Sandwich and Half-Sandwich Derivatives of Platensimycin: Synthesis and Biological Evaluation

• Published in: Organometallics 2012-08, Vol.31 (16), p.5760-5771
• Main Authors: Patra, Malay, Gasser, Gilles, Wenzel, Michaela, Merz, Klaus, Bandow, Julia E, Metzler-Nolte, Nils
• Format: Article
• Language: English
• ISSN: 0276-7333; 1520-6041
• DOI: 10.1021/om201146c

The multistep synthesis and biological evaluation of five structurally diverse, chiral and achiral CpMn­(CO)3 (4, 7 and 8), (η6-arene)­Cr­(CO)3 (5), and [3]­ferrocenophane-1-one (6) containing platensimycin (1) derivatives are described in this report. The structures were inspired by the antibiotic platensimycin. All the chiral compounds presented in this report are racemates. The new compounds were unambiguously characterized by 1H and 13C NMR spectroscopy, mass spectrometry, IR spectroscopy, and elemental analysis and in certain cases by X-ray crystallography (4, 16, 18, and 29). The antibacterial and antitumor activity of selected derivatives was tested. Molecular modeling suggests that the derivatives described here may well fit into the active site of the FabF enzyme, which is the biological target of platensimycin. Hence, the antimicrobial activities of our new bioorganometallices 4–8 and the protected amide intermediates 15, 17, 18, 23, 28, 29, and 31 were tested against various Gram-positive and Gram-negative bacterial strains. However, all compounds were inactive up to concentrations of 180 μg/mL. The cytotoxicity of compounds 4 and 6 and the protected amide intermediates 15, 17, 18, 23, 28, 29, and 31 was tested against HepG2 and PT45 mammalian cancer cell lines. Surprisingly, all compounds containing a trimethylsilylethyl ester functionality at the aromatic ring (17, 23, 29, and 31) displayed rather high cytotoxicity between 2 and 9 μM.