Synthesis, characterization and in vitro antitumour activity of a series of novel platinum(II) complexes bearing Schiff base ligands

• Published in: European journal of medicinal chemistry Vol. 53; pp. 168 - 175
• Main Authors: Proetto, Maria, Liu, Wukun, Hagenbach, Adelheid, Abram, Ulrich, Gust, Ronald
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 01.07.2012; Elsevier
• Subjects: Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Cytotoxicity; Diarylsalene; Humans; Inhibitory Concentration 50; Life Sciences & Biomedicine; Ligands; Medical sciences; Miscellaneous; Models, Molecular; Molecular Conformation; Organoplatinum Compounds - chemical synthesis; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Schiff base platinum complexes; Schiff Bases - chemistry; Science & Technology; Synthesis; Schiff base platinum complexes; Cytotoxicity; Synthesis; Diarylsalene; STEREOCHEMISTRY; RESISTANCE; DIAZA-COPE-REARRANGEMENT
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.03.053

A series was neutral platinum(II) complexes bearing OCH3- or F-substituted 3,4-bis(4-fluorophenyl)-1,6-bis(2-hydroxyphenyl)-2,5-diazahexa-1,5-dienes (diarylsalenes) were synthesized and tested for in vitro antitumour activity. The growth inhibitory effects depended on the configuration and the substitution pattern of the salicylidene moiety. The lead compound [meso-3,4-bis(4-fluorophenyl)-1,6-bis(2-hydroxyphenyl)-2,5-diazahexa-1,5-diene]platinum(II) (1-Pt) reduced the cell growth of MCF-7 (IC50 = 7.6 μM) and MDA-MB 231 cells (IC50 = 10.0 μM), but was inactive against HT-29 cells at the used concentration range (IC50 > 20 μM). The change of the configuration (meso→d,l) at the 1,2-diimino-1,2-diarylethane bridge and methoxy substitution led to completely inactive compounds, while fluorine substituents increased the antiproliferative effects depending on their position (3-F < 5-F < 4-F < 6-F). Complex 10-Pt (6-F: IC50(MCF-7) = 1.5 μM, IC50(MDA-MB 231) = 1.3 μM, IC50 (HT-29) = 2.6 μM) was as active as cisplatin (IC50(MCF-7) = 1.6 μM, IC50(MDA-MB 231) = 1.5 μM, IC50(HT-29) = 4.1 μM). 3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxyphenyl)-2,5-diazahexa-1,5-dienes were synthesized and coordinated to platinum. Methoxy substitution in the salicylidene moiety completely terminated the in vitro cytotoxicity, while fluorine substituents increased the antiproliferative effects depending on their position (3-F < 5-F < 4-F < 6-F). [Display omitted] ► Synthesis and biological activity of Schiff base [meso-3,4-diarylsalene]platinum(II) complexes. ► Change from meso to d,l configuration reduced the activity. ► OCH3 substitution leads to inactive compounds, F substituents increase the cytotoxicity. ► Complex 10-Pt was as active as cisplatin against MCF-7, MDA-MB 231 and HT-29 cells.