How to modify 7-azaindole to form cytotoxic Pt(II) complexes: Highly in vitro anticancer effective cisplatin derivatives involving halogeno-substituted 7-azaindole

The platinum(II) dichlorido and oxalato complexes of the general formula cis-[PtCl2(nHaza)2] (1–3) [Pt(ox)(nHaza)2] (4–6) involving 7-azaindole halogeno-derivatives (nHaza) were prepared and thoroughly characterized. A single-crystal X-ray analysis of cis-[PtCl2(3ClHaza)2]·DMF (1·DMF; 3ClHaza symbolizes 3-chloro-7-azaindole) revealed a distorted square-planar arrangement with both the 3ClHaza molecules coordinated through their N7 atoms in a cis fashion. In vitro cytotoxicity of the complexes was evaluated by an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay against the HOS (osteosarcoma), MCF7 (breast adenocarcinoma) and LNCaP (prostate adenocarcinoma) human cancer cell lines. The dichlorido complexes 1–3 (IC50 = 3.8, 3.9, and 2.5 μM, respectively) showed significantly higher in vitro anticancer effect against HOS as compared with cisplatin, whose IC50 = 37.7 μM. The biological effect of cisplatin against MCF7 (IC50 = 24.5 μM) and LNCaP (IC50 = 3.8 μM) was also exceeded by 1–3 (except for 2 against LNCaP), but the difference can be classified as significant only in the case of 1 (IC50 = 3.4 μM) and 3 (IC50 = 2.0 μM) against MCF7. The molecular pharmacological studies (RNA synthesis by T7 RNA polymerase in vitro) proved that 1–3 bind to DNA in a similar manner as cisplatin, since the RNA synthesis products of 1–3 and cisplatin showed a similar sequence profile of major bands.

The cis-[PtCl2(nHaza)2] (1–3) and [Pt(ox)(nHaza)2] (4–6) complexes involving 7-azaindole halogeno-derivatives (nHaza) were studied. The platinum(II) dichlorido complexes 1–3 showed considerable anticancer effect against MCF7, HOS and LNCaP, which is caused by the effective inhibition of DNA-dependent-RNA-synthesis as a consequence of the DNA binding of 1–3.Figure optionsDownload as PowerPoint slideHighlights
► Pt(II) dichlorido (1–3) and oxalato (4–6) complexes were prepared and characterized.
► The complexes involve 7-azaindole halogeno-derivatives as N-donor ligands.
► In vitro cytotoxicity against the MCF7, HOS and LNCaP human cancer cells was studied.
► The Pt(II) dichlorido complexes are significantly more cytotoxic than cisplatin.
► Complexes 1–3 bind to DNA and inhibit the DNA-dependent-RNA-synthesis.