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Group 9 organometallic compounds for therapeutic and bioanalytical applications
Ma D.-L.1; Chan D.S.-H.1; Leung C.-H.2
2014
Source PublicationAccounts of Chemical Research
ISSN14842
Volume47Issue:12Pages:3614−3631
Abstract

(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.

DOI10.1021/ar500310z
URLView the original
Indexed BySCIE
Language英语
WOS Research AreaChemistry
WOS SubjectChemistry, Multidisciplinary
WOS IDWOS:000346683200022
The Source to ArticleScopus
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Cited Times [WOS]:173   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorMa D.-L.; Leung C.-H.
Affiliation1.Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
2.State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Ma D.-L.,Chan D.S.-H.,Leung C.-H.. Group 9 organometallic compounds for therapeutic and bioanalytical applications[J]. Accounts of Chemical Research,2014,47(12):3614−3631.
APA Ma D.-L.,Chan D.S.-H.,&Leung C.-H..(2014).Group 9 organometallic compounds for therapeutic and bioanalytical applications.Accounts of Chemical Research,47(12),3614−3631.
MLA Ma D.-L.,et al."Group 9 organometallic compounds for therapeutic and bioanalytical applications".Accounts of Chemical Research 47.12(2014):3614−3631.
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