The serendipitous discovery of the anticancer drug cisplatin cemented medicinal inorganic chemistry as an independent discipline in the 1960s. Luminescent metal complexes have subsequently been widely applied for sensing, bio-imaging, and in organic light-emitting diode applications. Transition-metal complexes possess a variety of advantages that make them suitable as therapeutics and as luminescent probes for biomolecules. It is thus highly desirable to develop new luminescent metal complexes that either interact with DNA through different binding modes or target alternative cellular machinery such as proteins as well as to provide a more effective means of monitoring disease progression. In this Review, we highlight recent examples of biologically active luminescent metal complexes that can target and probe a specific biomolecule, and offer insights into the future potential of these compounds for the investigation and treatment of human diseases.
Approved drugs have favourable or validated pharmacokinetic properties and toxicological profiles, and the repositioning of existing drugs for new indications can potentially avoid expensive costs associated with early-stage testing of the hit compounds. In recent years, technological advances in virtual screening methodologies have allowed medicinal chemists to rapidly screen drug libraries for therapeutic activity against new biomolecular targets in a cost-effective manner. This review article outlines the basic principles and recent advances in structure-based virtual screening and highlights the powerful synergy of in silico techniques in drug repositioning as demonstrated in several recent reports.
CONSPECTUS: 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 different 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....
The interactions of a series of platinum(II) Schiff base complexes with c-myc G-quadruplex DNA were studied. Complex [PtL(1a)] (1 a; H(2)L(1a)=N,N'-bis(salicylidene)-4,5-methoxy-1,2-phenylenediamine) can moderately inhibit c-myc gene promoter activity in a cell-free system through stabilizing the G-quadruplex structure and can inhibit c-myc oncogene expression in cultured cells. The interaction between 1 a and G-quadruplex DNA has been examined by (1)H NMR spectroscopy. By using computer-aided structure-based drug design for hit-to-lead optimization, an in silico G-quadruplex DNA model has been constructed for docking-based virtual screening to develop new platinum(II) Schiff base complexes with improved inhibitory activities. Complex [PtL(3)] (3; H(2)L(3)=N,N'-bis{4-[1-(2-propylpiperidine)oxy]salicylidene}-4,5-methoxy-1,2-phenylenediamine) has been identified with a top score in the virtual screening. This complex was subsequently prepared and experimentally tested in vitro for its ability to stabilize or induce the formation of the c-myc G-quadruplex. The inhibitory activity of 3 (IC(50)=4.4 muM) is tenfold more than that of 1 a. The interaction between 1 a or 3 with c-myc G-quadruplex DNA has been examined by absorption titration, emission titration, molecular modeling, and NMR titration experiments, thus revealing that both 1 a and 3 bind c-myc G-quadruplex DNA through an external end-stacking mode at the 3' terminal face of the G-quadruplex. Such binding of G-quadruplex DNA with 3 is accompanied by up to an eightfold increase in the intensity of photoluminescence at lambda(max)=652 nm. Complex 3 also effectively down-regulated the expression of c-myc in human hepatocarcinoma cells.
Breakthrough advances in chemistry and biology over the last two decades have vastly expanded the repertoire of nucleic acid structure and function with potential application in multiple areas of science and technology, including sensing and analytical applications. DNA oligonucleotides represent popular tools for the development of sensing platforms due to their low cost, rich structural polymorphism, and their ability to bind to cognate ligands with sensitivity and specificity rivaling those for protein enzymes and antibodies. In this review, we give an overview of the "label-free" approach that has been a particular focus of our group and others for the construction of luminescent DNA-based sensing platforms. The label-free strategy aims to overcome some of the drawbacks associated with the use of covalently-labeled oligonucleotides prevalent in electrochemical and optical platforms. Label-free DNA-based probes harness the selective interaction between luminescent dyes and functional oligonucleotides that exhibit a "structure-switching" response upon binding to analytes. Based on the numerous examples of label-free luminescent DNA-based probes reported recently, we envisage that this field would continue to thrive and mature in the years to come.
A panel of stable [Au(R-C--N--C)(N-heterocyclic carbene)](+) complexes displays prominent in vitro anticancer properties; [Au(C--N--C)(IMe)]CF(3)SO(3) (1, IMe = 1,3-dimethylimidazol-2-ylidene) significantly poisons topoisomerase I in vitro and suppresses tumor growth in nude mice model.
In this perspective, we highlight recent examples in the development of transition metal complexes as modulators of inflammatory and autoimmune responses.
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