• [$$] A New Day for J&J February 22, 2012
• Midday Glance: Pharmaceuticals companies February 22, 2012
• J&J CEO Switch Is A Necessary Step Forward February 22, 2012
• Sifting Through Ampio Pharmaceuticals' Pipeline February 22, 2012
• J.&J. Offers Concessions to Win Approval for Synthes Deal February 22, 2012
• UPDATE 2-Medicines Co 4th-qtr profit tops estimates; shares up February 22, 2012
• [video] Who is Johnson & Johnson's New CEO, Alex Gorsky? February 22, 2012
• J.& J. Chief to Resign One Role February 22, 2012
• Hip Maker Discussed Failures February 22, 2012
• FTC Approves Final Orders Settling Valeant Pharmaceuticals Case February 22, 2012

• The Secret to Success may be to Fail Fast February 20, 2012
  It is important to design projects so the most critical experiments are performed as soon as possible. That way, if you are going to fail, you fail quickly – and cheaply. All failures provide information you can use to redesign your project. Alternatively, you can drop the project and move on to other things. I [...]
• Increase the Accuracy of Your Supervisor’s Reviews of Your Performance February 13, 2012
  Accurate reviews of your job performance are critical to job promotions, raises, and annual bonuses. Therefore, it is essential that both you and your supervisor get it right. However, many bosses, including some good ones, may be out of touch with your overall performance and forget to acknowledge some of your accomplishments. What should you [...]

[Perspectives] Dodging Drug-Resistant Cancer with Diamonds

Merkel, T. J., DeSimone, J. M

By Derek Lowe

Note: Other Chemistry blogs under “Panopharma”.

• Max Gergel's Second Odd Book February 22, 2012
  I mentioned the fearsome memoirs of Max Gergel here, but not many people know that he wrote another volume. "The Ageless Gergel", out of print for who knows how long, is available here in PDF form. I have to note that it's even more rambling and formless than "Excuse Me Sir, Would You Like to Buy a Bottle of Isopropyl Bromide", and one also gets the impression that he used up a lot of his show-stopping anecdotes in the first book as well. I should also mention that the entire last section of the book is an account of a European vacation, during which no chemistry intrudes, and that the whole thing ends as if Gergel suddenly looked at his watch. But there are some interesting chemical stories buried in there, and it's worth skipping through some parts to find them. This one's pretty typical: I had been visiting Will at the plant in Elgin, South Carolina, and noticed that he smelled goaty. For that matter, the other workers seemed to have a goaty odor, too. I inquired the reason, and he took me to the source, an isolated section of the plant, which smelled horrendous. A large glass still, one that would have delighted a moonshiner in the old whiskey-making days was stinking up Hardwicke Chemical Co. and the surrounding farms. Now fatty acids have a rank odor smelling like rancid butter. The absolute worst member of the series is isovaleric acid. This smells like rancid butter with a soupgon of goat and old sneakers thrown in for good measure. As bad as it smells, the acid chloride derived from it is worse. It is so volatile that it will chase a visitor and leave its far from subtle mark. The odor is soap, water and Lysol resistant. This acid chloride reacts with mucous membrane so that while you are rendered ill by the obnoxious odor, the acid chloride is hydrolyzing with your perspiration as a reactant and eats away your lips, eyeballs and tongue. Hardwicke, committed to make this monster, was only too happy to find' Columbia Organic Chemicals Co., Inc., as a "farmout" and once more we were making something no one else wanted to make. We had never had such a dreadful assignment. Anyone working with this "superstink" is branded and given a wide berth. No matter how amorous his spouse may be, passion crumples despite baths, Chlorox and Dentine. For a while we made isovaleroyl chloride at Cedar Terrace. It created pandemonium among residents who first sniffed each other, came to the plant to sniff us, and then sniffled to their lawyers. Unfortunately, I can't quite put that acid chloride on my list of things I won't work with, because I have worked with it. But I can imagine that making it by the barrel would be a pretty repellent business, for sure. A 25-gram bottle was enough for me.
• Scaling Up a Strange Dinitro Compound (And Others) February 22, 2012
  I wrote here about a very unusual dinitro compound that's in the clinic in oncology. Now there's a synthetic chemistry follow-up, in the form of a paper in Organic Process R&D. It's safe to say that most process and scale-up chemists are never going to have to worry about making a gem-dinitroazetidine - or, for that matter, a gem-dinitroanything. But the issues involved are the same ones that come up over and over again. See if this rings any bells: Gram quantities of (3) for initial anticancer screening were originally prepared by an unoptimized approach that was not suitable for scale-up and failed to address specific hazards of the reaction intermediates and coproducts. The success of (3) in preclinical studies prompted the need for a safe, reliable, and scalable synthesis to provide larger supplies of the active pharmaceutical ingredient (API) for further investigation and eventual clinical trials. Yep, it's when you need large, reliable batches of something that the inadequacies of your chemistry really stand out. The kinds of chemistry that people like me do, back in the discovery labs, often has to be junked. It's fine for making 100mg of something to put in the archives - and tell me, when was the last time you put as much as 100 milligrams of a new compound into the archives? But there are usually plenty of weak points as you try to go to gram, then hundreds of grams, then kilos and up. Among them are: (1) Exothermic chemistry. Excess heat is easy to shed from a 25-mL round-bottom flask. Heat is not so easily lost from larger vessels, though, and the number of chemists who have had to discover this the hard way is beyond counting. The world is very different when everything in the flask is no longer just 1 cm away from a cold glass wall. (2) Stirring. This can be a pain even on the small scale, so imagine what a headache it is by the kilo. Gooey precipitates, thick milkshake-like reactions, lumps of crud - what's inconvenient when small can turn into a disaster later on, because poor stirring leads to localized heating (see above), incomplete reactions, side products, and more. (3) Purification. Just run it down a column? Not so fast, chief. Where, exactly, do you find the columns to run kilos of material across? And the pumps to force the stuff through? And the wherewithal to dispose of all that solid-phase stuff once you've turned it all those colors and it can't be used again? And the time and money to evaporate all that solvent that you're using? No, the scale-up people will go a long way to avoid chromatography. Precipitations and crystallizations are the way to go, if at all possible. Reproducibility. All of these factors influence this part. One of the most important things about a good chemical process is that it works the same flippin' way every single time. As has been said before around here, a route that generates 97% yield most of the time, but with an occasional mysterious 20% flop, is useless. Worse than useless. Squeezing the mystery out of the synthesis is the whole point of process chemistry: you want to know what the side products are, why they form, and how to control every variable. Oh yeah. Cost.Cost-of-goods is rarely a deal-breaker in drug research, but that's partly because people are paying attention to it. In the med-chem labs, we think nothing of using exotic reagents that the single commercial supplier marks up to the sky. That will not fly on scale. Cutting out three steps with a reagent that isn't obtainable in quantity doesn't help the scale-up people one bit. (The good news is that some of these things turn out to be available when someone really wants them - the free market in action). There are other factors, but those are some of the main ones. It's a different world, and it involves thinking about things that a discovery chemist just never thinks about. (Does your product tend to create a fine dust on handling? The sort that might fill a room and explode with static electricity sparks? Can your reaction mixture be pumped through a pipe as a slurry, or not? And so on.) It looks as if the dinitro compound has made it through this gauntlet successfully, but every day, there's someone at some drug company worrying about the next candidate.

Alphabetical by University Name:

A  *  B  * C  * D  *  E  * F  *  G *  H 

I  * J  *   K  *  L  *  M  *  N  *  O  *  P   

Q *  R  *  S  *  T  *  U  *  V  *  W  *  X  * Y

By State:

Dynamic Periodic Table – An interactive periodic table

Visual Elements Periodic Table - A striking representation of the chemical elements drawing on the symbolism that surrounds them from the commonplace to the mythological

• BREAKING NEWS: Error Undoes Faster-Than-Light Neutrino Results February 22, 2012
  It appears that the faster-than-light neutrino results, announced last September by the OPERA collaboration...
• Ancient Elephants Followed the (Female) Leader February 21, 2012
  Seven-million-year-old footsteps reveal today's elephants lived in family groups much like their prehistoric kin
• Video: I, Fishbot February 21, 2012
  Study finds fish follow a robot when it makes swimming easier
• It's Official: Physics Is Hard February 21, 2012
  Even computers think finding equations that describe the progression of a system through time is difficult
• Some Planets Are Alien Invaders February 21, 2012
  Billions of stars may have snatched their most distant worlds
• Podcast: Alaskan Hunters, Battling Microbes, and Improving Street Smarts February 21, 2012
  Part two of some of our favorite stories from AAAS 2012
• ScienceShot: Water World Is New Type of Planet February 21, 2012
  Hubble spies liquid planet with atmosphere composed mostly of water
• Podcast: Scientists—The Next Generation February 21, 2012
  Who are the researchers of the future?
• A Practical Blueprint for a Low-Carbon Electric World? February 20, 2012
  New report presents “transformative” technologies to wean world from fossil fuel-based electricity
• Nuclear Reactors Not Needed to Make the Most Common Medical Isotope February 20, 2012
  New technique uses a medical cyclotron to produce radioisotope

• Nanorobots Deliver
  DNA aptamers are short strands that have high binding affinity for a target protein that can be used as triggers for releasing cargo from delivery vehicles. Douglas et al. (p. … [Read more]
• Supramolecular Polymers Explained
  While polymers are constructed from chemically bonded units, supramolecular polymers arise through reversible linkages, such as hydrogen bonding and electrostatic interactions. Recent advances in the field of supramolecular polymer science … [Read more]
• Life of Li
  Because lithium primarily exists in silicate minerals on continents, the variations of Li isotopes in marine sedimentary rocks reflect the degree of silicate weathering and formation of new sediments on … [Read more]
• Driving Forces
  The physical properties that control the motions of Earth's tectonic plates are difficult to predict accurately on a global scale. Large-scale geodynamic models are continually becoming more powerful, but controversies … [Read more]
• Defective Gene Detective
  Identifying genes that give rise to diseases is one of the major goals of sequencing human genomes. However, putative loss-of-function genes, which are often some of the first identified targets … [Read more]
• Toward Quantum Computing
  Quantum computers are expected to be able to tackle problems that would take classical computers many lifetimes to solve. Nonabelian states of matter can store quantum information in their topology, … [Read more]
• From Plant to Plastic
  Petroleum is primarily used as fuel, but it is also used in the production of plastics. Thus, if biomass were to replace petroleum as society's carbon feedstock, a means of … [Read more]
• Plastid Origins
  The glaucophytes, represented by the alga Cyanophora paradoxa, are the putative sister group of red and green algae and plants, which together comprise the founding group of photosynthetic eukaryotes, the … [Read more]
• Adapting to the Cold
  The gating of potassium channels is temperature sensitive, suggesting that these channels must adapt to function efficiently in the extreme cold. Garrett and Rosenthal (p. 848, published online 5 January; … [Read more]
• From NO to Complement
  To complete their development in the mosquito, ookinetes—reproductive stages of the malaria parasite Plasmodium—must traverse the midgut epithelium and avoid being detected and lysed by the mosquito complement system thioester-containing … [Read more]

• [Letters] Comment on "Rapid Cancer Detection by Topically Spraying a {gamma}-Glutamyltranspeptidase-Activated Fluorescent Probe"
  A recent report from Urano et al. described the development of near-infrared (NIR) probes for cancer detection using chemical bioconjugation of targeting agents. Here, I highlight an alternative strategy to develop cancer-selective NIR imaging and theranostic agents without chemical conjugation.
  Shi, C.
• [Letters] Response to Comment on "Rapid Cancer Detection by Topically Spraying a {gamma}-Glutamyltranspeptidase-Activated Fluorescent Probe"
  It takes considerable time and effort to create a successful imaging agent for clinical translation. In general, there are two approaches to developing new agents—bottom-up and top-down—which we compare here.
  Kobayashi, H., Choyke, P. L.
• [Perspectives] Viral and Inflammatory Triggers of Neurodegenerative Diseases
  Here, we synthesize research behind the emerging hypothesis that inflammation—which can result, for example, from viral infections—can initiate and propagate chronic neuronal dysfunction, an event that precedes the clinical onset of many neurodegenerative diseases. Therapeutic approaches that target immunological pathways in the prodromal phase of diseases might decrease the incidence of neurodegenerative disorders and increase the therapeutic window for neuroprotection.
  Deleidi, M., Isacson, O.
• [Research Articles] MicroRNA-21 Promotes Fibrosis of the Kidney by Silencing Metabolic Pathways
  Scarring of the kidney is a major public health concern, directly promoting loss of kidney function. To understand the role of microRNA (miRNA) in the progression of kidney scarring in response to injury, we investigated changes in miRNA expression in two kidney fibrosis models and identified 24 commonly up-regulated miRNAs. Among them, miR-21 was highly elevated in both animal models and in human transplanted kidneys with nephropathy. Deletion of miR-21 in mice resulted in no overt abnormality. However, miR-21–/– mice suffered far less interstitial fibrosis in response to kidney injury, a phenotype duplicated in wild-type mice treated with anti–miR-21 oligonucleotides. Global derepression of miR-21 target mRNAs was readily detectable in miR-21–/– kidneys after injury. Analysis of gene expression profiles up-regulated in the absence of miR-21 identified groups of genes involved in metabolic pathways, including the lipid metabolism pathway regulated by peroxisome proliferator–activated receptor-α (Pparα), a direct miR-21 target. Overexpression of Pparα prevented ureteral obstruction–induced injury and fibrosis. Pparα deficiency abrogated the antifibrotic effect of anti–miR-21 oligonucleotides. miR-21 also regulated the redox metabolic pathway. The mitochondrial inhibitor of reactive oxygen species generation Mpv17l was repressed by miR-21, correlating closely with enhanced oxidative kidney damage. These studies demonstrate that miR-21 contributes to fibrogenesis and epithelial injury in the kidney in two mouse models and is a candidate target for antifibrotic therapies.
  Chau, B. N., Xin, C., Hartner, J., Ren, S., Castano, A. P., Linn, G., Li, J., Tran, P. T., Kaimal, V., Huang, X., Chang, A. N., Li, S., Kalra, A., Grafals, M., Portilla, D., MacKenna, D. A., Orkin, S. H., Duffield, J. S.
• [Research Articles] T-Type Calcium Channel Blockers That Attenuate Thalamic Burst Firing and Suppress Absence Seizures
  Absence seizures are a common seizure type in children with genetic generalized epilepsy and are characterized by a temporary loss of awareness, arrest of physical activity, and accompanying spike-and-wave discharges on an electroencephalogram. They arise from abnormal, hypersynchronous neuronal firing in brain thalamocortical circuits. Currently available therapeutic agents are only partially effective and act on multiple molecular targets, including -aminobutyric acid (GABA) transaminase, sodium channels, and calcium (Ca2+) channels. We sought to develop high-affinity T-type specific Ca2+ channel antagonists and to assess their efficacy against absence seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model. Using a rational drug design strategy that used knowledge from a previous N-type Ca2+ channel pharmacophore and a high-throughput fluorometric Ca2+ influx assay, we identified the T-type Ca2+ channel blockers Z941 and Z944 as candidate agents and showed in thalamic slices that they attenuated burst firing of thalamic reticular nucleus neurons in GAERS. Upon administration to GAERS animals, Z941 and Z944 potently suppressed absence seizures by 85 to 90% via a mechanism distinct from the effects of ethosuximide and valproate, two first-line clinical drugs for absence seizures. The ability of the T-type Ca2+ channel antagonists to inhibit absence seizures and to reduce the duration and cycle frequency of spike-and-wave discharges suggests that these agents have a unique mechanism of action on pathological thalamocortical oscillatory activity distinct from current drugs used in clinical practice.
  Tringham, E., Powell, K. L., Cain, S. M., Kuplast, K., Mezeyova, J., Weerapura, M., Eduljee, C., Jiang, X., Smith, P., Morrison, J.-L., Jones, N. C., Braine, E., Rind, G., Fee-Maki, M., Parker, D., Pajouhesh, H., Parmar, M., O'Brien, T. J., Snutch, T. P.
• [Research Articles] Phosphorylated {alpha}-Synuclein in Parkinson's Disease
  Phosphorylated α-synuclein (PS-129), a protein implicated in the pathogenesis of Parkinson’s disease (PD), was identified by mass spectrometry in human cerebrospinal fluid (CSF). A highly sensitive and specific assay was established and used to measure PS-129 together with total α-synuclein in the CSF of patients with PD, other parkinsonian disorders such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), and healthy individuals (a total of ~600 samples). PS-129 CSF concentrations correlated weakly with PD severity and, when combined with total α-synuclein concentrations in CSF, contributed to distinguishing PD from MSA and PSP. Further rigorous validation in independent cohorts of patients, especially those where samples have been collected longitudinally, will determine whether the concentration of PS-129 in CSF will be useful for diagnosing PD and for monitoring PD severity and progression.
  Wang, Y., Shi, M., Chung, K. A., Zabetian, C. P., Leverenz, J. B., Berg, D., Srulijes, K., Trojanowski, J. Q., Lee, V. M.- Y., Siderowf, A. D., Hurtig, H., Litvan, I., Schiess, M. C., Peskind, E. R., Masuda, M., Hasegawa, M., Lin, X., Pan, C., Galasko, D., Goldstein, D. S., Jensen, P. H., Yang, H., Cain, K. C., Zhang, J.
• [Editors' Choice] Sleepless and Diabetic
  Cheng, M. H.
• [Editors' Choice] The Mutation That Broke the Cell's Back
  Hong, D. S.
• [Editors' Choice] Using Genomics to Get Rid of Pests
  Nyendak, M.
• [Editors' Choice] Learning, Customized for Your Brain
  Wang, W.