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

Abstract The platinum(II) dichlorido and oxalato complexes of the general formula cis -[PtCl 2 ( n Haza) 2 ] ( 1 – 3 ) [Pt(ox)( n Haza) 2 ] ( 4 – 6 ) involving 7-azaindole halogeno-derivatives ( n Haza) were prepared and thoroughly characterized. A single-crystal X-ray analysis of cis -[PtCl 2 ( 3Cl Haza) 2 ]·DMF ( 1 ·DMF; 3Cl Haza symbolizes 3-chloro-7-azaindole) revealed a distorted square-planar arrangement with both the 3Cl Haza 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 (IC 50  = 3.8, 3.9, and 2.5 μM, respectively) showed significantly higher in vitro anticancer effect against HOS as compared with cisplatin , whose IC 50  = 37.7 μM. The biological effect of cisplatin against MCF7 (IC 50  = 24.5 μM) and LNCaP (IC 50  = 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 (IC 50  = 3.4 μM) and 3 (IC 50  = 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.