title: Novel bis-C,N-cyclometalated iridium(III) thiosemicarbazide antitumor complexes: interactions with human serum albumin and DNA, and inhibition of cathepsin B.
abstract: A series of new organoiridium(III) complexes [Ir(N-C)(2)(N-S)]Cl (HN-C = 2-phenylpyridine (Hppy), N-S = methyl thiosemicarbazide (1), phenyl thiosemicarbazide (2) and naphtyl thiosemicarbazide (3)) have been synthesized and characterized. The crystal structure of (1) has been established by X-ray diffraction, showing the thiosemicarbazide ligand bound to the iridium atom as N,S-chelate. The cytotoxicity studies show that they are more active than cisplatin (about 5-fold) in T47D (breast cancer) at 48 h incubation time. On the other hand, very low resistance factors (RF) of 1-3 in A2780cisR (cisplatin-resistant ovarian carcinoma) at 48 h were observed (RF ≈ 1). Ir accumulation in T47D cell line after 48 h continuous exposure for complexes 1-3 are higher than that corresponding to cisplatin (about 10 times). The complexes 1-3 bind strongly to HSA with binding constants of about 10(4) M(-1) at 296 K, binding occurring at the warfarin site I for 2. Complexes 2 and 3 are also capable of binding in the minor groove of DNA as shown by Hoechst 33258 displacement experiments. Furthermore, complex 2 is also a good cathepsin B inhibitor (an enzyme implicated in a number of cancer related events), being the enzyme reactivated by cysteine.
authors.affiliation: Departamento de Química Inorgánica and Regional Campus of International Excellence Campus Mare Nostrum, Universidad de Murcia and Instituto Murciano de Investigación Biosanitaria (IMIB), E-30071- Murcia, Spain. jruiz@um.es
authors.forename: José
authors.initials: J
authors.lastname: Ruiz
authors.forename: Consuelo
authors.initials: C
authors.lastname: Vicente
authors.forename: Concepción
authors.initials: C
authors.lastname: de Haro
authors.forename: Delia
authors.initials: D
authors.lastname: Bautista
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000188:drug therapy; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007495:Iridium / Q000737:chemistry*; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry; D010051:Ovarian Neoplasms / Q000188:drug therapy; D012663:Semicarbazides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D012663:Semicarbazides; D012709:Serum Albumin; D007495:Iridium; C005151:thiosemicarbazide; D004247:DNA; D002401:Cathepsin B