Structure−Activity Relationships of Highly Cytotoxic Copper(II) Complexes with Modified Indolo[3,2-<i>c</i>]quinoline Ligands

A number of indolo[3,2-c]quinolines were synthesized and modified at the lactam unit to provide a peripheral binding site able to accommodate metal ions. Potentially tridentate ligands HL1a−HL4a and HL1b−HL4b were reacted with copper(II) chloride in isopropanol/methanol to give novel five-coordinate copper(II) complexes [Cu(HL1a−4a)Cl2] and [Cu(HL1b−4b)Cl2]. In addition, a new complex [Cu(HL5b)Cl2] and two previously reported compounds [Cu(HL6a)Cl2] and [Cu(HL6b)Cl2] with modified paullone ligands HL5b, HL6a, and HL6b, which can be regarded as close analogues of indoloquinolines HL1b, HL4a, and HL4b, in which the pyridine ring was formally substituted by a seven-membered azepine ring, were synthesized for comparison. The new ligands and copper(II) complexes were characterized by 1H and 13C NMR, IR and electronic absorption spectroscopy, ESI mass spectrometry, magnetic susceptibility measurements in solution at 298 K ([Cu(HL1a)Cl2] and [Cu(HL4b)Cl2]), and X-ray crystallography ([Cu(HL3b)Cl2]·3DMF, [Cu(HL4b)Cl2]·2.4DMF, HL5b and [Cu(HL5b)Cl2]·0.5CH3OH). All complexes were tested for cytotoxicity in the human cancer cell lines CH1 (ovarian carcinoma), A549 (non-small cell lung cancer), and SW480 (colon carcinoma). The compounds are highly cytotoxic, with IC50 values ranging from nanomolar to very low micromolar concentrations. Substitution of the seven-membered azepine ring in paullones by a pyridine ring resulted in a six- to nine-fold increase of cytotoxicity in SW480 cells. Electron-releasing or electron-withdrawing substituents in position 8 of the indoloquinoline backbone do not exert any effect on cytotoxicity of copper(II) complexes, whereas copper(II) compounds with Schiff bases obtained from 2-acetylpyridine and indoloquinoline hydrazines are 10 to 50 times more cytotoxic than those with ligands prepared from 2-formylpyridine and indoloquinoline hydrazines.