WWWTP? BBC's Sherlock Edition

Chemical degradation by microscope? Incorrectly-scrawled structures? Wikipedia analyses?
Looks like Scotland Yard should send their consulting detective back to University.

I'm referring, of course, to Sherlock, the BBC reboot that re-imagines Detective Sherlock Holmes and his partner Dr. John H. Watson as modern* Londoners, with text messages and nicotine patches in place of telegrams and pipes. Quick reminder: the Sherlock of Sir Arthur Conan Doyle's original books represents the first fictional character ever recognized by the Royal Society of Chemistry for contributions to science.

Sherlock Holmes hacks into a secret British government database and finds...pyridine and phenol!
Credit: Benedict Cumberbatch and BBC-One

In "The Hounds of Baskerville," Holmes and Watson investigate claims of a giant, red-eyed monster lurking outside - wait for it - a secret military research laboratory called Baskerville. Naturally, the dynamic duo break into the lab under false pretenses, questioning a scientist accused of genetically re-engineering a pet bunny to glow green.**

They later return to Baskerville with a hypothesis: a psychoactive drug, perhaps hidden in an innocuous foodstuff. Holmes sets to work using the analytical instrument of choice for modern chemists - the light microscope. Using nothing more than a pipette and glass window that would have made Bob Woodward proud, Sherlock performs some crude chemical degradation studies:

Who needs NMR, kinetic studies, or a mass spectrometer? I have a mallet and a watch-glass.
Credit: BBC-One

(I'm guessing Sherlock wrote "D-Deuterium?" at the top left to remind himself that the evil research agency might have tried improving their mind-control drug's physicochemical properties : )

The silly Hollywood chemistry builds to a peak when Dr. Watson timidly investigates a scary chemical structure on the lab wall. Don't blink; it's only on-screen for about a second:

"Vancomycin" - Close enough for television?
Source: BBC-One

Well, at least the creators got something right - vancomycin certainly ranks as a "chemical weapon," but it's for killing marauding bacteria, not innocent townsfolk. That chlorocyclohexane on the right *should* be fully aromatic, and I'm sure if I had a higher-res image, I'd start to spot some more structural snafus.

I won't spoil any more of the show, but there's a few other chemical flights of fancy, such as Sherlock analyzing multiple components of floor wax using nothing more than some colored test tubes and his nose. Readers, cue up your online streaming service of choice, and have a look at episode 2.2 - let me know if I've missed more molecular mishaps.

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* Spoiler - the goofy hat remains. Not a bad look, if you ask me.

**The show does mention that the green fluorescent protein was isolated from a jellyfish, which might be the most accurate science in the entire episode.

Antibiotic Purple Rain

Did you know scientists used Clostridium species to produce industrial solvents from cellulose?
Did you know anaerobic (oxygen-free) bacteria produced polyketides?
(I didn't!)

This Angewandte Chemie article by Prof. Christian Hertweck (HKI, Germany) held many such surprises for me. While poking around in bacterial genomes, Hertweck and team discovered gene sequences for secondary metabolites, or what organic chemists usually call "natural products". When they cultured a certain Clostridium strain from their collection, a deep purple dye emerged.

Dubbed clostrubin (see right), the pigment possesses several striking features. First, its shape: this five-ring topology, dubbed a benzo[a]tetraphene, has never been documented from living organisms. Second, although polyketides commonly come from other microbes, this is the first the team had ever observed in an anaerobe. To compound the mystery further, the folding pattern itself - polyketides come from long chains of simple precursors - had never been seen.

Most exciting for all involved: the compound shows high activity in assays against MRSA and VRE, two highly resistant strains feared for their prevalence in hospital-based infections.

So, who wants to be the first to make it?

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.