Hyperspeed Hyperforin

Kudos to the Maimone group (UC-Berkeley), who have published in JACS ASAP what seems to be the speediest synthesis of a hyperforin on record - just ten steps!

Perhaps this lends more credence to the Eastgate's "current complexity" index, which measures synthetic simplification over time thanks to improved methods. But who would have guessed that in just five short years this synthesis would telescope from 50 steps down to just 10? Strychnine, albeit a very different challenge, took nearly 60 years to simplify from 30 steps down to Vanderwal's highly-convergent six.

For Chemists: Steps of interest include a highly-oxidized [4+2] diketene cycloaddition, a iodoacetate-promoted ring expansion, and a highly modular synthesis widely amenable to analogue production.

For Everyone Else: Why should I care that this ungainly-looking molecule was made faster than before? First, hyperforin and related secondary metabolites (natural products produced by living organisms) isolated from famous folk remedy St. John's wort suggest new avenues for the treatment of of malaria and certain forms of depression. Second, if chemists can make variations on this molecule in roughly one-fifth the time, we can expect a venturesome start-up somewhere to begin fleshing out the SAR (what chemical modifications product what activities?) in record time.

Friday Fun: Insane in the Membrane

...CARBORANES in the Brain!*

Source: ACS Chemical Neuroscience | Sydney University 

From the pages of the (relatively new) journal ACS Chemical Neuroscience, comes this report about development of new antidepressants with rather...interesting appendages. The adamantyl (1) and Cookson's diketone (3) molecules shouldn't surprise, but the rest? You're not imagining things - those are blood-brain barrier-penetrant lead molecules based on cubane (2) and closo- and nido-carboranes (4,5). At 20 mg/kg, compounds 2 and 5 restore significant function to mice following stress tests. The authors indicate that, although the caged compounds look pretty huge, they're actually fairly isosteric (similar size) to a phenyl group, yet possess rugged metabolic stability.

*With apologies to Cypress Hill

Pharma Mascots - Cartoon Stand-Ins for Disease

Credit: Time Magazine

While glancing through some magazines yesterday, I came across a troubling ad for Abilify (aripiprazole). It’s not the drug that irks me, but rather the imagery - in the ad, depression takes the form of a sad, hovering blue bathrobe, stalking the nervous patient down the sidewalk.

I get it. Abilify helps a lot of people with severe depression feel normal enough to get outside and live. But the picture carries a menacing subtext: Without this med, depression will cover you and weigh you down, like a thick, fuzzy robe of gloom.

Credit: mucinex.com

This is, of course, nothing new. Marketers make their livings playing on our subconscious reactions to colors, smells, and situations. But pharmaceutical marketing takes the message one step further. Many people recognize the signs and symptoms of disease: sore joints, skin discoloration, cough, fever, blurred vision. But do they know about the underlying condition, or anything about the drugs* used to treat it?

Well, cartoons to the rescue! Nowadays, each med gets its very own mascot, a stand-in for all the aches and pains brought on by the specific problem. For Uloric (febuxostat), a gout flare treatment, a man carries an Erlenmeyer flask full of green liquid meant to represent uric acid (which is actually a white solid). His obviously stunted gait and heaving effort evokes gout’s painful inflammation. Pristiq (desvenlafaxine), an antidepressant marketed by Wyeth before the Pfizer takeover, showed a sad, small wind-up doll, meant to show the effort needed to “get going” when depressed.

Credit: lamisil.com

Lamisil (terbinafine) needed a mascot to represent a fairly common locker room ailment – foot fungus. The myco-avatar? Meet Digger, a small, spiky, yellow critter who represents discomfort and skin discoloration. His long claws are meant to simulate the scratching and burning brought on by infection.

Finally, Mucinex (guaifenisin) gives us Mr. Mucus, a hefty green glob used as a mucus analogy. He is, perhaps, the most over-the-top mascot, in that his only function seems to sit around as chronic congestion might.

Do these disease caricatures actually help someone, say, decide between two alternative treatments? Or appreciate the risks and side effects behind a certain treatment? Or are they just cute graphics to put on T-shirts and coffee mugs?

*In case you’re wondering, I didn’t forget: here’s the structure of the drugs

Update (12/24/11) - Added guaifenisin, generic name for Mucinex. The same generic drug is indeed found in several OTC medications.