/chemistry , Thiosemicarbazones/chemistry , X-Ray DiffractionABSTRACT
Four new copper(II) complexes containing phosphonium substituted hydrazone (L) with the formulations [CuL]Cl(3), [Cu(phen)L]Cl(4), [Cu(bpy)L]Cl(5), [Cu(dbpy)L]Cl(6), (where L = doubly deprotonated hydrazone; phen = 1,10'-phenanthroline; bpy = 2,2'-bipyridine; dbpy = 5,5'-dimethyl-2,2'-bipyridine) have been synthesized. The compounds were characterized by elemental analysis, spectroscopic methods and in the case of crystalline products by X-ray crystallography. The cytotoxicity and topoisomerase I (topo I) inhibition activities of these compounds were studied. It is noteworthy that the addition of N,N-ligands to the copper(II) complex lead to the enhancement in the cytotoxicity of the compounds, especially against human prostate adenocarcinoma cell line (PC-3). Complex 4 exhibits the highest activity against PC-3 with the IC50 value of 3.2 µΜ. The complexes can also inhibit topo I through the binding to DNA and the enzyme.
