Haystack Follow-up – Familiar Faces, Ladderanes



V. Mascitti (credit: Pfizer)

Regular readers of The Haystack over at CENtral Science Blog network might have seen my post on Pfizer’s modified dapagliflozin-inspired leads. While writing, I couldn’t fight the nagging feeling that I had heard the head Pfizer scientist’s name (Vincent Mascitti) before, perhaps from another paper.  I poked around through some old literature, and it hit me: he’s the ladderane guy!

Back in 2005, Corey and Mascitti prepared the first enantioselective (single mirror image of a compound) synthesis of pentacycloanammoxic acid (JACS 2006, 128, 3118-3119). This C₂₀ fatty acid, first discovered in deep-sea bacteria by Dutch researchers in 2002, provides an extremely rigid lipid bilayer to bacterial cell membranes, which biologists believe shields them from their own toxic metabolic byproducts – anammoxic bacteria utilize ammonia for energy, and produce hydrazine (rocket fuel) and hydroxylamine as waste products en route to N₂ and H₂O.

Mascitti finished the total synthesis in about 20 steps, most of which are variations on [2+2] photoaddition (making 4-membered rings from 2 alkenes), followed by ring contractions to access linear cyclobutane “chains.” The authors relate that the molecule is highly strained (roughly 75 kcal / mole), which surrounds its biosynthesis in a shroud of mystery: how does one make these energetically unfavorable ring systems, and especially in the dark? (Deep sea, remember?)

L. MacGillivray (credit: U. Iowa)

Two suggestions play out in the recent literature. In 2004, Len MacGillivray, a materials chemist at U-Iowa, demonstrated solid-state ladderane formation by nudging two conjugated polyolefins next to each other and adding a dash of UV light to promote [2+2] ring formation. Corey, meanwhile, suggested that an unknown enzymatic pathway from a highly unsaturated docosahexaenoic (22 carbons) acid derivative might produce these lipids.

A 2009 paper by the original isolation team (Damsté and coworkers) performed in silico comparisons of the genetic machinery required for lipid synthesis between anammoxic and aerobic bacteria. Their conclusions? Most of the enzymatic evidence supports radical cyclization of a long conjugated tail (see below), although the authors tease that the ladderane portion could be made by a separate process, and recruited into the fatty acid later on.

credit: Biology Direct, 2009, 4, p. 12

Rare Earths, Common Problem

Rare earth elements have made quite a stir lately: just last month, both Discover and National Geographic have written full articles about these 17 unique metals, which comprise the top part of the periodic table “f-block” (plus scandium and yttrium). Pundits and scientists alike are anxious that the US won’t be able to compete in the high-tech sector with scarce domestic rare earth supply.

Discover’s Hugh Aldersey-Williams (July / Aug 2011, p. 62) takes the historic view, starting from the elements’ first discovery in Ytterby, Sweden (1787, yttrium) and wending through the myriad of uses for the rare earths in modern-day electronics, hybrid cars, lighting, and materials.  The NatGeo article (June 2011, p. 136) takes a decidedly more polemically charged stance, peeking over the fence at China’s 97% share of the world rare earths market. Reporter Tim Folger argues that China’s unmatched mining infrastructure, coupled with lax environmental restrictions and cheap labor, make it tough for US miners to compete, despite the importance of a regular supply – the world demand for technology items such as iPods, wind turbines, flatscreens, and military equipment may drive lanthanide demand to a projected 185,000 tons by 2015, of which the US can only account for 5,000 tons of production. Worse, Folger bases this estimate on the production of a single mine (Molycorp) in California.

So what’s the impact for synthetic chemists?

Many of our favorite reactions use these metals. Lanthanum and scandium triflate promote aldols, acetylation, imine addition, cyclopropanation, and guest-star in new reagents like Leighton’s “EZ-crotyl” (JACS 2011, 6517). Samarium diiodide, a 1-electron reducing agent with a penchant for carbonyls and halides, underlies the Evans-Tischenko and Barbier couplings.  Cerium ammonium nitrate (CAN), a stable, off-the-shelf oxidizer, plucks off TBS and PMB groups, and promotes oxidative fragmentations. Perhaps even more worrisome is that the cerium and samarium reactions usually use the metal-containing reagent in large excess.

How can we fix the problem? New labs might find themselves conducting cost-benefit analyses simply to see if the improved reactivity or selectivity offered by these metals is worth their increased price (the Hoveyda-Grubbs 2^nd-gen catalyst, a highly active precious metal catalyst based on still-rarer ruthenium, runs $671 USD / 2g).  Perhaps the NSF will step in to issue challenge grants to develop catalytic processes intended to wean us from rare earth excesses. Either way, we’ve got to figure it out soon; as the US has shifted to a service-based economy, we’ve lost many skilled laborers (steel workers, miners, heavy industry) and may not be able to increase our rare earth capacity quickly enough.

Updates (July 28, 8:15PM) - Ever-helpful editor @carmendrahl informs me of a fantastic rare earth cover story from C&EN.  Others showed me the WIRED post about the US stealth fleet.

(July 30, 7:40AM) - Here's a July 2011 story in Scientific American debating the potential for harvesting rare earths from ocean floor sediment. Says Duke researcher Cindy Van Dover: "Four thousand meters in the deep ocean is a long way down"

(August 27, 10:36PM) - Commenter gippgig refers to Science News cover story, see here

Chemistry Kits - Getting Your Hands Dirty

Many science bloggers bemoan the disappearance of the chemistry set, a seemingly anachronistic toy for the Millenials, who might rather Skype, LARP, Geocache, or Tweet (Note: All real activities with very little risk of injury or mess). Scientists especially detest the new “Chemical-Free Chemistry Kit” by Elenco, an educational products company that also sells models of Julius Caesar’s head, a color-in-the-countries globe, and an aluminum triceratops (who was real, btw).  JAYFK and Speakeasy Science jumped into the fray, suggesting that the Kit enhances public fears over the words “chemicals” and “chemistry,” making them synonymous with “evil.”

Should these fears deprive our youth of the chance to make beautiful alum crystals or basement fireworks?

Playing with dangerous things at an early age has a special place in my heart, a flame rekindled in a recent Collectors Weekly article by Lisa Hix. She recounts the laundry list of potentially dangerous compounds the pre-WWII generation could experiment with: potassium nitrate (explosives), sodium ferrocyanide (dyes), sulfuric acid (batteries), and even uranium ore (radioactivity). Most of the cases include hand-drawn images of young boys dressed in ties and lab coats, pouring liquids at eyeball-scorching closeness with no goggles.

Well, I may never have been that cavalier, but I was allowed a certain leniency to play with dangerous things as a child. Whenever thermometers would break, my brother and I would scoop the mercury (yup, mercury) into a little jar and play with it, watching the tiny spheres break apart and glom back together on the glass surface. Cyanoacrylate polymers (Superglue) could stick anything to anything, especially your hands to your face. When we learned that peroxide solution would make blood foam up, we would intentionally pour it on all sorts of things (much parental dismay) to see if we could duplicate the effect. A middle-school experiment to demonstrate how color of transition metals depended on ligation environment went horribly wrong, blasting bright green liquid all over the floor (and us), but I recall being fascinated how the metal complex color changed back to blue when it hit the floor (Readers: Can you guess the metal?). I also discovered that the same compound could permanently stain my lab apron and the concrete floor. Today, much of my current lab attire has holes, stains, and smudges that won't come out with any measure of bleach.

Perhaps my favorite example of theory - experiment - practice came from the day I discovered urushiol, one of the oily components of poison ivy leaves that produce an allergic skin response.  I had a theory based on “like dissolves like” that I could perhaps pick the poison ivy barehanded, and then wash away the urushiol with a suitable solvent, such as isopropyl alcohol (rubbing alcohol). Well, you can guess where this story goes: I went to the doctor with horrific, oozing, itchy bumps all up and down both hands. I had successfully taught myself about skin absorption of common chemicals, which I remember every time I accidentally get some methylene chloride on my lab gloves.

Update (July 30, 6:30PM) - Changed, at commenter gippgig's suggestion, the words "toxic and deadly" in para. 3 to "potentially dangerous." Gippgig correctly points out that potassium nitrate is not itself toxic (its danger comes from potential to construct explosives), and both uranium ore and thiocyanides are not themselves highly poisonous.

Illegal Drugs Spur Chemists to Create Cures

White powders marketed on grocery shelves as “bath salts” are quickly becoming problematic for politicians and police, as reported in the July 17^th New York Times.  These “salts,” derivatives of a compound called methylenedioxypyrovalerone (MDPV) cause many of the same symptoms as methamphetamine intoxication. The wide availability of these new mixtures, compounded by their ease of synthesis and seemingly no lack of supply, has led to an explosion in their abuse (Note: I won’t cover the chemistry behind MDPV, the active ingredient, because my in silico mentor David Kroll’s posts on Terra Sigilata have mostly covered it).

That’s the gist of the article, in which illicit chemical synthesis fuels a new drug craze, and the public perception of chemists is dragged down again by sound bites such as “state bans thwarted by chemists who have to change only one molecule… to make [the salts] legal.” What happened to fair and balanced coverage?

For every illegal manufacturer of psychoactive compounds hoping for addiction to promote sales, there are many more chemists working on analogs of bioactive substances to treat disease.  Compounds that show high potential for abuse tend to interact with three neurotransmitters: serotonin, dopamine, and norepinephrine. In the case of bath salts, the main ingredient is a norepinephrine-dopamine reuptake inhibitor (NDRI), which allows these neurotransmitters to stay longer in the synapse, creating feelings of pleasure and wakefulness. Phenethylamines, such as MDPV, meth, or Ecstasy, the popular club drug, are one major class of compounds which activates these receptors, and are easily tweaked synthetically to prepare drug leads for Parkinson’s disease, schizophrenia, and ADHD.

Prof. David E. Nichols, of Purdue University, has devoted much of his career to understanding the mechanisms by which addictive drugs can interact with brain receptors, and designing novel compounds to take advantage of these traits (See this October 30, 2010 Wall Street Journal piece for Nichols’ comments regarding black market applications of his academic work). Prof. Nichols has synthesized variants of psilocybin, mescaline, and notably for this particular story, MMAI, a “cyclized” version of a typical methamphetamine scaffold.  On the day the NYT article went to press, Prof. Nichols had a J. Med. Chem. ASAP publication (DOI: 10.1021/jm200334c) appear online, in which his group prepared four new methylated analogs of their lead compound dihydrexidine. This analog, developed off the phenethylamine scaffold, has been shown to bind to the D₁ dopamine receptor, and both improve blood flow to the brain and to reverse Parkinson's-like symptoms.



Photo Credit: obrag.org

 Two other medicinal chemists are using methamphetamine derivatives as “Trojan horses” to trick the body into immunizing itself against the drugs. Their end goal is a vaccine that could be administered to control meth addiction. Kim Janda, of the Scripps Research Institute, and F. Ivy Carroll of the Research Triangle Institute (just down the block from David Kroll!) have both recently reported their groups’ respective efforts towards methamphetamine vaccines. Each group strategically introduces a hapten, an immunological “stamp” that latches onto a human protein, which the body can use to recruit white blood cells to the foreign substance.

Janda (JACS 2011, 6587) attaches a six-carbon chain ending in a thiol (SH) group to the amino group of (+)-methamphetamine, the more potent enantiomer, and observes high antibody titres in mouse models. Carroll (J Med Chem, 2011, ASAP) also uses a sulfur antigen, but attaches his via an amide linker connected to the aromatic core. After connecting this linker to a suitable immune-responsive protein, Carroll generates a monoclonal antibody with a 6.8 nm K_D for (+)-meth.

Update (July 30, 6:50PM) - Changed "bloodstream" to "synapse," since commenter gippgig is (again) correct that the compounds influence synaptic function, not bloodstream chemistry. Thanks!

Osteoporitic Mice in Space

Clinical trials will have one last hurrah on the Final Frontier: According to a July 5 press release from Amgen and UCB Pharma, the last flight of the space shuttle program (STS-135 on Shuttle Atlantis) will carry mice receiving a sclerostin antibody to counter bone density loss. Mild osteoporosis (bone loss) and muscle atrophy are nothing new to astronauts (or cosmonauts, taikonauts, etc.), whose bodies change due to lack of normal gravity and from "skeletal disuse" brought on by insufficient exercise in spacecraft - you can't easily jog a mile when your track is 122.17 feet long.

I hadn't heard about UCB Pharma until this press release, although it's surprising, given that they have nearly 9,000 people across 40 countries! UCB proudly proclaims three (3) core products: Cimzia (certolizumab), Vimpat (lacosamide), and Neupro (rotigotine). Cimzia, an anti-inflammatory monoclonal antibody, comes with a catch: it's marketed in Europe for rheumatoid arthritis, but in the US, it's exclusively marketed for Crohn's, a bowel disorder. The other two are more "small-molecule" (and thus up my alley).  Lacosamide is a simple benzyl- and acetyl-protected O-methylserine used to treat epileptic and neuropathic pain. Hmm....a small peptide affecting the brain...wonder if it'll be Scheduled?  You betcha.

Rotigotine, a chiral (S-enantiomer) tetrahydronaphthylphenol with a stapled-on thiophenylamine, has been approved for Parkinson's and RLS.  Its story is equally convoluted: the molecule was originally developed by Aderis Pharma, which used to be Discovery Pharma. As Aderis, it was acquired by Schwarz pharma in 2005, and Schwarz as a whole acquired by UCB a few years later.  Got that?  Four companies, one molecule, roughly twelve years. 

Aside from these products, UCB's cash cow is Keppra (levetiracetam, for neropathic pain) and several generics, among them Zyrtec (allergies) and omeprazole (heartburn and GERD).  Their total haul for all meds? 2.8 billion Euros / year in net sales.

Update (July 30, 7:25PM) - Phew! Commenter gippgig spurs me to make some (important) changes to the (previously incorrect) drug structures. I've also changed the description of lacosamide from "homoserine" to "O-methylserine."

Chew on This - Druglike Plant Phenols

Two URI chemists inadvertently sparked a syrupy turf war earlier this year, when they announced the isolation of quebecol, a newly-identified phenolic produced from the processing of maple syrup (see WIRED and WSJ-Blogs). Sugar makers in Vermont, fiercely proud of their own product, figured the name was a concession to the study’s sponsors, the Quebec Federation of Maple Syrup Producers. The authors indicate that these compounds might have biological activity, but they don’t expand on any early guesses. I won’t take sides in this heated debate, but it’s good to see renewed public interest in healthy plant phenols. 

Phenol itself – simply a benzene ring with an “OH” attached – was first isolated from coal tars, and under its common name carbolic acid sold for wound cleaning and sterilization. This was commonplace in the early 1900s, before the many side effects of phenol overexposure (skin burns, CNS depression, respiratory distress, or coma) were fully realized.

For plants, the phenol motif forms the backbone of lignin, the “cement” which holds components of the cell wall together. Metabolites of this omnipresent polymer have evolved to serve as insecticides, fungicides, and plant pigments. In some cases, these phenolics repel herbivores such as horses and cattle, and there are many documented cases of poisoning following leaf or bark ingestion.

You may already be familiar with many common phenols as components of flavorings and herbal medicines: vanillin, eugenol (clove oil), and guaiacol, a dark note produced from roasting beans or nuts. In fact, thymol, a prominent flavor of the herb thyme, synergizes the activity of the fungicide itraconazole against several common pathogenic fungi.   It’s thought that this synergy occurs through disruption of the MAPK signaling pathway in the fungus, or by oxidative stress.

In addition to freshening breath, many chewing gums now contain magnolia bark extracts. Two biphenols, magnolol and honokiol, form the bulk of these extracts, which exhibit a range of biological activities. In gum, the compounds tackle the malodorous bacteria found between teeth after lunch. As a pure compound, honokiol shows neuroprotective, antibacterial, antiviral, and even anti-cancer activity in drug-resistant cell lines. To expedite production of honokiol analogues, several short total syntheses were recently reported (32-54% over four or five steps).  Most utilize a Suzuki-Miyaura coupling to join the biphenol core, and a final Claisen rearrangement to transfer an allyl group from oxygen to the aromatic core.

An entire post, maybe a book, could be written about the current all-star of healthy phenolics, resveratrol. Found in wine and seaweed, it has been the beneficiary of all sorts of good claims, from cardiovascular improvements to possible life extension. In fact, Sirtris Pharmaceuticals, founded in 2004, focused on resveratrol analogues as potential modulators of sirtuins, proteins known to serve multiple roles in gene transcription and caloric regulation (*Note: as reported in C&EN, the company now suggests that these analogues may bind not to the sirtuin active site, but to another site on the protein). Sirtris, later acquired by GSK, recently announced that they would cease research on resveratrol itself, and focus instead on analogues based on the core structure.

To be honest, this small collection barely scratches the surface of the phyto-powers lurking undiscovered beneath the skins of fruits, spices, and bark.  Luckily, the nomenclature faux pas can be solved… might I suggest seearrohl?


Updates (July 18) - Fixed spelling of "reservatrol", "resrvtravol", err, dangit! Thanks Lila!
(July 30, 7:02PM) - Commenter gippgig warns that the inhibition of sirtuins by resveratrol may be an artifact of the data, and may instead activate AMP-kinase. For those interested in more plant phenolics, Napoleon's Buttons [Le Couteur and Burreson, 2004] covers them in Chapters 1 & 7.

Wachet auf!

Good morning, internet!  This is See Arr Oh, signing on for the first time under my own name.  Well, still a pseudonym, but it gives me the freedom to speak my own thoughts and post what I want. 

What do people do on "first posts?"  (Besides embarass themselves and create fodder to look back on in five years and say "Why on Earth did I write that?")  Guess I'll set some ground rules...

1.  This blog will reach out to the wider world about science, and especially chemistry. 

2. Wherever possible, I will link to / credit / provide a reference for work I've borrowed from other places.  To me, intellectual property theft ranks up there with walking into the Louvre, punching the garde de sécurité, and throwing tomatoes at Mona Lisa.

3. I want to try to develop as a writer and communicator.  Please, please prompt me with suggestions, comments, or rebukes in the commentary.  Even if it's to correct my grammar or point out a glaring omission.

Well, guess I'll go mull about my first "real" post....thanks for tuning in!