title: 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.
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia; Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Malaysia.
authors.forename: Mok Piew
authors.initials: MP
authors.lastname: Heng
authors.affiliation: Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Saravana Kumar
authors.initials: SK
authors.lastname: Sinniah
authors.affiliation: Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Wuen Yew
authors.initials: WY
authors.lastname: Teoh
authors.affiliation: Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Kae Shin
authors.initials: KS
authors.lastname: Sim
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia; Chemistry Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah, Saudi Arabia.
authors.forename: Seik Weng
authors.initials: SW
authors.lastname: Ng
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Malaysia.
authors.forename: Yoke Kqueen
authors.initials: YK
authors.lastname: Cheah
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Kong Wai
authors.initials: KW
authors.lastname: Tan
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D003603:Cytotoxins / Q000737:chemistry* / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000737:chemistry / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D009532:Nickel / Q000737:chemistry / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D012545:Schiff Bases / Q000737:chemistry / Q000494:pharmacology; D013379:Substrate Specificity; D013739:Testosterone / Q000737:chemistry / Q000494:pharmacology*; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology*; D014961:X-Ray Diffraction
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; D004273:DNA, Neoplasm; D008024:Ligands; D012545:Schiff Bases; D013882:Thiosemicarbazones; D013739:Testosterone; D009532:Nickel
keywords: Cytotoxicity; DNA; Nickel; Schiff base