1. Conor Black, C.M.Black@warwick.ac.uk
Department of Chemistry
Supervisor: Dr Abraha Habtemariam
Conclusion
•Both the ligands and the complexes were synthesised in a wide range of yields; unusually, the methodology used for the complexes proved very
successful for the synthesis of C^C ligands, but not for C^N ligands.
•The problems with solubility experienced with complex 4 could potentially prevent the complexes from being effective in vivo. In other iridium
complexes of this type, solubility in water comes from displacement of the halogen ligand present by H2O to form an aqua complex, so it is
possible that the iodine ligand is too stable to be displaced easily. To counter this, the synthesis could be repeated with the use of KCl or KBr
instead of KI to try and synthesise Ir-Cl and Ir-Br complexes.
References
[1] Z.Liu et al, Angew. Chem. Int. Ed. , 2014, 53, 3941-3946
[2] J. Tönnemann, J. Risse, Z. Grote, R.Scopellitiand K. Severin, Eur. J. Inorg. Chem. , 2013, 4558-4562
[3] C. Segarra, E. Mas-Marzá, M. Benítez, J. A. Mata and E. Peris, Angew. Chem. Int. Ed., 2012, 51,
10841-10845
Complexes
Acknowledgements
I would like to thank my supervisor, Dr Abraha
Habtemariam, as well as Dr Prinessa Chellan, for their
help and advice throughout the project, and the rest of
the PJS group for their support.
Synthesis of N-Heterocyclic Carbene Iridium
Complexes for Anticancer Drugs
Introduction
•The use of transition metals like iridium in chemotherapy dates back to the discovery of the
anticancer effects of the platinum-based drug cisplatin in the 1970’s. This drug, often referred to
as the “penicillin of cancer drugs”, is still widely used today; cisplatin, and two of its derivatives,
carboplatin and oxaliplatin, are involved in nearly 50% of all cancer therapies worldwide[1].
However, platinum-based drugs have a number of side effects, and a number of cancer cell types
display or can develop resistance to their use. The development of alternatives to platinum-based
drugs is therefore an important area of research. My project focuses on the synthesis of new
iridium-based complexes, which can then be tested to determine their anticancer properties.
Pt
Pt Pt
Cl
ClH3N
H3N
H3N
H3N O
O
O
O
O
O
O
O
H2
N
N
H2
1
2 3
Figure 1-cisplatin (1), and its derivatives
carboplatin (2) and oxaliplatin (3)
Methodology
[IrCp*Cl2]2NN
R1
R2X, THF (dry), RT, 24 hrs
NN
R1 R2
X
Cs2CO3 (5 eq.), KI (5 eq.),
MeCN (dry), reflux, 24 hours Ir
I
L'
LOR MeCN, reflux, 5 days
OR Na2CO3, KBr, MeCN, RT, 48 hrs where L^L'=
C^C or C^N
chelating
ligandX=Cl, Br
•The complexes were synthesised via reactions carried out in acetonitrile between an iridium dimer, [IrCp*Cl2]2, which was made according to a
literature procedure[2], and an imidazole-based ligand. The ligands were mainly made by reacting methylimidazole or benzylimidazole with an
alkyl halide in tetrahydrofuran as a solvent at room temperature. Complexation required use of a base, caesium carbonate, to deprotonate the
ligands, and potassium iodide; both used according to a literature procedure[3]. These were mixed with the dimer and the ligands, and the
resulting solution refluxed for 24 hours. All of the complexes synthesised are believed to be novel.
Ir Cl
Cl
Ir
Cl
Cl
[IrCp*Cl2]2=
Characterisation and Efficacy
•The compounds were characterised by 1H NMR and mass spectrometry.
An example of 1H NMR characterisation is provided for complex 4.
Ir
I
L'
L
N
C
N
Me C
N
C
N
Me C
F
N
C
N
Me C
CO2Me
N
C
N
Me C
Me
N
C
N
Me C
CN
N
C
N
Me N
N
C
N
C
N
C
N
Me NH2
L^L':
N
C
N
Me
N
N
4 (61%) 5 (61%)
11 (44%)
6 (42%) 7a
12 (67%)
10b8 (49%) 9a
a=Complexes detected by mass spec but not fully isolated; b=trace of complex
detected by mass spec, but not enough present to be isolated
•A UV-Vis experiment was carried out to determine if complex 4 was
active in the reduction of the biological molecule NAD. The complex was
found to be insoluble in water, so it was dissolved in DMSO and the
sample diluted with water, then mixed with NAD and sodium formate, a
hydride source. The experiment proved inconclusive; the lack of aqueous
solubility could pose to be a challenge in the use of the complexes as
anticancer agents.
NN
R1 R2X, THF (dry), RT, 24 hrs
NN
R1 R2
X
Cs2CO3 (5 eq.), KI (5 eq.),
MeCN (dry), reflux, 24 hours Ir
I
L'
LOR MeCN, reflux, 5 days
OR Na2CO3, KBr, MeCN, RT, 48 hrs where L^L'=
C^C or C^N
chelating
ligandX=Cl, Br
Ir Cl
Cl
Ir
Cl
Cl
*
Ir
I
N
C
N
Me
C
*
* *
*
*
*
*
*
*
*
*
*
*
* *
*
*
*
*
*
NMR Solvent
(CDCl3)
H2O
(in CDCl3)
MeCN