Cordial Chemistry: Syrup of Violets

Today's talk at the Chemical Heritage Foundation was by one of my fellow Fellows, Rebecca Laroche, on syrup of violets and Robert Boyle. It had long been known that adding an acidic material, such as lemon juice, to syrup of violets turned it a rose color. (More creepily, kids apparently used to hold pansies, also a member of the viola family, over ant hills to watch them change color, presumably from the formic acid produced by the ants.) Boyle is credited with the discovery that this botanical extract also changed color when exposed to alkalis, turning green (see his report here). This led to the development of a panel of pH sensitive indicators, helpful in chemical analysis in Boyle's time and now.

The color changes are due to the anthocyanins in the violets (the same thing that makes red cabbage change color with pH). Syrup of violets is not hard to make, you can find a modern recipe here, not much changed from the older recipes (see an assortment here), and you can buy it.

After Rebecca's talk a group of us went to lunch and, quite serendipitously, on the menu were drinks made with syrup of violets. Since some of us had writing to do this afternoon, we eschewed the vodka versions, but gave the club soda tonics a whirl. I wanted to see what happened when you added acid, would I get a pale rose drink? Alas, it seems not.

Turns out that commercial syrup of violets has citric acid added to it, which turns the pure syrup red, or it would if artificial colors were not added to make it violet again. Since it's already in the red form, adding more acid doesn't change the color.

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What makes a molecule beautiful?

I just finished a piece for the March issue of Nature Chemistry on what (in my mind) make a molecule beautiful. I will admit a preference for sparer, less baroque structures. (If you want to know more about my molecular aesthetic, you'll have to wait for the piece to appear!). In the meantime there is an article in this month's Nature Chemistry with the intriguing title "Quantifying the Chemical Beauty of Drugs" [Bickerton et al. Nature Chem. 4, 93-97 (2012), full text is free]. It's not so much beauty in the abstract these chemists are trying to quantitatively capture, but desirability. How attractive is this molecule as a target for drug development? Would a chemist be willing to surrender time and bench space to the synthesis of this molecule?

The model takes as its inspiration Lipinski's rule of 5. If most or all of Lipinski's five characteristics are present, a molecule has a good chance of being a viable candidate for an oral drug [Lipinkski et al. Adv. Drug Dev. Rev. 23 3-25 (1997)]. The goal is to develop an expert model system, one that mimics (or improves on) a chemist's intuition about what makes for a good drug.

Earlier work had suggested that chemical fashion sense is drifting toward more baroque structures for their drugs, despite various rule sets that suggest that bloated molecules are less likely to survive to clinical trials. Chemists apparently like their molecules "tractable" (which would seem to mitigate against molecular overelaboration?), synthetically and otherwise! Molecular docility is desirable.

For a somewhat darker take on chemical intuition and seat of the pants drug design read "Chemists in the Shadows" by Adam Piore in March's Discover Magazine. The article focuses on underground chemists who are developing new recreational pharmaceuticals that skirt current drug laws (steroids for athletes, and rave drugs). The conceptual framework used by some of these chemists would be familiar to any medicinal chemist (particularly in the early days, before QSAR).

Pain relief in a cup of tea

I took a fall skiing last week¹, my skis went in one direction, my knees in the other. The audible pop sounded and felt much like what happens when I break the cartilage in the joint of a chicken. Argh.

Not surprisingly my knee hurts (though it's not all that swollen compared to the time I tore the ligament in my ankle, where the swelling was quite spectacular). I'm taking ibuprofen for the pain. NSAIDs, such as aspirin, naproxen, and ibuprofen are effective antinociceptives² - painkillers. But I'm also adding a dollop of caffeine to each dose. It turns out that caffeine is an effective adjuvant for NSAID (non-steroidal anti-inflammatory drugs).

NSAIDs work by blocking the activity of prostaglandins, molecules that are used by the body in many signaling roles, including the signaling of pain. If the signal from my knee to the brain that says "pain" doesn't get through, it doesn't hurt (though it may still be hurt).

Adding around 100 mg of caffeine (roughly what's in my big mug of FTGFOP³ Assam tea) to 400 mg of ibuprofen makes it 2 to 3 times more effective in relieving acute pain. [Forbes et al. Clin Pharmacol Ther. 1991 49(6):674-84.] Onset of pain relief is faster and the duration is markedly increased as well. Caffeine appears to increase the availability of the NSAID at the signaling site.

So sitting by the fire with a cup of tea (and an ice pack on my knee) is soothing in more ways than one...

1. Full disclosure: I fell in the lift line, my skis got entangled when I tried to retrieve the pole that got stuck in the snow. I'd love to say I did this catching an edge on a glorious powder run.
2. The word nociceptive was coined in 1904 by Charles Scott Sherrington to try to disentangle the psychological perception of pain from the physiological response. Noci- comes from the Latin nocere - to harm (think noxious and innocuous)
3. FTGFOP, Finest Tippy Golden Flowery Orange Pekoe, a description of the leaves, Orange Pekoe has nothing to do with any particular flavor of tea, including orange!
4. Food Research International Vol 29, Nos 3-4, pp. 325-330.

Inert gases aren't always inert

Earlier this week I posted about the intoxicating effects of nitrogen gas at high pressures, which leads divers to substitute helium for nitrogen. An astute reader wondered in the comments why argon wasn't used, as it is substantially cheaper. It turns out that argon is even more potent intoxicant than nitrogen at high pressures! But aren't argon and helium inert gases?

The elements in the last column in the periodic table comprise what IUPAC (the International Union of Pure and Applied Chemists is to chemists what the IOC is to sports) calls Group 18, but what most of us learned in high school to call the noble or rare, gases. Helium, argon, neon, krypton, xenon and radon are indeed all gases under standard conditions, but the modifier misses the mark by a bit.

Rare? Take a deep breath, you've just inhaled about 100 mg of argon. Almost 1% of the atmosphere is argon; there is almost three times as much argon in the air as there is CO₂. "Noble" generally means "unreactive" to a chemist. The noble metals, such as gold and platinum are resistant to oxidation - they don't rust - unlike the "base" metals such as iron and copper. Much like gold and platinum, under the right conditions these inert gases can be made to react. The first noble gas compound - xenon hexafluoroplatinate - was synthesized in 1962, but there were earlier clues that these gases might not be completely unreactive. The anesthetic effect of xenon had been observed in the 1930s, and reports of its use in clinical settings appeared in the late 1940s.

The mechanism by which nitrogen, argon and xenon behave as anesthetics isn't completely understood. The best theories at the moment suggest that the gases interact with ion channels - but whether they binding chemically or physically is not clear.

Silver linings

Yesterday I had a round of minor surgery. When all was said and done, the surgical site was cauterized with what a nineteenth century physician would have called "lunar caustic" -- silver nitrate to a modern chemist or physician. I have to admit my first geeky thought was, "how does that work?"

Silver nitrate has been used for a long time as a cauterizing agent. In 1826 John Higginbottom, a British physician wrote An essay on the application of the lunar caustic in the cure of certain wounds and ulcers. My physician used a solution of AgNO₃, Higginbottom almost certainly used a solid mixture of silver nitrate and silver chloride, but other than that the basic treatment protocol hasn't changed in almost 200 years. Higginbottom notes that the application "smarts" and I would guess that it must have. I felt it, even with a good local anesthetic. The good 19th physician also prescribed adjuvant therapy ("I took away ten ounces of blood and administered purgative medicine") which my physician sensibly eschews!

So why is the stuff called lunar caustic? The caustic part is obvious, silver nitrate is an effective oxidizing agent for organic molecules, including biomolecules. Alchemists associated silver with the moon, its Latin name, argentum derives from "white, shining".

Urrrrrr - it itches!

The spring was cold and so the itch to get outdoors once the warm weather arrived was hard to resist. As moms will tell you, scratching just makes the itching worse, and scratching even metaphorical itches can raise welts. Ask anyone who has heeded the siren call of summer and ended up with hives, or worse yet, encountered a patch of poison ivy.

My niece and I took a tour last week of the Mutter Museum in Philadelphia which has a great collection of wax models of dermatological pathology, used for teaching students in the days before slides and PowerPoint, including hives or urticaria. The name comes from the Latin for nettle, and the resulting skin wheals certainly bear some resemblance to nettle stings (as my youngest can attest after a close encounter with that plant). Histamine leaking from mast cells in the skin is responsible for hives' principal misery - itching.

True misery is reserved for those who have contacted Toxicodendron radicans - poison ivy - or a relative. These plants produce urushiol, which binds tightly to proteins in the skin. Molecules like this are called haptens, which comes from the Greek "to fasten". Antibodies don't recognize the small molecule until it fastens onto its target. Then the body reacts, in this case triggering the characteristic linear rash, and keeps reacting until the invader detaches from its binding site.

Despite the similarity in names between urticaria and urushiol, they come from different roots. Urushiol was first isolated from the Japanese lacquer tree - the urushi - by a Japanese chemist, Miyama.

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Other haptens can react with the same sites as urushiol, including substances found in mango skin and fresh cashew nuts, with similar unfortunate consequences.

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Urushiol isn't just a weekend gardener's nuisance, but can cause serious problems for fire fighters in working brush fires in areas such as the California hills, where poison sumac, another urushiol producing plant, thrives. The chemistry gives some clues to helping prevent and treat urushiol reactions. Application of an organic derivative of an absorbent mineral (bentonite) can soak up and trap any oil before it reaches the skin and binds- this is the principal behind the commercial product Ivy Block. Alternatively, something that binds strongly to the urushiol target but is not itself a hapten could act as a preventative. D-Limonene, found in citrus skins, has been floated as a possibility, but I couldn't find any evidence that it works!

Once the stuff has bound, you just have to wait it out. It takes a couple of weeks for the bulk of the urushiol-protein complexes to break down. In the meantime, steroids can reduce the inflammatory reaction and histamine blockers, H1 (like Benadryl) or H2 (Tagamet or Zantac) can provide some relief from the itch.

Agonists and Allergies

My mast cells are leaking histamine and I am miserable. Histamine is a small molecule that binds to receptors in a wide variety of tissues including, alas, the respiratory system. It happens to increase vascular permeability - in other words, it's causing fluids to leak through my capillilary walls and into my nose. Sigh.

I'm fighting back by taking a histamine antagonist, diphenhydramine to be precise. Antagonists bind to a receptor and block its response, in this case inhibiting the H1 histamine receptors in the respiratory tract (H2 receptors cluster in the gastrointestinal tract - and so H2 antagonist, like Zantac, are used to treat heartburn). Agonists are molecules that bind to a receptor and cause a response. Why would you want to take something that binds to a histamine receptor and provoke a response? Turns out there are a couple of drugs that are histamine agonists, including one for Meniere's disease and another that may have theraputic potential for diabetes.

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What does the term amine have to do with camel dung? Read about it here.