Metal-Dependent Cytotoxic and Kinesin Spindle Protein Inhibitory Activity of Ru, Os, Rh, and Ir Half-Sandwich Complexes of Ispinesib-Derived Ligands

Ispinesib is a potent inhibitor of kinesin spindle protein (KSP), which has been identified as a promising target for antimitotic anticancer drugs. Herein, we report the synthesis of half-sandwich complexes of Ru, Os, Rh, and Ir bearing the ispinesib-derived N,N-bidentate ligands (R)- and (S)-2-(1-amino-2-methylpropyl)-3-benzyl-7-chloroquinazolin-4(3H)-one and studies on their chemical and biological properties. Using the enantiomerically pure (R)- and (S)-forms of the ligand, depending on the organometallic moiety, either the SM,R or RM,S diastereomers, respectively, were observed in the molecular structures of the Ru- and Os(cym) (cym = η6-p-cymene) compounds, whereas the RM,R or SM,S diastereomers were found for the Rh- and Ir(Cp*) (Cp* = η5-pentamethylcyclopentadienyl) derivatives. However, density functional theory (DFT) calculations suggest that the energy difference between the diastereomers is very small, and therefore a mixture of both will be present in solution. The organometallics exhibited varying antiproliferative activity in a series of human cancer cell lines, with the complexes featuring the (R)-enantiomer of the ligand being more potent than the (S)-configured counterparts. Notably, the Rh and Ir complexes demonstrated high KSP inhibitory activity, even at 1 nM concentration, which was independent of the chirality of the ligand, whereas the Ru and especially the Os derivatives were much less active

Ferrocenyl Derivatives of the Anthelmintic Praziquantel: Design, Synthesis, and Biological Evaluation

The design, synthesis, and biological evaluation of 18 ferrocenyl derivatives (4A-12A and 4B-12B) of the most well-known drug against schistosomiasis, namely praziquantel (PZQ), are reported. These compounds, which have been all isolated as racemates, were unambiguously characterized by (1)H and (13)C NMR spectroscopy, mass spectrometry, and elemental analysis as well as by X-ray crystallography for 4A, 5A, and 7A. Cytotoxicity studies revealed that the complexes were moderately toxic toward a cervical cancer cell line (HeLa) and, importantly, significantly less active toward a noncancerous cell line (MRC-5). The in vitro anthelmintic activity of the 18 ferrocenyl PZQ derivatives was tested against adult Schistosoma mansoni, and values in the micromolar range (26-68 μM) were determined for the four most active compounds. It was also demonstrated using two compounds of the series as models (8A and 8B) that the complexes were stable when incubated for 24 h at 37 °C in human plasma

Sandwich and half-sandwich derivatives of Platensimycin: synthesis and biological evaluation

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