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MotW16: Anticancer properties of Ruthenium(II) complexes

Ruthenium(II) complexes of the general formula [(η6-arene)Ru(XY)Z]+ were studied for their anticancer properties in A2780 human ovarian cancer cells and A549 human lung cancer cells (Inorg. Chem. 2009, 48, 9444–9453, DOI: 10.1021/ic9013366). The specific arenes used included p-cymene, hexamethylbenzene, and biphenyl), XY denotes o-phenylenediamine, o-benzoquinonediimine or 4,5-dimethyl-o-phenylenediamine, and Z denotes Cl, Br, or I. In particular, redox-active diamine ligands were tested for their inhibitory growth properties for those cancer cells.

The researchers found that when the oxidized ligand (o-bqdi) was present in the Ruthenium complex, it showed no activity in inhibiting the growth of cancer cells. While the ligand (o-pda) showed the highest inhibitory activity against A2780 ovarian cancer cells, none of the complexes showed any activity against the A549 lung cancer cells. The paper states that the presence of GSH in 15-mol equiv reduced complex 4 completely to o-pda from o-bqdi. The o-bqdi chelating ligand, when reduced to an o-pda chelating ligand, acts as an inhibitory complex. However, in human cells, GSH is naturally present in 2-10mM concentrations, which is significantly lower than the 15-mol equiv concentration. Because there was no activity in complex 4 in either cancerous cell, the paper concludes that the reduction process from GSH is too slow. Also, reoxidation from oxygen (air) prevents the reduction to o-pda from taking place.

The authors also state that the low activity of the oxidized chelated ligand may be the result of the stabilizing effect the π-acceptor o-bqdi has on the Ruthenium complex, making it more difficult for Cl- to leave the complex. The Ru-Cl bond does not break as readily resulting in low hydrolysis that is required for reactions with DNA. The hydrolysis of Ru-Cl results in a [(η6-arene)Ru(II)(en)H2O]2+ that binds to DNA and forms a monofunctional adduct. The paper concludes that the low activity of the complexes in inhibiting cancer cells could be a result of a lack of hydrolysis. Hydrolysis allows the complex to form an adduct with the guanine. The ligands and complexes presented are interesting because of their potential cytotoxicity towards cancer cells.

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MotW 15: Promising Ruthenium Complexes as Anticancer Drugs

Organoruthenium complexes, of the form of [(η6-arene)RuII(YZ)X]+ (Inorg. Chem., 2008, 47, 11470–11486, DOI: 10.1021/ic801361m), are increasingly being studied for use in medicine. The arene is usually a phenyl derivative, YZ is usually a chelating ligand, and X is usually a halide, such as Cl. This type of compound has been studied to be used against cancer. Using the exmple with x=Cl, the Ru-Cl bond can be hydrolyzed and then act as a binding site for DNA, while the arene is a hydrophobic site of the complex, which protects the RuII from oxidizing to RuIII. The chelating ligand provides stability and as the size of the arene increases, the cytotoxicity to the cancer cells increases.

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The complex pictured, [(η6-Tha)Ru(bipy(OH)O)(9-EtG-N7)][PF6], contains the bipy(OH)O chelating ligand, and showed a large increase in the cytotoxicity toward human ovarian and human lung cancer cells. The tetrahydroanthracene (tha) “faces” protect the RuII against oxidation. Examining the crystal structures shows CH/π interactions between the bipyridine ligand and tetrahydroanthracene are important for stabilizing the interaction between [(η6-Tha)Ru(bipy(OH)O)(9-EtG-N7)][PF6] and proteins. Although this complex was not tested for activity against ovarian and lung cancer cell lines, A2780 and A549 respectively, other complexes with the tetrahydroanthracene (tha) moity were tested and proved to be most active against the ovarian cancer cell line. Ruthenium complexes such as [(η6-Tha)Ru(bipy(OH)O)(9-EtG-N7)][PF6] have been shown to mimic iron binding in the human body and the ligand, bipy(OH)O, helps the complex bind to DNA in ways that another antitumor compound, cisplatin, cannot. This shows extreme promise as a therapeutic as cisplatin tumor toxicity is not as high with some types of tumors.

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Fatty Foods Affect Brain Before Weight

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High amounts of fat in food, such as ice cream, not only affect a person’s stomach but also their brain. Some of the fat travels to the brain, which then causes the brain to send out signals to all of the cells in the body. These signals “tell” the cells to disregard the hormones leptin and insulin, which tell the body to “stop” eating to regulate body weight. When a human eats, these hormones send signals to the body to stop eating once the body is full, but these hormones do not always work when a human eats something enjoyable like “junk” food. Leptin is released to stop the feeling of hunger by fat tissue in the body and insulin slows the desire for food by increasing in the pancreas after detection of blood sugar from a meal.

In a study done at the University of Texas Southwestern Medical Center at Dallas, Dr. Deborah Clegg analyzed what kinds of fats affected the brain in this way. Dr. Clegg believes that the fat actually changed the chemical composition of the brain because the fat is incorporated into the brain. Dr. Clegg performed this study by looking at effects of different fats on the brain of animals after exposure by three different methods: injection directly into the brain, feeding the animal through a stomach tube, and infusion into the carotid artery a few times a day. Palmitic acid and oleic acid were the specific fats used. Palmitic acid is a saturated fatty acid and is found in foods such as butter and beef while oleic acid is an unsaturated fatty acid found in food such as olive oil. The results showed that palmitic acid affected the signaling pathways of the leptin and insulin over about three days while the oleic acid did not affect the hormones. These studies were done on animals but Dr. Clegg believes that the saturated fatty acids will affect a human’s brain in a similar way. In another study with rats, the saturated fats, especially palmitic acid, caused the insulin modulator to localize to the cell membranes in the hypothalamus, which slowed the insulin signaling in the brain. Dr. Clegg hopes to soon determine a way to reverse the effects of the palmitic acid on the brain signaling.

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New Research Finds Novel Uses for Old Drugs

A recent article in C&EN reports that scientists at the University of North Carolina at Chapel Hill School of Medicine and the University of California, San Francisco have developed and experimentally tested a technique to predict new target diseases for existing drugs. The team, led by Bryan L. Roth and Brian K. Shoichet, developed a computational method that compares how similar the structures of all known drugs are to the naturally occurring ligands of disease targets within cells. In their study, the scientists showed that the method predicts potential new uses as well as unexpected side effects of approved drugs.

Many of the most successful drugs on the market today are being prescribed for ailments that are quite different from the ones they were originally designed to treat since many drugs have been found to bind to multiple targets. Sometimes these interactions lead to new uses for well established drugs. At other times, they may cause harmful side effects. Either way, knowing about these interactions allows for better use of drugs.

In the new method, drug receptors are not defined by structure or sequence but by the ligands that bind to them. This approach differs from structure-based approaches which usually use a receptor’s crystal structure as a starting point.

“This approach uncovered interactions between drugs and targets that we never could have predicted simply by looking at the chemical structures,” said senior study author Bryan Roth, M.D., Ph.D., professor of pharmacology and director of the National Institute of Mental Health Psychoactive Drug Screening Program at UNC. “We may now have a way to predict what side effects are likely to occur from treatment before we even put a drug into clinical testing.” internetchemistry.com

By using a modified version of an already established algorithm used to search gene-sequence databases, compounds were screened against a database of targets, asking how much the compounds looked like the ligands. The team compared 3,665 approved or investigational drugs with hundreds of targets which were defined by their ligands. The researchers predicted thousands of unanticipated interactions and experimentally tested 30 of them. Of these 30, they confirmed 23 of the interactions.

In one case, the team found  that Rescriptor, which inhibits the enzyme HIV reverse transcriptase, also inhibited the histamine H4 receptor. The scientists have linked Rescriptor binding to histamine H4 at physiologically relevant concentrations to some of the painful side effects that the drug has. In another example, the antidepressant Prozac, whose primary target is the serotonin transporter, bound the beta-1 adrenerfic receptor, a G-protein-coupled receptor (GPCR) that usually binds such compounds as epinephrine and norepinephrine.

Roth states that the power of their approach is that it can be used to uncover the real targets of pharmaceutical compounds quickly and efficiently, and will probably lead to a greater understanding of the many molecular targets of each drug. Consequently, this new method will be an important step forward for chemists to design drugs that act on multiple targets.

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A Natural Lock on Tumor Growth

At the University of California, researchers have been studying RNA interface(RNAi), a naturally occurring system that turns genes on and off, and the proteins drosha and dicer. The research has focused on spacial and temporal regulations of RNAi. Researchers hope that a better understanding of these regulations will help to lead to improved medical applications of controlling the RNAi system. This emerging research is going to be essential in future medical endeavors especially in biomedical applications such as gene therapy.

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Research on drosha and dicer proteins is already being applied to the medical field. According to a study in the New England Journal of Medicine, women who had ovarian tumors with high levels of the proteins Dicer and Drosha survived for an average of 11 years or more, while women who had lower levels survived only a median of around 3 years. Researchers hope that a better understanding of Dicer and Drosha might someday help guide treatment or lead to new types of therapy. These two proteins are essential in RNA interference. In the study, Anil K. Sood, M.D., University of Texas M.D. Anderson Cancer Center, in Houston, and his colleagues looked for Dicer and Drosha in the tissue from 111 women with advanced epithelial ovarian cancer. They found that 60 percent of the cancer tissues had low levels of Dicer, 51 percent had low levels of Drosha, and 39 percent had low levels of both. This study is the largest yet to link RNA interface with any cancer survival rates.

“In the past, people used to think that miRNA might actually promote tumor growth, but there is some emerging thought that some of the miRNAs might keep tumors from growing and actually function as a tumor suppressor,” says Sood, who is an associate professor of cancer biology.

Unfortunately this research does not have immediate application for women with ovarian cancer. However the finding may eventually help doctors to better determine if a patient needs more aggressive treatments.

This new research is causing many biotechnology companies to look at this lock-and-key mechanism as a potential way to fight other diseases. They are working to create new synthetic molecules called small interfering RNAs. These siRNAs are being tested as a way to treat eye disease and age-related macular degeneration.

J. Am. Chem. Soc., 2009. DOI: 10.1021/ja905596t

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MotW14 – A nonreducible, high-valent Mn(V) complex

MotW14-ic0609251-mol02wResearch involving the formation and characterization of high-valent Mn complexes has been slow. They are proposed to be active intermediates in biological and synthetic reactions, such as epoxidations and hydroxylations. They are also important intermediates in NR group transfer reactions, or pericyclic reactions in which a pi bond is  transformed into a sigma bond while another sigma bond migrates.

At John Hopkins University, a manganese(V) imido complex [(TBP8Cz)MnV(NMes)] was synthesized from the Mn(III) complex [(TBP8Cz)MnMIII]  (Lansky, D.; Kosack, J.; Narducci Sarjeant, A.; Goldberg, D. Inorg. Chem. 2006, 45, 8477-8479). Even with a high-valent MnV center, the complex is very resistant to reduction. The 1H-NMR spectrum showed a diamagnetic molecule, indicating a low-spin MnV (d2) species. The structure was confirmed via X-ray crystallography. The crystal contains two independent molecules, with the imido axial ligands pointing away from each other. A short Mn-N imido distance suggests a stronger pi overlap between the terminal imido ligand and the empty metal dxz/dyz orbitals. The metal ion is 0.55 Angstroms above the average plan of the four pyrrole N atoms.

Reactions of the Mn(V) complex with alkenes were unsuccessful. H-atom abstraction should be able to occur in this molecule, but it was completely unreactive toward even a highly reactive H-atom donor. This lack of reactivity shows that the complex cannot undergo even weak H abstraction. The explanation could be that the rate-determining step is the reduction of MnV to MnIV which is not easily reached, and therefore the thermodynamics do not favor the H abstraction. The complex is also very resistant to reduction, even as a high-valent species, as shown by the electochemical data.

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MotW13 – A Potential Metal-Free Cancer Drug

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Metal-DNA adducts are popular molecules for cancer treatment.  However, the metal-based drugs have been associated with unwanted side effects such as nausea, nephrotoxicity (toxicity to kidney cells), and myelosuppression (suppression of bone marrow activity).  Researchers have therefore been geared toward synthesizing metal-free cancer drugs.  A research team at the Indian Institute of Technology in Bombay  has created a new bis(phosphite) ligand) and corresponding complexes of selenium and gold with thioether functionalities (D. Suresh, Maravanji S. Balakrishna, Krishnan Rathinasamy, Dulal Panda and Joel T. Mague Dalton Trans., 2008, 2285 – 2292).

All three compounds were examined for cytotoxic activity in a HeLa (human cervix epitheloid carcinoma) cell line.  While the bis(phosphite) ligand and bis(sulfide) derivative of the ligand significantly inhibited growth of the HeLa cells, the selenium and gold complexes did not.  By testing both the bis(phosphite) ligand and bis(sulfide) derivative in the HeLa line with annexin V and a propidium iodide apoptosis detection kit, the researchers discovered that both compounds caused cell death by apoptosis, using specialized mechanisms within the cell to shed membrane-bound particles.  The creation of a cancer drug that could potentially reduce or eliminate the side effects of metal-based drugs could help make treatment more bearable for patients as well as possibly attack resistant cells more effectively.

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MotW12 – potential prodrugs for Alzheimer’s disease

MotW12-b815404j-co340wThe molecule for this week comes from research out of the Medicinal Inorganic Chemistry Group at the University of British Columbia in Vancouver and concerns altering pyridinone N-substituents to optimize activity as potential prodrugs for Alzheimer’s disease (Lauren E. Scott, Brent D. G. Page, Brian O. Patrick and Chris Orvig. Dalton Trans., 2008, 6364 – 6367). The research focuses on using metal-binding pyridinone prodrugs for Alzheimer’s disease treatment because of their brain targeting abilities as well as their antioxidant characteristics. Pyridinones are already approved for therapeutic purposes in some areas of the world and, since hydroxypridinones are good at binding to metals, the N-substituent can be modified which in turn alters the structure without changing metal binding capabilities.

In previous research, it was found that molecules that contain a glucose moiety can easily target the brain. Based on this, the researchers aimed to attach a glucose moiety at the 3-hydroxyl oxygen.  This glucose moiety can then be enzymatically removed once the molecule reaches the target leaving the metal binding agent. The copper complexes 3-Hydroxy-2-methyl-1-phenyl-4(1H)-pyridinone (Hppp) and 3-hydroxy-2-methyl-4(1H)-pyridinone (Hnbp) were synthesized. Copper was used as it is one of the redox active metals involved in Alzheimer’s disease and because it has a higher affinity for amerliorate toxic beta-amyloid deposits, which are found in the brains of affected patients.  It was found that the Hppp and Hnbp significantly reduced the amount of amerliorate toxic beta-amyloid deposits and there was no significant difference between the Hppp copper complex and the Hnbp copper complex in efficiency.

I found this research both interesting and important as there is currently no cure for Alzheimer’s disease. It is also interesting to see how inorganic chemistry can be applied to solving problems in medical and biological settings . I am hopeful that in a few years we will see a similar drug or concept that will help cure Alzheimer’s disease.

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Molecule of the Week (11): Organometallic carbon-oxygen bond cleavage

MotW11This article focuses on the synthesis of iron catalysts which are less toxic than those used in industry (Ryan J. Trovitch, Emil Lobkovsky, Marco W. Bouwkamp, Paul J. Chirik. Organometallics 2008 27, 6264-6278). Oxidative addition is a common process involved in organometallic chemistry. This process typically constitutes a two electron redox reaction and is more common when late transition metal complexes are involved. This molecule is part of continuing research as chemists strive to replace toxic and expensive precious metal catalysts with more cost effective and benign iron compounds. However, such research also requires a deeper understanding of the elementary steps involved in oxidative addition catalysis.

The Chirik laboratory at Cornell University has reported the synthesis of aryl-substituted bis(imino)pyridine iron dinitrogen compounds that have the capacity of functioning as efficient catalysts for hydrogenation and hydrosilylation of olefins and alkynes. Even more interesting is that some of these iron containing catalysts were able to promote catalytic cycloisomerizations. Fortunately, researchers have found a convenient way to synthesize four coordinate bis(imino)pyridine iron aklyls. One possible focus of future research may include extending this approach to sp2 hybridized alkenyl to allow the synthesis of the desired vinyl compound. One ongoing problem these researchers face is that many of the iron containing catalysts they attempt to synthesize are too unstable to perform organometallic bond cleavage. Overall, this research could provide advantages over those currently used in industry, especially when considering toxicity. I am hopeful that we will eventually reach a point where more reactions can be carried out with non-toxic catalysts.

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