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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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« Science Gifts: Experiments At Home | Main | Advice For Those Trying High-Throughput Screening »

November 28, 2012

Think Your Drug Is Strange-Looking? Beat This.

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Posted by Derek

We have a late entry in this year's "Least Soluble Molecule - Dosed In Vivo Division" award. Try feeding that into your cLogP program and see what it tells you about its polarity. (This would be a good ChemDraw challenge, too). What we're looking at, I'd say, is a sort of three-dimensional asphalt, decorated around its edges with festive scoops of lard.
The thing is, such structures are perfectly plausible building blocks for various sorts of nanotechnology. It would not, though, have occurred to me to feed any to a rodent. But that's what the authors of this new paper managed to do. The compound shown is wildly fluorescent (as well you might think), and the paper explores its possibilities as an imaging agent. The problem with many - well, most - fluorescent species is photobleaching. That's just the destruction of your glowing molecule by the light used to excite it, and it's a fact of life for almost all the commonly used fluorescent tags. Beat on them enough, and they'll stop emitting light for you.

But this beast is apparently more resistant to photobleaching. (I'll bet it's resistant to a lot of things). Its NMR spectrum is rather unusual - those two protons on the central trypticene show up at 8.26 and 8.91, for example. And in case you're wondering, the M+1 peak in the mass spec comes in at a good solid 2429 mass units, a region of the detector that I'm willing to bet most of us have never explored, or not willingly. The melting point is reported as ">300 C", which is sort of disappointing - I was hoping for something in the four figures.

The paper says, rather drily, that "To direct the biological application of our 3D nanographene, water solubilization is necessary", but that's no small feat. They ended up using Pluronic surfactant, which gave them 100nm particles of the stuff, and they tried these out on both cells and mice. The particles showed very low cytotoxicity (not a foregone conclusion by any means), and were actually internalized to some degree. Subcutaneous injection showed that the compound accumulated in several organs, especially the liver, which is just where you'd expect something like this to pile up. How long it would take to get out of the liver, though, is a good question.

The paper ends with the usual sort of language about using this as a platform for chemotherapy, etc., but I take that as the "insert technologically optimistic conclusion here" macro that a lot of people seem to have loaded into their word processing programs. The main reason this caught my eye is that this is quite possibly the least drug-like molecule I've ever seen actually dosed in an animal. When will we see its like again?

Comments (26) + TrackBacks (0) | Category: Chemical News | Drug Assays


1. SP on November 28, 2012 9:13 AM writes...

You have to ask yourself what inspired them to include the t-butyl groups. Did they have the undecorated version, look at it, and say, "Hmm, needs a little more grease?"

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2. patentgeek on November 28, 2012 9:21 AM writes...

I made compounds roughly 2/3 this size when a postdoc for Steve Zimmerman. The fluorescence of deutero-acetone solutions under UV was beautiful, and nitro or methoxy substituents provided a rainbow of NMR tubes on my bench. Ours were designed as probes for studying DNA intercalation.

Therapeutic applications dubious certainly, but electronic properties interesting.

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3. David Borhani on November 28, 2012 9:27 AM writes...

@ 1, SP: t-butyl groups probably lend stability during the final oxidative closure. Without them I would guess you really would get asphalt = tar!

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4. Hap on November 28, 2012 9:34 AM writes...

I wonder if you could sulfonylate/dealkylate it to get a sulfonate salt. Of course, I don't know if you would just get an amphiphobic brick by doing that, or if it actually would help with the solubility.

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5. Anonymous on November 28, 2012 9:46 AM writes...

@1 - Without the bulky groups, the intermediate would be insoluble in everything on God's green earth.

Also, "nanographene" LOL.

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6. Boghog on November 28, 2012 10:06 AM writes...

@1 - to improve the sp2/sp3 ratio of course ;-) (no doubt the authors are completely oblivious to such drug developability indices)

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7. Alex W on November 28, 2012 10:31 AM writes...

Well, it's festive at least. I'd hang one on my Christmas tree but I don't think I have enough model kit pieces. I'd be quite impressed at anyone who *did*.

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8. noko marie on November 28, 2012 10:46 AM writes...

The metabolite ID folks can't wait to figure out which t-butyl is getting hydroxylated by what p450. Not. Betcha it comes out in the feces, though, still glowing.

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9. CoulombicExplosion on November 28, 2012 11:15 AM writes...

I'm impressed they got this kind of thing to fly on a mass spec - there are no ionizable groups to speak of. Maybe via MALDI with Na+ or some other alkali squatting on top of one of the pi systems? Most of the petroleomic mass spec data I've seen that look at asphaltenes still typically have some heteroatom (typically sulfur) so there's at least some lone pairs to glom onto.

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10. Makke on November 28, 2012 11:19 AM writes...

Isn't the central linker with those ultra down-field protons a triptycene, not a trypticene?

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11. milkshaken on November 28, 2012 11:53 AM writes...

As Gregor Samsa awoke one morning from uneasy dreams he found himself transformed in his bed into a gigantic vermin bug...

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12. Anonymous on November 28, 2012 12:30 PM writes...

"insert technologically optimistic conclusion here"...brilliant turn of phrase!

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13. Anonymous on November 28, 2012 12:50 PM writes...

I would imagine the t-butyl group is necessary just for NMR purposes. What I feel sorry for is the person who has to bring this in for a job interview. Hopefully, it won't be for a medchem position.

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14. Anon on November 28, 2012 1:02 PM writes...

I seem to recall fullerenes being decorated and dosed in animals (even a fullerene-based HIV protease inhibitor). That must compete for most un-drug like.

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15. Myma on November 28, 2012 1:10 PM writes...

Look on the bright side: it could be a semi-permanent liver imaging agent.

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16. Anonymous on November 28, 2012 1:44 PM writes...

One would hope that the highly paid experts would be able to reach a consensus on this one.

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17. emjeff on November 28, 2012 2:01 PM writes...

"Festive Scoops of Lard" would be a good name for a punk rock band...

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18. Boghog on November 28, 2012 3:23 PM writes...

Good grief: there is barrelene at the core. Howard Zimmerman must be turning in his grave.

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19. anon the II on November 28, 2012 4:15 PM writes...

Actually building it in Chemdraw was pretty easy. I made the platter with a bunch of benzenes and added the t-butyls. I had to move a double bond. Then I made two more copies and connected them with long bonds. Then I opened it in Chem 3D, MM2'd it a bit and sent it back out as a .pdb and a chemdraw document.

I enjoy drawing godawful molecules.

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20. Anon on November 28, 2012 10:50 PM writes...

Re: 9

Maldi would work quite fine - in fact you could probably run that molecule 'neat,' no matrix. It looks absorptive enough at whatever laser frequency you want to throw at it, so it can self-ionize. Anthracene, for instance, works quite well this way.

And needless to say, 2429Da is trivial for a MALDI-TOF.

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21. db on November 29, 2012 8:59 AM writes...

Looks like someone took a chainsaw to activated carbon.

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22. Morten G on November 29, 2012 9:49 AM writes...

So pretty!
Guanidine might be a good option for solubilising. Or at least let you use less detergent to get it off the sides of your plastic.

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23. Flatland on November 29, 2012 2:42 PM writes...

Looks like something I'd make in my job. 'Course, my job involves organic electronics, not organisms. Might be a nice material for replacement of fullerenes in solar cell applications. Wait...
Any bets on whether this will be used in a head to head comparison with the fullerene infused olive oil rat life extension 'study'?

PS. I say 'study' above because there is a nice video on youtube where someone tries to dissolve c60 in olive oil. It goes as you might suspect.

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24. pharm on November 29, 2012 3:59 PM writes...

That c60 in olive oil video lead to some interesting places like c60 making your immortal, what is that even about and how did miss something so over the top

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25. D.J. on November 29, 2012 6:58 PM writes...

Well, they've gone from vitro to vivo to rodents. Next up is higher order mammals and humans, right? I seem to recall Derek writing about aggressively pushing what medium for tests...

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26. Secondaire on December 7, 2012 6:19 PM writes...

Looks a little like by-products that came out of my undergrad research on fullerene substructures (way back in the Jurassic period) Dude, I'd bet if you stacked this thing into sandwich complexes with lithium or ilk, it would be a superconductor.

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