TY - JOUR
T1 - Group 9 organometallic compounds for therapeutic and bioanalytical applications
AU - Ma, Dik Lung
AU - Chan, Daniel Shiu Hin
AU - Leung, Chung Hang
N1 - This work is supported by Hong Kong Baptist University (Grant FRG2/13-14/008), Centre for Cancer and Inflammation Research, School of Chinese Medicine (Grant CCIR-SCM, HKBU), the Health and Medical Research Fund (Grant HMRF/ 13121482), the Research Grants Council (Grants HKBU/ 201811, HKBU/204612, and HKBU/201913), the French National Research Agency/Research Grants Council Joint Research Scheme (Grant A-HKBU201/12), the State Key Laboratory of Synthetic Chemistry, the Science and Technology Development Fund, Macao SAR (Grant 103/2012/A3), and the University of Macau (Grants MYRG091(Y3-L2)-ICMS12-LCH, MYRG121(Y3-L2)-ICMS12-LCH, and MRG023/LCH/2013/ ICMS).
PY - 2014/12/16
Y1 - 2014/12/16
N2 - (Chemical Equation Presented) Compared with organic small molecules, metal complexes offer several distinct advantages as therapeutic agents or biomolecular probes. Carbon atoms are typically limited to linear, trigonal planar, or tetrahedral geometries, with a maximum of two enantiomers being formed if four different substituents are attached to a single carbon. In contrast, an octahedral metal center with six different substituents can display up to 30 di fferent stereoisomers. While platinum- and ruthenium-based anticancer agents have attracted significant attention in the realm of inorganic medicinal chemistry over the past few decades, group 9 complexes (i.e., iridium and rhodium) have garnered increased attention in therapeutic and bioanalytical applications due to their adjustable reactivity (from kinetically liable to substitutionally inert), high water solubility, stability to air and moisture, and relative ease of synthesis. In this Account, we describe our efforts in the development of group 9 organometallic compounds of general form [M(C∧N)2(N∧N)] (where M = Ir, Rh) as therapeutic agents against distinct biomolecular targets and as luminescent probes for the construction of oligonucleotide-based assays for a diverse range of analytes. Earlier studies by researchers had focused on organometallic iridium(III) and rhodium(III) half-sandwich complexes that show promising anticancer activity, although their precise mechanisms of action still remain unknown. More recently, kinetically-inert group 9 complexes have arisen as fascinating alternatives to organic small molecules for the specific targeting of enzyme activity. Research in our laboratory has shown that cyclometalated octahedral rhodium(III) complexes were active against Janus kinase 2 (JAK2) or NEDD8-activating enzyme (NAE) activity, or against NO production leading to antivasculogenic activity in cellulo. At the same time, recent interest in the development of small molecules as modulators of protein-protein interactions has stimulated our research group to investigate whether kinetically-inert metal complexes could also be used to target protein-protein interfaces relevant to the pathogenesis of certain diseases. We have recently discovered that cyclometalated octahedral iridium(III) and rhodium(III) complexes bearing C∧N ligands based on 2-phenylpyridine could function as modulators of protein-protein interactions, such as TNF-α, STAT3, and mTOR. One rhodium(III) complex antagonized STAT3 activity in vitro and in vivo and displayed potent antitumor activity in a mouse xenograft model of melanoma. Notably, these studies were among the first to demonstrate the direct inhibition of protein-protein interfaces by kinetically-inert group 9 metal complexes. Additionally, we have discovered that group 9 solvato complexes carrying 2-phenylpyridine coligands could function as inhibitors and probes of β-amyloid fibrillogenesis. Meanwhile, the rich photophysical properties of iridium complexes have made them popular tools for the design of luminescent labels and probes. Luminescent iridium(III) complexes benefit from a high quantum yield, responsive emissive properties, long-lived phosphorescence lifetimes, and large Stokes shift values. Over the past few years, our group has developed a number of kinetically-inert, organometallic iridium(III) complexes bearing various C∧N and N∧N ligands that are selective for G-quadruplex DNA, which is a DNA secondary structure formed from planar stacks of guanine tetrads stabilized by Hoogsteen hydrogen bonding. These complexes were then employed to develop G-quadruplex-based, label-free luminescence switch-on assays for nucleic acids, enzyme activity, small molecules, and metal ions.
AB - (Chemical Equation Presented) Compared with organic small molecules, metal complexes offer several distinct advantages as therapeutic agents or biomolecular probes. Carbon atoms are typically limited to linear, trigonal planar, or tetrahedral geometries, with a maximum of two enantiomers being formed if four different substituents are attached to a single carbon. In contrast, an octahedral metal center with six different substituents can display up to 30 di fferent stereoisomers. While platinum- and ruthenium-based anticancer agents have attracted significant attention in the realm of inorganic medicinal chemistry over the past few decades, group 9 complexes (i.e., iridium and rhodium) have garnered increased attention in therapeutic and bioanalytical applications due to their adjustable reactivity (from kinetically liable to substitutionally inert), high water solubility, stability to air and moisture, and relative ease of synthesis. In this Account, we describe our efforts in the development of group 9 organometallic compounds of general form [M(C∧N)2(N∧N)] (where M = Ir, Rh) as therapeutic agents against distinct biomolecular targets and as luminescent probes for the construction of oligonucleotide-based assays for a diverse range of analytes. Earlier studies by researchers had focused on organometallic iridium(III) and rhodium(III) half-sandwich complexes that show promising anticancer activity, although their precise mechanisms of action still remain unknown. More recently, kinetically-inert group 9 complexes have arisen as fascinating alternatives to organic small molecules for the specific targeting of enzyme activity. Research in our laboratory has shown that cyclometalated octahedral rhodium(III) complexes were active against Janus kinase 2 (JAK2) or NEDD8-activating enzyme (NAE) activity, or against NO production leading to antivasculogenic activity in cellulo. At the same time, recent interest in the development of small molecules as modulators of protein-protein interactions has stimulated our research group to investigate whether kinetically-inert metal complexes could also be used to target protein-protein interfaces relevant to the pathogenesis of certain diseases. We have recently discovered that cyclometalated octahedral iridium(III) and rhodium(III) complexes bearing C∧N ligands based on 2-phenylpyridine could function as modulators of protein-protein interactions, such as TNF-α, STAT3, and mTOR. One rhodium(III) complex antagonized STAT3 activity in vitro and in vivo and displayed potent antitumor activity in a mouse xenograft model of melanoma. Notably, these studies were among the first to demonstrate the direct inhibition of protein-protein interfaces by kinetically-inert group 9 metal complexes. Additionally, we have discovered that group 9 solvato complexes carrying 2-phenylpyridine coligands could function as inhibitors and probes of β-amyloid fibrillogenesis. Meanwhile, the rich photophysical properties of iridium complexes have made them popular tools for the design of luminescent labels and probes. Luminescent iridium(III) complexes benefit from a high quantum yield, responsive emissive properties, long-lived phosphorescence lifetimes, and large Stokes shift values. Over the past few years, our group has developed a number of kinetically-inert, organometallic iridium(III) complexes bearing various C∧N and N∧N ligands that are selective for G-quadruplex DNA, which is a DNA secondary structure formed from planar stacks of guanine tetrads stabilized by Hoogsteen hydrogen bonding. These complexes were then employed to develop G-quadruplex-based, label-free luminescence switch-on assays for nucleic acids, enzyme activity, small molecules, and metal ions.
UR - http://www.scopus.com/inward/record.url?scp=84918560899&partnerID=8YFLogxK
U2 - 10.1021/ar500310z
DO - 10.1021/ar500310z
M3 - Journal article
C2 - 25369127
AN - SCOPUS:84918560899
SN - 0001-4842
VL - 47
SP - 3614
EP - 3631
JO - Accounts of Chemical Research
JF - Accounts of Chemical Research
IS - 12
ER -