Novel bis-C,N-cyclometalated iridium(III) thiosemicarbazide antitumor complexes: interactions with human serum albumin and DNA, and inhibition of cathepsin B.

José Ruiz, Consuelo Vicente, Concepción de Haro, Delia Bautista

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

Inorganic chemistry 2013 Jan 18

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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.

Citation

José Ruiz, Consuelo Vicente, Concepción de Haro, Delia Bautista. Novel bis-C,N-cyclometalated iridium(III) thiosemicarbazide antitumor complexes: interactions with human serum albumin and DNA, and inhibition of cathepsin B. Inorganic chemistry. 2013 Jan 18;52(2):974-82