Structure-activity relationships of highly cytotoxic copper(II) complexes with modified indolo[3,2-c]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 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.
Primik
Michael F
MF
Institute of Inorganic Chemistry, University of Vienna, Währinger Str. 42, A-1090 Vienna, Austria.
Göschl
Simone
S
Jakupec
Michael A
MA
Roller
Alexander
A
Keppler
Bernhard K
BK
Arion
Vladimir B
VB
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C523706:(Cu(4-methylcoumarin-6,7-dioxactetate)(phenanthroline)2); D000970:Antineoplastic Agents; D007211:Indoles; D009942:Organometallic Compounds; D011804:Quinolines