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.

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.

As you search for relevant examples / topics for your MotW assignment, it is important to recognize that there is not a ‘correct’ way to search. Ultimately, the correct method is the one that leads to an answer or solution. Notice I didn’t say the answer, rather an answer, as the question will likely evolve during the search process (and it is a process). The more paths / methods you can employ for gathering information and ideas the better, and like most everything worth doing, deliberate practice is required.

If you are having difficulties finding appropriate examples, try using Google Scholar (http://scholar.google.com) to investigate a topic you have some interest in learning more about. I provide a couple examples below (all Scholar searches excluded patents were limited from 2009 to the present).

• Perhaps you have an interest in metal containing enzymes so you search Scholar using “metalloenzymes” and find a review paper on structure–function relationships in metalloenzymes. While the paper provides background, it doesn’t specifically include crystal structures. You do notice an interesting figure with several cool structures so you search again using the keywords “hydrogenase model” and find an interesting paper on iron-only hydrogenase active site models.
• Searching using the keywords “anticancer metal complex” would lead you to a paper on a Gold(I) complex with anticancer properties. While that might not be exactly what you wanted to find, you read the first several paragraphs and find a reference to “metal thiosemicarbazone complexes” and search Google Scholar again. Here you find a paper on Cu(II) and Ni(II) thiosemicarbazonates that you find completely fascinating.

Browse your ‘hit lists’ beyond the first page and then look at specific journals to narrow the range of your chosen topic. Is a transition metal involved? Is the compound molecular? Is a cif available for download or will you have to request it from the CCDC? While these are simple examples, you should take it as far as your interest, time, and patience allow!

One final tip for now. As soon as we have chosen an article for your MotW assignment, start writing. You may find it necessary to change topics only after you begin writing. Have a backup plan and please, have fun with it!

At John Hopkins University, a manganese(V) imido complex [(TBP₈Cz)Mn^V(NMes)] was synthesized from the Mn(III) complex [(TBP₈Cz)MnM^III]  (Lansky, D.; Kosack, J.; Narducci Sarjeant, A.; Goldberg, D. Inorg. Chem. 2006, 45, 8477-8479). Even with a high-valent Mn^V center, the complex is very resistant to reduction. The ¹H-NMR spectrum showed a diamagnetic molecule, indicating a low-spin Mn^V (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 d_xz/d_yz 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 Mn^V to Mn^IV 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.

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.

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.

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.

]]> http://www.justachemblog.net/molecule-of-the-week-10-organometallic-carbon-oxygen-bond-cleavage/feed/ 0 http://www.justachemblog.net/molecule-of-the-week/ http://www.justachemblog.net/molecule-of-the-week/#comments Mon, 08 Dec 2008 04:14:59 +0000 awood http://www.justachemblog.net/?p=489

This week’s molecule comes from research at the University of Calabria, Italy about Pt(II) and Pd(II) complexes which may be active as anticancer agents (Pucci, D.; Bellusci, A.; Bernardini, S.; Bloise, R.; Crispini, A.; Federici, G.; Liguori, P.; Lucas, M.F.; Russo, N.; Valentini, A., Dalton Transactions, 2008, 5897-5904). The research focused on the synthesis of metal-complexes with two chelating ligands, 2-hydrocyclohepta-2,4,6-trienone (tropolone) and dihexadecyl-2,2′-bipyridine-4,4′-dicarboxylate (bipy), around either Pt(II) or Pd(II) metal centers. Pt is often used as a metal center in anti-cancer drugs, and Pd was introduced with the hope of reducing the toxicity of previous Pt drugs. Both compounds were successfully synthesized and analyzed by X-ray diffraction.

The geometry about the Pt(II) metal is distorted square planar and the molecule is essentially planar. The metal complexes were tested in vitro against the human prostate DU145 and hormone-sensitive LNCaPcell lines. The two chelating ligand system was more active at cell growth inhibition than other studied complexes. The complexes are known to inhibit tumor growth by binding to a cell’s DNA and inducing cell apoptosis or necrosis. These metal-based anticancer drugs are important because they seem to be more effective in lower doses, which would decrease toxicity. Also the specific bipy ligand which allows strong pi-pi bonds may cause further conformational changes in a cell’s DNA which might increase efficiency. The Calabria researchers plan to investigate the mechanisms of these inhibitory complexes in future work.

This molecule interested me because of its long, linear chains and near planar shape. It’s cool to take a look at the potential drugs of tomorrow.

The molecule of the week comes from ongoing research by Dr. Randolf Thummel at the University of Houston (Zeping Deng, Huan-Wei Tseng, Ruifa Zong, Dong Wang, and Randolph Thummel. Inorg. Chem. 2008, 47, 1835 – 1848).  The article focuses on research done in the catalytic decomposition of water into hydrogen and oxygen using diruthenium complexes.  One of the major hurdles which must be overcome in order for hydrogen is the large scale production of hydrogen in an environmentally friedly way.  Currently, hydrogen is produced from hydrocarbons or through the electrolysis of water.  Using hydrocarbons does not solve the problems of oil dependency and using electrolysis requires large amounts of electricity, which would likely be produed by burning coal.  The ultimate goal of the Thummel group is to produce a photocatalyst which will use UV- light to carry out the redox reaction converting water into hydrogen gas and oxgyen gas. The ability to catalyze the decomposition of water is partly due to the presence of the two ruthenium centers so close to one another.  A molecule of water binds to each metal center and hydrogen is release through an oxidation process.  The oxgyen atoms are then within close enough proximity to react to form diatomic oxygen.  Currently, the diruthenium complex is able to catalyse the decomposition of water only in a highly acidic (pH=1) solution in the presence of Ce(IV).  The role of the Ce(IV) is as a sacrificial oxidant.  Future research by the Thummel group will focus on further understanding the specific mechanism involved in the catalysis reaction with the eventual goal of using UV-light to drive the reaction.

However I didn’t choose this molecule because it looked “cool”.  I found the molecule’s ability to bind to cancerous cells and fluoresce to be particularly appealing.  Previously, most known platinum (II) anticancer compounds did not flouresce which was promblematic because the best way to study living cells was using a digital fluorescence microscopy technique.  Achieving a fluorescent metal-based molecule allows researchers to study the chemical processes platinum undergoes once it binds to tumor cells, providing better insight to fighting cancer.  In the case of cis-[Pt(A9opy)Cl2], studies showed that upon photolysis, the carbon-carbon double bond remained stable and did not isomerize.  Although the molecule is less effective than cisplatin, the most common metal-based chemotherapeutic drug, it proved to be fairly active against most tumor cells.  Further studies into the synthesis of related compounds and more in-depth biological research will be conducted in order to eventually find a drug that is less toxic and more active against a wider range of tumor lines.