Ruthenium pincer complexes for light activated toxicity: Lipophilic groups enhance toxicity

Yifei Sun; Sanjit Das; Spenser R. Brown; Emily R. Blevins; Fengrui Qu; Nicholas A. Ward; Shawn Aiden Gregory; Chance M. Boudreaux; Yonghyun Kim; Elizabeth T. Papish

doi:10.1016/j.jinorgbio.2022.112110

Ruthenium pincer complexes for light activated toxicity: Lipophilic groups enhance toxicity

Yifei Sun, Sanjit Das, Spenser R. Brown, Emily R. Blevins, Fengrui Qu, Nicholas A. Ward, Shawn Aiden Gregory, Chance M. Boudreaux, Yonghyun Kim, Elizabeth T. Papish

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Nine ruthenium CNC pincer complexes (1–9) were tested for anticancer activity in cell culture under both dark and light conditions. These complexes included varied CNC pincer ligands including OH, OMe, or Me substituents on the pyridyl ring and wingtip N-heterocyclic carbene (NHC) groups which varied as methyl (Me), phenyl (Ph), mesityl (Mes), and 2,6-diisopropylphenyl (Dipp). The supporting ligands included acetonitrile, Cl, and 2,2′-bipyridine (bpy) donors. The synthesis of complexes 8 and 9 is described herein and are fully characterized by spectroscopic (¹H NMR, IR, UV–Vis, MS) and analytical techniques. Single crystal X-ray diffraction results are reported herein for 8 and 9. The other complexes (1–7) are reported elsewhere. The four most lipophilic ruthenium complexes (6, 7, 8, and 9) showed the best activity vs. MCF7 cancer cells with complexes 6 and 9 showing cytotoxicity and complex 7 and 8 showing light activated photocytotoxicity. The distribution of these compounds between octanol and water is reported as log(D_o/w) values, and increasing log(D_o/w) values correlate roughly with improved activity vs. cancer cells. Overall, lipophilic wingtip groups (e.g. Ph, Mes, Dipp) on the NHC ring and a lower cationic charge (1+ vs. 2+) appears to be beneficial for improved anticancer activity.

Original language	English
Article number	112110
Journal	Journal of Inorganic Biochemistry
Volume	240
DOIs	https://doi.org/10.1016/j.jinorgbio.2022.112110
State	Published - Mar 2023
Externally published	Yes

Funding

We gratefully acknowledge support from the NIH (R15-GM132803-01 and R15-GM132803-02) to ETP and YK. SRB was supported by the US Department of Education as a GAANN Teaching Fellow (P200A180056). We thank NSF MRI program (CHE 1726812, PI Cassady) and UA for the purchase of a MALDI TOF/TOF MS and Dr. Qiaoli Liang for MS experimental work. We thank Dr. Ken Belmore for assistance with the NMR experiments. We thank NSF CHE MRI 1828078 and UA for the purchase of the SC XRD instrument. We thank NSF CHE MRI 1919906 and UA for the purchase of an NMR spectrometer. SAG and ERB participated in this project via the NSF REU program (EEC-1950855, PI Summers). We thank Dr. Igor Fedin for the use of a UV–Vis instrument. We gratefully acknowledge support from the NIH ( R15-GM132803-01 and R15-GM132803-02 ) to ETP and YK. SRB was supported by the US Department of Education as a GAANN Teaching Fellow ( P200A180056 ). We thank NSF MRI program (CHE 1726812, PI Cassady) and UA for the purchase of a MALDI TOF/TOF MS and Dr. Qiaoli Liang for MS experimental work. We thank Dr. Ken Belmore for assistance with the NMR experiments. We thank NSF CHE MRI 1828078 and UA for the purchase of the SC XRD instrument. We thank NSF CHE MRI 1919906 and UA for the purchase of an NMR spectrometer. SAG and ERB participated in this project via the NSF REU program (EEC-1950855, PI Summers). We thank Dr. Igor Fedin for the use of a UV–Vis instrument.

Keywords

Anticancer
Light activation
Lipophilic ligands
N-heterocyclic carbenes
Pincer ligands
Ruthenium

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10.1016/j.jinorgbio.2022.112110

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title = "Ruthenium pincer complexes for light activated toxicity: Lipophilic groups enhance toxicity",

abstract = "Nine ruthenium CNC pincer complexes (1–9) were tested for anticancer activity in cell culture under both dark and light conditions. These complexes included varied CNC pincer ligands including OH, OMe, or Me substituents on the pyridyl ring and wingtip N-heterocyclic carbene (NHC) groups which varied as methyl (Me), phenyl (Ph), mesityl (Mes), and 2,6-diisopropylphenyl (Dipp). The supporting ligands included acetonitrile, Cl, and 2,2′-bipyridine (bpy) donors. The synthesis of complexes 8 and 9 is described herein and are fully characterized by spectroscopic (1H NMR, IR, UV–Vis, MS) and analytical techniques. Single crystal X-ray diffraction results are reported herein for 8 and 9. The other complexes (1–7) are reported elsewhere. The four most lipophilic ruthenium complexes (6, 7, 8, and 9) showed the best activity vs. MCF7 cancer cells with complexes 6 and 9 showing cytotoxicity and complex 7 and 8 showing light activated photocytotoxicity. The distribution of these compounds between octanol and water is reported as log(Do/w) values, and increasing log(Do/w) values correlate roughly with improved activity vs. cancer cells. Overall, lipophilic wingtip groups (e.g. Ph, Mes, Dipp) on the NHC ring and a lower cationic charge (1+ vs. 2+) appears to be beneficial for improved anticancer activity.",

keywords = "Anticancer, Light activation, Lipophilic ligands, N-heterocyclic carbenes, Pincer ligands, Ruthenium",

author = "Yifei Sun and Sanjit Das and Brown, {Spenser R.} and Blevins, {Emily R.} and Fengrui Qu and Ward, {Nicholas A.} and Gregory, {Shawn Aiden} and Boudreaux, {Chance M.} and Yonghyun Kim and Papish, {Elizabeth T.}",

note = "Publisher Copyright: {\textcopyright} 2022",

year = "2023",

month = mar,

doi = "10.1016/j.jinorgbio.2022.112110",

language = "English",

volume = "240",

journal = "Journal of Inorganic Biochemistry",

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T1 - Ruthenium pincer complexes for light activated toxicity

T2 - Lipophilic groups enhance toxicity

AU - Sun, Yifei

AU - Das, Sanjit

AU - Brown, Spenser R.

AU - Blevins, Emily R.

AU - Qu, Fengrui

AU - Ward, Nicholas A.

AU - Gregory, Shawn Aiden

AU - Boudreaux, Chance M.

AU - Kim, Yonghyun

AU - Papish, Elizabeth T.

PY - 2023/3

Y1 - 2023/3

N2 - Nine ruthenium CNC pincer complexes (1–9) were tested for anticancer activity in cell culture under both dark and light conditions. These complexes included varied CNC pincer ligands including OH, OMe, or Me substituents on the pyridyl ring and wingtip N-heterocyclic carbene (NHC) groups which varied as methyl (Me), phenyl (Ph), mesityl (Mes), and 2,6-diisopropylphenyl (Dipp). The supporting ligands included acetonitrile, Cl, and 2,2′-bipyridine (bpy) donors. The synthesis of complexes 8 and 9 is described herein and are fully characterized by spectroscopic (1H NMR, IR, UV–Vis, MS) and analytical techniques. Single crystal X-ray diffraction results are reported herein for 8 and 9. The other complexes (1–7) are reported elsewhere. The four most lipophilic ruthenium complexes (6, 7, 8, and 9) showed the best activity vs. MCF7 cancer cells with complexes 6 and 9 showing cytotoxicity and complex 7 and 8 showing light activated photocytotoxicity. The distribution of these compounds between octanol and water is reported as log(Do/w) values, and increasing log(Do/w) values correlate roughly with improved activity vs. cancer cells. Overall, lipophilic wingtip groups (e.g. Ph, Mes, Dipp) on the NHC ring and a lower cationic charge (1+ vs. 2+) appears to be beneficial for improved anticancer activity.

AB - Nine ruthenium CNC pincer complexes (1–9) were tested for anticancer activity in cell culture under both dark and light conditions. These complexes included varied CNC pincer ligands including OH, OMe, or Me substituents on the pyridyl ring and wingtip N-heterocyclic carbene (NHC) groups which varied as methyl (Me), phenyl (Ph), mesityl (Mes), and 2,6-diisopropylphenyl (Dipp). The supporting ligands included acetonitrile, Cl, and 2,2′-bipyridine (bpy) donors. The synthesis of complexes 8 and 9 is described herein and are fully characterized by spectroscopic (1H NMR, IR, UV–Vis, MS) and analytical techniques. Single crystal X-ray diffraction results are reported herein for 8 and 9. The other complexes (1–7) are reported elsewhere. The four most lipophilic ruthenium complexes (6, 7, 8, and 9) showed the best activity vs. MCF7 cancer cells with complexes 6 and 9 showing cytotoxicity and complex 7 and 8 showing light activated photocytotoxicity. The distribution of these compounds between octanol and water is reported as log(Do/w) values, and increasing log(Do/w) values correlate roughly with improved activity vs. cancer cells. Overall, lipophilic wingtip groups (e.g. Ph, Mes, Dipp) on the NHC ring and a lower cationic charge (1+ vs. 2+) appears to be beneficial for improved anticancer activity.

KW - Anticancer

KW - Light activation

KW - Lipophilic ligands

KW - N-heterocyclic carbenes

KW - Pincer ligands

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JO - Journal of Inorganic Biochemistry

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ER -

Ruthenium pincer complexes for light activated toxicity: Lipophilic groups enhance toxicity

Abstract

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Keywords

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