Impact factors

Have you ever taken a few seconds to explore the impact factors of your favorite journals? If you've never done it before, I highly recommend taking a closer look at the ISI Web of Knowledge, especially the Journal Citation Reports (JCR). Whether or not you believe impact factors doesn't really matter--it's pretty interesting nonetheless.

For instance, the first article ever published with my name on it was in Organic Letters, which has an impact factor of 4.368 according to JCR. More recently, some of my work could be read in the international edition of Angewandte Chemie--impact factor 9.596. Does this mean I am slowly moving up the ladder of scientific respect? Well, there is actually a lot of debate about this subject, and some people believe that journal impact factors don't accurately represent the real importance of journals; would it be better to just use actual article citation numbers?

Before I move on, I think it is pretty important to understand how impact factor is calculated. Here is what goes into an impact factor calculation:



Using Angewandte Chemie International Edition as a real life example--in 2005 there were 11384 other articles citing articles from the year 2004, and 10620 other articles citing articles from the year 2003, for a grand total of 22004 citations. Divide this by the total number of articles published in 2003 and 2004 (2293) to get 9.596, the impact factor. Pretty simple, right? Well, the JCR reports a number of other interesting factors including the immediacy index (number of cites to "current" articles divided by number of current articles), journal cited half life (the median age of articles that are cited in the current year), and several graphs that condense some of this information.

Does the impact factor really measure the quality of a journal (or the importance of the articles published in the journal)? Well, it is true that some of the journals that I consider to be the best in the field have some of the highest impact factors. On the other hand, it's important to keep in mind that these numbers also reflect the latest trends in the literature. Availability of journals can be an issue, along with the amount of current interest and publication in a particular area.

Below is a condensed list of my favorite journals and their 2005 JCR impact factors:

Protein folding

Another interesting link that my husband recently pointed out:

Folding@Home project (FAH)

Basically, using a technique called "distributed computing," researchers in the Pande group at Stanford hope to better understand protein folding and mis-folding. This of course is a noble cause, as incorrect protein folding or aggregation might be responsible for a variety of disease states; Alzheimer's, Huntington's, Parkinson's, and the big one--cancer (as related to p53)--have all been linked to protein misbehavior. Instead of using a supercomputer for all of these protein folding calculations, FAH relies on people like us to download and run software devoted to their cause. While there are almost 200,000 active CPUs in FAH, a typical supercomputer has only 5000. So far FAH has been quite successful, as of March 21, 2007 over 40 publications have been attributed to FAH calculations.

Would you be willing to donate your computer's down time to a good cause?

Gypsum megacrystals

picture taken from Garcia-Ruiz, J.M. et al. 2007 Geology 35(4), 327.

Although this isn't exactly a chemistry article, it is most certainly chemistry related, and I hope that you will agree that these pictures are too awesome to believe. The gigantic crystals pictured above made the cover of this month's Geology. Almost 80 years ago, the excavation of caves and tunnels at the Naica mine (112km Southeast of Chihuahua, Mexico) led to the discovery of meter-sized single crystals of selenite, which is one of the four crystal forms of gypsum. (The other three forms are satin spar, desert rose, and gypsum flower. As a side note, when I was younger I had a great collection of rocks and minerals that included a very nice sample of desert rose). Often these crystals of calcium sulfate dihydrate are found coated in calcite (calcium carbonate), celestite (strontium sulfate), or trace amounts of iron oxide, which give the crystals either a white or slightly red hue; selenite is colorless/transparent in its pure form. Amazingly, the Cueva de los Cristales (Cave of Crystals) contains selenite crystals up to 11 meters in length and 1 meter thick, with minimal contamination from other minerals.

While several have made conjectures as to how these crystals formed, none had been investigated carefully until now. Garcia-Ruiz and coworkers set out to explain the formation and growth of the Naica megacrystals after closely considering several factors. First, gypsum is slightly soluble in water, with a maximal solubility observed at 58 degrees C; conveniently, water samples from the Naica mines have temperatures ranging from 48-59 degrees C. Thus, the water found in the area is slightly supersaturated for gypsum and slightly undersaturated for the anhydrite form of calcium sulfate, suggesting a self-feeding mechanism. In other words, crystal growth might have been driven by a solution controlled anhydrite-gypsum phase transition. Calculation of the nucleation rate indicated that this suggested mechanism is a probable one, but only within a very narrow range of temperatures--46 to 60 degrees C. Such calculations indicate that these crystals have been growing in the caves at Naica for over one million years!

For more information:

The Largest Crystals on Earth

More pictures

Photovoltaic devices from viruses

Viral capsids are attractive scaffolds for the preparation of nanomaterials; they are highly robust in nature, monodisperse, easy to assemble, and small in size. In particular, the hollow tube-like capsid of the tobacco mosaic virus (TMV) provides an intriguing template for the development of organic nanowires. When fully assembled, each TMV particle is 300nm in length and is made up of over 2000 identical protein subunits that can be assembled into other aggregate structures; depending on pH and ionic strength conditions during assembly.

Thus, the idea to create light-harvesting systems out of assembled TMV capsids is not a surprising one. In fact, in the literature numerous methods have been developed to modify both the interior and exterior of the viral capsid with inorganic substrates,[1,2,3] but little success has been as been achieved with organic ones. So you can imagine that I was especially excited when I saw the title "Self-Assembling Light-Harvesting Systems from Synthetically Modified Tobacco Mosaic Virus Coat Proteins" in JACS quite recently. Ever since Prof. Matthew Francis gave a seminar here, I've had his group website bookmarked and have been watching for new developments.

In nature, sunlight is converted into chemical bonds with a high efficiency, mostly due to the fact that photosynthetic systems incorporate several types of chromophores (covering a large spectral bandwidth) spaced precisely to optimize energy transfer. In an attempt to mimic the ingenuity of nature, Miller and coworkers utilized a mutant TMV monomer bearing a reactive cysteine residue. At pH 7 in a phosphate buffer, this reactive cysteine was coupled with maleimide functionalized Oregon Green (primary donor), tetramethylrhodamine (secondary acceptor), or Alexa Fluor 594 (acceptor). In order for this to work, FRET must occur between the selected donors and acceptor, and these dyes were chosen for their high degree of overlap in the solar spectrum as well as their high extinction coefficients and stability. By mixing various ratios of donor and acceptor monomers together and then adjusting ionic strength and pH, both disk and long rod aggregate structures were formed; the attached chromophores apparently had no effect on the systems ability to self assemble. A ratio of 33:1 (donor Oregon green) to acceptor (Alexa Fluor 594) produced an overall efficiency of 47%, while the 3-chromophore system containing 8:4:1 Oregon green: tetramethylrhodamine: Alexa Fluor 594 resulted in a stunning 90% efficiency!



Though it is a simple concept, the combination of self-assembling biological scaffolds and synthetic organic chromophores seems to have great potential for the development of new solar cells.

Organometallics, the final frontier?

For the past few months I've been following the work coming out of the Meggers lab at the University of Pennsylvania. A nice summary of their ruthenium based protein kinase inhibitors was recently published in Synlett [1], and while I'm certainly a little rusty on organometallic chemistry, I find their approach fascinating nonetheless.

Exploring chemical space with organometallics makes complete sense; carbon-based molecules can only form linear, trigonal planar, or tetrahedral geometries, so why not explore elements that are pentavalent or hexavalent and can thus form unique bioactive scaffolds? In a recent lecture, Meggers pointed out that an asymmetric tetrahedral carbon can form 2 stereoisomers, but an octahedral center with six substituents can form 30 different stereoisomers. (For those non-believers, Meggers had actually drawn out all 30 different stereoisomers on a slide).

In their search for a octahedral carbon-substitute, Meggers and coworkers concentrated on ruthenium because of its low cost, low toxicity (in the II and III oxidation states), high stability, and synthetic tractability. Using the ATP-competitive protein kinase inhibitor staurosporine as the basis for a ruthenium ligand, a small library of complexes was synthesized (100 members total, with 12 different ligands overall). Screening against several kinases revealed that several of the ruthenium based inhibitors were quite potent, with IC50 values in the nanomolar range. What I find most amazing is the fact that the staurosporine-based pyridocarbazole ligand is 19,000 times less potent than the ruthenium complex containing the same ligand. Further application of this strategy has led to the discovery of highly selective protein kinase inhibitors (for Pim-1, GSK-3, MSK-1), some with picomolar binding constants. A crystal structure confirmed the initial hypothesis that the ruthenium center is not involved in any direct interactions with the protein; the metal center works to orient the organic ligands in a conformation that favors binding.

Reactions that work

Looking for a way to prepare nucleoside-5'-carboxylic acids? Then I have just the reaction for you. Using a procedure adapted from Epp and Widlanski [1], one can easily make these carboxylic acids in just under three hours. In my hands, this reaction has worked wonderfully every single time, producing relatively pure product without much effort on my part; over the years it has become one of my favorite reactions.

Here is a sample procedure, exactly as it appears in my lab notebook:

Place 5g of acetonide protected adenosine in a 100ml round bottom flask. Add stir bar, 11.53g of DIB and 0.51g of TEMPO. Add 15ml of acetonitrile to 15ml of water and add to the reaction flask. Stir. After about 15 minutes the the reaction will turns a deep brown-orange color and the components begin to dissolve. Shortly after this a white precipitate forms. Stir for an additional 3 hours. Filter the solid and triturate sequentially with acetone and diethyl ether (3x each, 15ml). Dry the resulting solid under vacuum. No further purification necessary.

Yield: 4.98g, 96.8%

Large or small scale, the yield for this reaction is usually in the 90% range.

Bioethics and DCA

Earlier this week I got an email from a boy in China, asking me to send him a compound that was synthesized by one of my lab-mates and was subsequently shown to kill cancer cells. At first I thought the email was spam, but after closer inspection I realized that it wasn't; he wasn't well informed, but had obviously read an article related to our lab's work and wanted the compound to give to his mother. Unfortunately, because this drug is still in pre-clinical phase my lab can't do anything to help cancer patients like this Chinese boy's mother. I felt awful and didn't know what an appropriate response would be to his email.

Anways, this relates to an article that I read at the end of this week entitled "Cancer patients opt for unapproved drug." It was pretty fascinating and made me think. Basically, in January, Bonnet and coworkers [1] at the University of Alberta demonstrated that the small molecule dichloroacetate (DCA) can force cancer cells to undergo apoptosis and decrease tumor growth with limited toxicity. It sounds too good to be true, but the science behind it makes sense. Cancer cells have a unique metabolic profile, as the glucose oxidation that normally takes place in the mitochondria is not functional; thus, the mitochondria is considered "inactive" and the cells rely on cytoplasmic aerobic glycolysis for energy production. As a result of this mitochondrial damage, tumors have increased glucose uptake and metabolism, and this is considered one of the better markers of cancer cells. Studies have shown that several human cancers cell lines have hyperpolarized mitochondria and reduced oxidative metabolism; through inhibition of the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK), DCA is able to reverse these changes to the mitochondria, which in turn allows tumor cells to be killed through apoptosis. Most amazingly, tumor volumes were reduced in of nude rats that drank DCA dissolved in drinking water and no toxicity was observed. As DCA has been used in clinical trials for the treatment of mitochondrial diseases and has a patented structure, big pharma wasn't interested in developing it as a drug.

This is where things start to get a little more interesting. After a little research on DCA, Jim Tassano, the owner of a pest control company in California, teamed up with chemist Joseph Ryan to make DCA. After they came up with a suitable synthesis, he set up two websites: one is devoted to selling this homemade DCA for veterinary use, and the other provides contains excerpts from the Bonnet paper as well as a DCA discussion forum with over 1,000 posted messages. Although the FDA has not approved of the use of DCA in humans, many of the posts on the forum are from cancer patients taking DCA and reporting on its effectiveness, a "clinical trial" of sorts. Researchers are worried that these patients are not only endangering themselves by taking an unapproved drug, but also hindering attempts of completing a real clinical trial. Approximately 95% of cancer drugs in clinical trials don't get approved for human use, usually due to ineffectiveness or undesirable side effects. Sadly many patients don't have time to wait for clinical trials to be completed, and therefore they are willing to subject themselves to the unknown in hopes of beating cancer.

I certainly see both sides of the issue. While the chemist in me cringes at the thought of ingesting any non-pharmaceutical grade chemical (the website that sells DCA claims a purity of more than 99%, with impurities of 0.5% monochloroacetic acid and/or trichloroacetic acid, which doesn't come close to the purity requirements for pharmaceuticals), my compassionate side wants to offer a ray of hope to those suffering.