期刊
INORGANIC CHEMISTRY
卷 59, 期 20, 页码 14879-14890出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.inorgchem.0c00957
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资金
- National Science Centre Poland (NCN) [UMO-2015/17/B/ST5/02331]
- University of Auckland (University of Auckland Doctoral Scholarship)
- Health Research Council of New Zealand
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-methyl-propyl)-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 S-M,R or R-M,S diastereomers, respectively, were observed in the molecular structures of the Ru- and Os(cym) (cym eta(6)-p-cymene) compounds, whereas the R-M,R or S-M,S diastereomers were found for the Rh- and Ir(Cp*) (Cp* = eta(5)-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.
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