ROS-activated prodrugs based on ferrocenyliminoboronates:
Redox dependent stability and cytotoxicity
Jakub Věžníka,b
, Martin Konhefrb
, Zdenka Fohlerovác,d,e
, Libuše Trnkováa
and Karel Lacinab
a
Department of Chemistry, Faculty of Science, Masaryk University
b
CEITEC - Central European Institute of Technology, Masaryk University
c
CEITEC - Central European Institute of Technology, Brno University of Technology
d
Department of Microelectronics, Faculty of Electrical Engineering and Communication, Brno University of Technology
e
Department of Biochemistry, Faculty of Medicine, Masaryk University
Kamenice 5, 625 00 Brno
jveznik@mail.muni.cz
Elevated levels of reactive oxygen species (ROS) have been detected in almost all types of cancers. ROS play an
interesting dualistic role in tumour proliferation, promoting its growth at certain levels and causing cell death
through oxidative stress at higher levels.1
Ferrocene derivates were observed to induce cell death through a
Fenton-like mechanism, where hydrogen peroxide reacts with iron to form hydroxyl radicals and other reactive
species that react with organic material.2
We have tested four commercially available ferrocene derivates and found the one with the lowest redox potential
(aminoferrocene) to be the most cytotoxic. Thus, four novel derivatives (Figure 1) consisting of aminoferrocene
and phenylboronic acid have been synthesized with the intent to use them as ROS-activated prodrugs. We have
employed a labile imine bond between these two components as it has shown accelerated hydrolysis under
oxidative conditions, and as such, it should release the cytotoxic agent in the area of elevated ROS levels.
The novel derivatives were characterized regarding their time-dependent stability in aqueous environments. Then,
we performed electrochemical measurements at oxidative conditions to confirm the ROS-responsivity of the
synthesized molecules. Finally, the cytotoxicity of the synthesized molecules was tested using cancer MG-63 cells
and noncancerous NIH-3T3 cells. Out of the derivatives prepared, para-isomers showed improved stability and
cytotoxicity over ortho-isomers.
Figure 1: The four prepared and studied (ferrocenylimino)methyl)phenylboronic acids
References
(1) Reczek, C. R.; Chandel, N. S. The Two Faces of Reactive Oxygen Species in Cancer. Annu. Rev. Cancer
Biol. 2017, 1 (1), 79–98. https://doi.org/10.1146/annurev-cancerbio-041916-065808.
(2) Yang, B.; Chen, Y.; Shi, J. Reactive Oxygen Species (ROS)-Based Nanomedicine. Chemical Reviews
2019. https://doi.org/10.1021/acs.chemrev.8b00626.
Acknowledgements
This research has been financially supported by the Ministry of Education, Youth and Sports of the Czech Republic under the
project CEITEC 2020 (LQ1601), by Masaryk University under the project (MUNI/A/1424/2019), and by the Czech Science
Foundation, grant nr.19-16273Y. We also acknowledge CF Nanobiotechnology supported by MEYS CR (LM2015043) and
CEITEC Nano+ project CZ.02.1.01/0.0/0.0/16_013/0001728.