Six novel ruthenium(II)– and osmium(II)–arene
complexes
with three modified indolo[3,2-c]quinolines have
been synthesized in situ starting from 2-aminoindoloquinolines and
2-pyridinecarboxaldehyde in the presence of [M(p-cymene)Cl2]2 (M = Ru, Os) in ethanol. All complexes
have been characterized by elemental analysis, spectroscopic techniques
(1H, 13C NMR, IR, UV–vis), and ESI mass
spectrometry, while four complexes were investigated by X-ray diffraction.
The complexes have been tested for antiproliferative activity in vitro
in A549 (non-small cell lung), SW480 (colon), and CH1 (ovarian) human
cancer cell lines and showed IC50 values between 1.3 and
>80 μM. The effects of Ru vs Os and modifications of the
lactam
unit on intermolecular interactions, antiproliferative activity, and
cell cycle are reported. One ruthenium complex and its osmium analogue
have been studied for anticancer activity in vivo applied both intraperitoneally
and orally against the murine colon carcinoma model CT-26. Interestingly,
the osmium(II) complex displayed significant growth-inhibitory activity
in contrast to its ruthenium counterpart, providing stimuli for further
investigation of this class of compounds as potential antitumor drugs.
The novel steroidal conjugates [M(η(5)-C(5)Me(5))Cl(LEV-ppy)] (M = Rh (1) and Ir (2)) bearing the lipophilic levonorgestrel group 17-α-[2-phenylpyridyl-4-ethynyl]-19-nortestosterone (LEV-ppy), where the chelating ligand is N and C-bound, have been prepared and characterized. Both compounds are more active than cisplatin (about 6-fold) in T47D (breast cancer) at 48 h incubation time. On the other hand, very low resistance factors (RF) of 1 and 2 in A2780cisR (cisplatin-resistant ovarian carcinoma) at 48 h were observed (RF = 0.9 and 1.1, respectively). The iridium steroidal compound 2 is twice as active as the non-steroidal analogue 2', whose promising anticancer activity has recently been reported by Sadler. Theoretical DFT calculations on complexes 1 and 2 at the B3LYP-D/def2-TZVP-ecp level of theory show that the strongest bond to the metal atom is the η(5)-interaction to the Cp* ligand and that both of them feature a rather strong metal-chlorine bond. The new steroidal conjugates 1 and 2 are able to bind to DNA according to Hoechst 33258 displacement experiments and ESI-TOF MS spectrometry studies. Complexes 1 and 2 are also cathepsin B inhibitors, an enzyme implicated in a number of cancer related events.
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