Abstract
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.
Highlights
There has been considerable progress in contemporary cancer medicine, but many tumor types are still difficult to treat
It is crucial to develop new compounds exhibiting fewer or, ideally, no side effects. This can be achieved through applying a variety of strategies, such as structural modification of tubulin-binding agents or design of new low molecular weight inhibitors of proteins involved in cell division
In the case of plinabulin, we found that replacing the phenyl moiety with ferrocene leads to compounds able to inhibit clinically relevant multidrug resistance transporters ABCB1 and ABCG2.11
Summary
There has been considerable progress in contemporary cancer medicine, but many tumor types are still difficult to treat. Used anticancer drugs, such as tubulin binding agents, taxanes (e.g., paclitaxel, docetaxel),[1−5] and Vinca alkaloids (vincristine and vinblastine)[6] exhibit numerous side effects.[7] it is crucial to develop new compounds exhibiting fewer or, ideally, no side effects. This can be achieved through applying a variety of strategies, such as structural modification of tubulin-binding agents or design of new low molecular weight inhibitors of proteins involved in cell division. A vast number of antimitotic agents have been synthesized[8−12] or isolated from natural sources,[13] and their biological properties have been extensively evaluated.
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