Cargando…
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 (...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783599582476763136 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7584371 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American
Chemical Society |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT łomzikmichał metaldependentcytotoxicandkinesinspindleproteininhibitoryactivityofruosrhandirhalfsandwichcomplexesofispinesibderivedligands AT hanifmuhammad metaldependentcytotoxicandkinesinspindleproteininhibitoryactivityofruosrhandirhalfsandwichcomplexesofispinesibderivedligands AT budniokaleksandra metaldependentcytotoxicandkinesinspindleproteininhibitoryactivityofruosrhandirhalfsandwichcomplexesofispinesibderivedligands AT błauzandrzej metaldependentcytotoxicandkinesinspindleproteininhibitoryactivityofruosrhandirhalfsandwichcomplexesofispinesibderivedligands AT makalanna metaldependentcytotoxicandkinesinspindleproteininhibitoryactivityofruosrhandirhalfsandwichcomplexesofispinesibderivedligands AT tchondanielm metaldependentcytotoxicandkinesinspindleproteininhibitoryactivityofruosrhandirhalfsandwichcomplexesofispinesibderivedligands AT lesniewskabarbara metaldependentcytotoxicandkinesinspindleproteininhibitoryactivityofruosrhandirhalfsandwichcomplexesofispinesibderivedligands AT tongkelvinkh metaldependentcytotoxicandkinesinspindleproteininhibitoryactivityofruosrhandirhalfsandwichcomplexesofispinesibderivedligands AT movassaghisanam metaldependentcytotoxicandkinesinspindleproteininhibitoryactivityofruosrhandirhalfsandwichcomplexesofispinesibderivedligands AT sohneltilo metaldependentcytotoxicandkinesinspindleproteininhibitoryactivityofruosrhandirhalfsandwichcomplexesofispinesibderivedligands AT jamiesonstephenmf metaldependentcytotoxicandkinesinspindleproteininhibitoryactivityofruosrhandirhalfsandwichcomplexesofispinesibderivedligands AT zafarayesha metaldependentcytotoxicandkinesinspindleproteininhibitoryactivityofruosrhandirhalfsandwichcomplexesofispinesibderivedligands AT reynissonjohannes metaldependentcytotoxicandkinesinspindleproteininhibitoryactivityofruosrhandirhalfsandwichcomplexesofispinesibderivedligands AT rychlikbłazej metaldependentcytotoxicandkinesinspindleproteininhibitoryactivityofruosrhandirhalfsandwichcomplexesofispinesibderivedligands AT hartingerchristiang metaldependentcytotoxicandkinesinspindleproteininhibitoryactivityofruosrhandirhalfsandwichcomplexesofispinesibderivedligands AT plazukdamian metaldependentcytotoxicandkinesinspindleproteininhibitoryactivityofruosrhandirhalfsandwichcomplexesofispinesibderivedligands |