Organometallic Ru(II), Os(II) and Rh(III) complexes of lapachol induce apoptosis in human tumour cell lines in the low μM range by a mode of action involving oxidative stress, especially in the case of the ruthenium compound.

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.

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 HL(1a)-HL(4a) and HL(1b)-HL(4b) were reacted with copper(II) chloride in isopropanol/methanol to give novel five-coordinate copper(II) complexes [Cu(HL(1a-4a))Cl(2)] and [Cu(HL(1b-4b))Cl(2)]. In addition, a new complex [Cu(HL(5b))Cl(2)] and two previously reported compounds [Cu(HL(6a))Cl(2)] and [Cu(HL(6b))Cl(2)] with modified paullone ligands HL(5b), HL(6a), and HL(6b), which can be regarded as close analogues of indoloquinolines HL(1b), HL(4a), and HL(4b), 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 (1)H and (13)C NMR, IR and electronic absorption spectroscopy, ESI mass spectrometry, magnetic susceptibility measurements in solution at 298 K ([Cu(HL(1a))Cl(2)] and [Cu(HL(4b))Cl(2)]), and X-ray crystallography ([Cu(HL(3b))Cl(2)]·3DMF, [Cu(HL(4b))Cl(2)]·2.4DMF, HL(5b) and [Cu(HL(5b))Cl(2)]·0.5CH(3)OH). 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 IC(50) 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.

Taken together, our results demonstrate the advantages of spheroid-based assays and underline the necessity of using different experimental models for reliable preclinical investigations assessing and better predicting the anticancer potential of new compounds.

Investigations of the influence of bulky groups in the equatorial ligand sphere of platinum(IV) compounds on the complexes' stability and reaction pattern were performed. Four dihydroxidoplatinum(IV) complexes were reacted with anhydrides, cinnamoyl chloride, and n-propyl isocyanate and yielded the symmetric dicarboxylated products or, if steric hindrance was observed, unsymmetrically substituted monocarboxylated analogues. With the aim of raising the steric demand, the following ligands were chosen: N-cyclohexylethane-1,2-diamine, N,N-dimethylethane-1,2-diamine, N,N-diethylethane-1,2-diamine, and N,N-diisopropylethane-1,2-diamine. All of the novel complexes were characterized by electrospray ionization mass spectrometry (ESI-MS), one- and two-dimensional NMR spectroscopy, elemental analysis, and reversed-phase HPLC; complexes B3, C3, C6, and D4 were also analyzed by X-ray diffraction. Additionally, the cytotoxicities of 10 compounds toward the cisplatin-sensitive cell line CH1 and the intrinsically cisplatin-resistant cell lines A549 and SW480 were investigated, and IC50 values down to the nanomolar range were found. To aid in the interpretation of structure-activity relationships, log k(w) values as a measure for the lipophilicity were determined for all of the new complexes, and the rates of reduction of C1, C3, and C4 relative to satraplatin were determined by means of NMR spectroscopy and ESI-MS.