Novel Bis-C,N-Cyclometalated Iridium(III) Thiosemicarbazide Antitumor Complexes: Interactions with Human Serum Albumin and DNA, and Inhibition of Cathepsin B

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 104 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.