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

[Image: see text] 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 (...

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Autores principales: Łomzik, Michał, Hanif, Muhammad, Budniok, Aleksandra, Błauż, Andrzej, Makal, Anna, Tchoń, Daniel M., Leśniewska, Barbara, Tong, Kelvin K. H., Movassaghi, Sanam, Söhnel, Tilo, Jamieson, Stephen M. F., Zafar, Ayesha, Reynisson, Jóhannes, Rychlik, Błażej, Hartinger, Christian G., Plażuk, Damian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584371/
https://www.ncbi.nlm.nih.gov/pubmed/33003697
http://dx.doi.org/10.1021/acs.inorgchem.0c00957
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author Łomzik, Michał
Hanif, Muhammad
Budniok, Aleksandra
Błauż, Andrzej
Makal, Anna
Tchoń, Daniel M.
Leśniewska, Barbara
Tong, Kelvin K. H.
Movassaghi, Sanam
Söhnel, Tilo
Jamieson, Stephen M. F.
Zafar, Ayesha
Reynisson, Jóhannes
Rychlik, Błażej
Hartinger, Christian G.
Plażuk, Damian
author_facet Łomzik, Michał
Hanif, Muhammad
Budniok, Aleksandra
Błauż, Andrzej
Makal, Anna
Tchoń, Daniel M.
Leśniewska, Barbara
Tong, Kelvin K. H.
Movassaghi, Sanam
Söhnel, Tilo
Jamieson, Stephen M. F.
Zafar, Ayesha
Reynisson, Jóhannes
Rychlik, Błażej
Hartinger, Christian G.
Plażuk, Damian
author_sort Łomzik, Michał
collection PubMed
description [Image: see text] 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 S(M),R or R(M),S diastereomers, respectively, were observed in the molecular structures of the Ru- and Os(cym) (cym = η(6)-p-cymene) compounds, whereas the R(M),R or S(M),S diastereomers were found for the Rh- and Ir(Cp*) (Cp* = η(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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spelling pubmed-75843712020-10-26 Metal-Dependent Cytotoxic and Kinesin Spindle Protein Inhibitory Activity of Ru, Os, Rh, and Ir Half-Sandwich Complexes of Ispinesib-Derived Ligands Łomzik, Michał Hanif, Muhammad Budniok, Aleksandra Błauż, Andrzej Makal, Anna Tchoń, Daniel M. Leśniewska, Barbara Tong, Kelvin K. H. Movassaghi, Sanam Söhnel, Tilo Jamieson, Stephen M. F. Zafar, Ayesha Reynisson, Jóhannes Rychlik, Błażej Hartinger, Christian G. Plażuk, Damian Inorg Chem [Image: see text] 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 S(M),R or R(M),S diastereomers, respectively, were observed in the molecular structures of the Ru- and Os(cym) (cym = η(6)-p-cymene) compounds, whereas the R(M),R or S(M),S diastereomers were found for the Rh- and Ir(Cp*) (Cp* = η(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. American Chemical Society 2020-10-02 2020-10-19 /pmc/articles/PMC7584371/ /pubmed/33003697 http://dx.doi.org/10.1021/acs.inorgchem.0c00957 Text en This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Łomzik, Michał
Hanif, Muhammad
Budniok, Aleksandra
Błauż, Andrzej
Makal, Anna
Tchoń, Daniel M.
Leśniewska, Barbara
Tong, Kelvin K. H.
Movassaghi, Sanam
Söhnel, Tilo
Jamieson, Stephen M. F.
Zafar, Ayesha
Reynisson, Jóhannes
Rychlik, Błażej
Hartinger, Christian G.
Plażuk, Damian
Metal-Dependent Cytotoxic and Kinesin Spindle Protein Inhibitory Activity of Ru, Os, Rh, and Ir Half-Sandwich Complexes of Ispinesib-Derived Ligands
title Metal-Dependent Cytotoxic and Kinesin Spindle Protein Inhibitory Activity of Ru, Os, Rh, and Ir Half-Sandwich Complexes of Ispinesib-Derived Ligands
title_full Metal-Dependent Cytotoxic and Kinesin Spindle Protein Inhibitory Activity of Ru, Os, Rh, and Ir Half-Sandwich Complexes of Ispinesib-Derived Ligands
title_fullStr Metal-Dependent Cytotoxic and Kinesin Spindle Protein Inhibitory Activity of Ru, Os, Rh, and Ir Half-Sandwich Complexes of Ispinesib-Derived Ligands
title_full_unstemmed Metal-Dependent Cytotoxic and Kinesin Spindle Protein Inhibitory Activity of Ru, Os, Rh, and Ir Half-Sandwich Complexes of Ispinesib-Derived Ligands
title_short Metal-Dependent Cytotoxic and Kinesin Spindle Protein Inhibitory Activity of Ru, Os, Rh, and Ir Half-Sandwich Complexes of Ispinesib-Derived Ligands
title_sort metal-dependent cytotoxic and kinesin spindle protein inhibitory activity of ru, os, rh, and ir half-sandwich complexes of ispinesib-derived ligands
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584371/
https://www.ncbi.nlm.nih.gov/pubmed/33003697
http://dx.doi.org/10.1021/acs.inorgchem.0c00957
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