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Weird Natural Product Time Again

So let’s take a break today by looking at some compounds that, to a good approximation, many synthetic organic chemists would agree shouldn’t even exist. Yep, it’s time for a dive into Weirdo Natural Products, as I do every so often around here. I’ll point out some of the more ridiculous features for the non-chemists in the crowd, but some of the structures may well speak for themselves (!)

First up is protogenin A, a subject of this recent paper. That’s a “poly-yne” molecule of course, with that tail of acetylene groups stretching off, and you will have to search hard to find anyone who’s made something like that synthetically. And if you’ve made one, it probably didn’t stick around – such things are not so stable, and start isomerizing, polymerizing, oxidizing, and just generally going to pieces on you pretty rapidly. The paper notes the difficulty of isolating these from the organisms that make them, for just those reasons. Presumably the reactivity is part of the reason for their existence; they’re believed to be bacterial defense compounds. Well, if not outright offensive warfare, because bacteria sure aren’t above those tactics, either. They’re good enough at that that the microorganisms producing these compounds are actually beneficial when growing around plants, because they’re particularly effective against oomycetes, a fungal-like class of organisms that cause some particularly nasty plant diseases.

In a broadly similar vein, we have jawsamycin, at right. Yep, five chiral cyclopropane rings, interrupted for some reason by an alkene that didn’t get cyclopropanated. This is not a very obvious structure to figure out from spectroscopy, partly because it’s so repetitive and partly because it’s so hard to believe (although you’re certainly notice quickly from the NMR spectra that you’re facing a big pile of cyclopropanes). But there are several of these poly-cyclopropyl things out there in the natural products world. Admittedly, one would qualify as “quite a few”, by most standards. The rings are formed (in this case) by odd iron-sulfur enzymes that make a ylide intermediate out of S-adenosylmethionine. It has strong antifungal activity, targeting a key enzyme in the construction of the fungal cell wall. And if you haven’t noticed the name, go back, look at it again, and think about movies from the 1970s. Yep, chemist humor strikes again!

Halicyclamine B, at right, is not a lot of fun to draw, and if you have some spare time you can probably do a better job of it than I did. But two six-membered rings fused into a 13-membered ring and a 15-membered ring, that’s not going to flow right onto the page no matter what. Marine sponges make a whole list of such things, some of which will feature in future installments of this series. Their biological activities are wide-ranging, and my impression is that many of them have not been convincingly assigned to any given target. If you have access to that book chapter linked above, you can brace yourself for some seriously distorted bonds as the authors attempt to draw all these things in a reasonably compact and understandable form. It is clear that natural products are under no obligation to present themselves in structures that can be rendered intelligible on the page. Update: I left a double bond out of this one at first, but don’t worry: it didn’t get any more normal looking.

OK, enough nitrogens for a moment. Take a look at sanguiin H-11, which is nothing if not overwhelmingly rich in oxygen functional groups. That’s a glucose buried in the middle of it, and if you know your plant natural products you’ll recognize a bunch of gallic acid-derived polyphenols around the margin of the thing. Fifteen phenols on one molecule enough for you? There’s a large family of such things (glucose surrounded by more phenolic stuff than the mind can take in), and their structural chemistry will make your ears ring and your eyes bulge. Here, try it out. This is the sort of thing you get when you open up the box labeled “tannin molecules”, and most people close it right back up again. Update: I’ve had to revise this structure, too – missed a carbonyl out of laziness, and made one ring too large, out of laziness (hit the 11-membered-ring tool in ChemDraw twice instead of one 11 and one 10, not a mistake I can say I’ve ever had the chance to make before. This one has strong effects on oxidative stress pathways in cells, probably through inhibiting activation of MAP kinase. But how it does that is a mystery to me! I’m just impressed that such a beast has cellular activity at all: show this thing to most medicinal chemists and you’ll get the sort of look that Clint Eastwood gives a lineup of villains as they come riding over a dusty ridge in the distance.

49 comments on “Weird Natural Product Time Again”

  1. RM says:

    natural products are under no obligation to present themselves in structures that can be rendered intelligible on the page

    I wonder if the emphasis should really be on the reverse. That is, synthetic compounds have a strong tendency to be 2D-compatible because they’re most often drawn before they’re actually made, and the chemists doing the drawing have a strong bias toward things that can be drawn nicely.

    1. Derek Lowe says:

      You know, I hadn’t considered that, but you could have a real point. Sort of like the battle scene in Star Trek II, if you can stand that comparison!

      1. Hadriel says:

        I think the structure for Halicyclamine B is missing 2 double bonds (couldn’t access the Tet. Lett. so I googled the name and…) It then becomes easy to envision its biosynthesis.

        I personally always try to draw some form of a chair/boat perspective drawing as opposed to flat structures. I concur with RM, since his comment echoes sentiments that med chem compounds are too flat.

        1. Derek Lowe says:

          It is indeed a bit more unsaturated – fixed!

      2. Kirk says:

        “Sulu, Z minus ten thousand meters.”

        1. Vader says:

          Star Trek II is the closest the franchise ever got to being magnificent science fiction, except for possibly the better Borg episodes. But there seems to have been some confusion just who it was who was stuck with two-dimensional thinking.

      3. Barry says:

        Clayton Heathcock used to open his talk on daphniphyllanes (sp?) telling how he spent an afternoon figuring out how to draw the before he could even think about how to synthesize them. Roger Ruggieri drew them quite a few times before he finished Heathcock’s route–and then surpassed it with his own (biomimetic?) cascade.

      4. LdaQuirm says:

        Ambassador, your ship is at an unusual angle…

    2. Joe Kelleher says:

      It’s always struck me as luckily convenient that every organic molecule I’ve seen could be drawn on a 2D surface. Even e.g. morphine and derivatives, which are customarily drawn with crossing bonds, could be drawn flat if you tolerated some distortion of the bond lengths, though that of course would make it even less representative of the true 3D structure. Is there any real molecule that cannot be drawn as a planar representation, presumably one containing a K3,3 graph in its connectivity?

      1. sgcox says:

        Try Ferrocene…

      2. Andrew Dalke says:

        About 9 years ago I processed PubChem to find topologically non-planar molecules. There weren’t many, and fewer which weren’t buckeyball-esque or proteins. My list is at http://www.dalkescientific.com/writings/diary/archive/2012/05/18/nonplanar_compounds.html , also linked-to in my name. Two of the most normal looking organic structures are Physalin R (https://pubchem.ncbi.nlm.nih.gov/compound/390566 ), and Isoschizogaline (https://pubchem.ncbi.nlm.nih.gov/compound/636755 ).

  2. Anonymous says:

    Many decades ago, I prepared a somewhat similar triyne that used as one of synthetic building blocks, 1,3,5-hexatriyne. I was not amused when researching it’s preparation that most of the references I encountered where in the Journal of Soot and Combustion Technology.

  3. Radioactive Man says:

    Hi Derek

    I think your sanguiin structure might be missing a carbonyl in the top-right gallic acid, and has an extra methylene in the bottom-right one. Yes, I did do a project purifying and characterising tannins once!

    1. Derek Lowe says:

      Right you are! I missed that carbonyl, but the ring size was because I just mashed down the ChemDraw 11-membered ring tool twice in a row. Fixed, and thanks.

  4. David Young says:

    Jawsamycin? “You’re going to need a bigger flask!”

    1. Joe says:

      Wish I could upvote!

    2. Yo Way Yo says:

      They should just name this Lexxamycin and call it a day.

    3. a says:

      Surely

      Jawsamycin? “You’re going to need a bigger column”

    4. Simon says:

      Please do weirdo actual drig compounds too!

      1. Simon says:

        Drug

    5. Leo Bleicher Bleicher says:

      You’re going to need more starting material.

  5. walt says:

    Such a throwback to days of organic chemistry. Used to be a simple theory that molecules fit receptors to either agonise or antagonise them.
    “inhibiting activation of MAP kinase. But how it does that is a mystery to me”
    The old dogma is maybe only somewhat true with many small molecules demonstrably work as gene therapies – by altering epigenetic and genetic expression. Multiple small molecules alter microRNA expression which has a cascade of knock on effects on gene expression… stuff gets pretty mysterious from there!

  6. luysii says:

    For a rather un-natural chemical analog of an un-natural product, have a look at biphenylene [ Science vol. 372 pp. 852 – 856 ’21 ]. As you know graphene looks like hexagonal bathroom tile, meaning it is planar. Biphenylene is the same thing except that it contains 4, 6 and 8 membered rings and is still planar. Why did they make it? For the same reason people climb Everest — because it’s there — in their minds at least. The synthesis is quite clever.

    1. FoodScientist says:

      Bulk graphite is planar. “Graphene”(single layers of partially reduced graphene oxide) is more puckered and bumpy with oxygen functional groups. If you actually made fully reduced graphene, it would just collapse and the sheets would stack back up into graphite.

  7. John Wayne says:

    I think I’ve seen that last structure as a hit in multiple HTS screens.

    1. False Postive Guy.... you made me laugh. says:

      Actually me too!

  8. Simon says:

    Nice “teeth” on jawsamycin! The double bond is clearly where one fell out in a feeding frenzy and hasn’t been replaced yet.

    1. albegadeep says:

      My initial thought was that the name was referring to the up-down pattern to the bonds matching the theme music (duh-DUH duh-DUH duh-DUH…). Alas, it’s clear I think more about music than sharks.

  9. Marcus Theory says:

    Cue three dozen papers from three dozen labs on how sanguiin is a “potent” (read: micromolar) inhibitor for Professor ____’s favorite cancer target….

  10. Hairless Joe says:

    With all those phenols on it, I bet I could develop film with sanguuin H-11.

  11. gippgig says:

    If you think protogenin A is weird, try mycomycin. Then there are the enediynes.
    Now, how about weird synthetic compounds? Try (1,1,1)-propellane; some really wacky xenon compounds such as the addition compound of xenon hexafluoride with 2 molecules of acetonitrile, the xenon acetylides, & AuXe4(Sb2F11)2; and the new high-pressure superconductors that are basically doped hydrogen.

  12. Bannem says:

    Probably well known around here, but for those of you who haven’t seen it before;

    ‘Molecules with Silly or Unusual Names’

    http://www.chm.bris.ac.uk/sillymolecules/sillymols.htm

  13. J H says:

    Off-topic, but Derek, while your blog is “recovering from COVID,” I encourage/implore/beg/plead that you bring back the smiles, laughs, and Dr. Evil chuckles:

    * Molecules with lots of ring strain. Preferably in 3D.
    * Molecules unusually devoted to nitrate and “per” groups
    * Chemistry conducted below -150C in the interests of delaying decomposition
    * Just another day with grad students and pyrophoric reagents
    * Revisiting the days when researchers experimented “just because” and not “oh God no”
    * Weird junk nature made … oh wait! 😁👍👍
    * Practical applications of noble gas oxides, or just entertaining uses
    * How pharma scoundrels scoundrel-ed and *got caught* and actually paid for their sins
    * “Natural” drugs that kill you … if the comments won’t kill you

    Thank you sir.

  14. JH says:

    How does one determine the structure of a blob like “sanguiin H-11”?

    It can’t be the epic tale of (cyano)cobalamin, but surely a little thought and process is involved even 60 years later.

  15. theasdgamer says:

    “(hit the 11-membered-ring tool in ChemDraw twice instead of one 11 and one 10, not a mistake I can say I’ve ever had the chance to make before.”

    Somebody forgot to lock up the ethanol in the storage locker again.

    1. BIOVIA draw guy says:

      I wish I had ChemDraw… I miss you – it’s been 8 years already….

    2. Florence's Flask says:

      Derek doesn’t drink-one of his few flaws, and his brother died from alcoholism.

      Feel good, mr troll?

  16. theasdgamer says:

    Derek mentioned spectroscopy and it brought back memories of a time when dinosaurs roamed the earth and I was doing research for my physics master’s thesis where I compared the midrange IR reflectance of a long chain simple organic alcohol to a similar long chain simple organic carboxylic acid. Both were solid at room temp so it was easy to make optical quality pellets out of them that I could use in existing equipment. One of the components was industrial grade, so there was some similarity to the uncertainty that you might find in the field.

    We did a fast fourier analysis on the reflectance data (it was my thesis advisor’s computer program where the mainframe was accessed using dial up acoustic modem where you had to put the landline receiver into the acoustic modem) and generated absorption data from the reflectance data so that I could compare the results with a library of absorption data of organic compounds and the match was pretty good.

    Then NASA comes along and uses the research for analyzing the atmospheres of planets and moons. And medicine uses it to avoid having to take samples of living tissue. (It turns out that there are capillaries at the back of the eye, so an ophthalmic exam could use a reflectance instrument to diagnose all kinds of conditions which could be signaled by organic compounds.)

    I got the idea for my thesis research project when we were studying the complex index of refraction in my Electromagnetic Fields class. The complex index of refraction includes components for both absorption and reflectance. (Physicists are picky and call absorption “attenuation.”) With my chemistry background, I saw a way to test whether there was a connection between absorption and reflectance. And so my thesis research project was born.

    The profs who judged my thesis oral defense told me that my project was really cool, especially since I came up with it all on my own. (All of my partners in crime in the physics program relied on advisors to come up with thesis projects for them.) I didn’t realize how cool until a spectroscopy journal asked me if I wanted them to retract an article that was published two years after my thesis that duplicated my research.

    If anyone is curious, here’s an explanation of the complex index of refraction including the physical meaning. (deep dive into physics)

    https://www.tf.uni-kiel.de/matwis/amat/admat_en/kap_5/backbone/r5_2_3.html

    I thought that maybe some chemists might find this kind of interesting because it’s chemical physics. Or maybe not.

  17. Charles says:

    Gee Mr. Gamer, way to put the kibosh on Derek’s comment threads. Sure would be appreciated by the rest of us if you found another sand box to play in. Perhaps get back on your meds as well.

    1. theasdgamer says:

      Go back to your peanuts.

      1. Florence's Flask says:

        You are boring us, gamer.

  18. Harvey 6'3.5" says:

    Did they ever find the structure of Thiotimoline?

    1. Simon says:

      With the one bond extended into the past, you have to find the structure before you find it, which presents difficulties.

      I think its like Aleutianamine which certainly has enough bond strain to go into the past and future. Check it out. http://musc.technologypublisher.com/technology/31775

  19. li zhi says:

    15 phenolic hydroxyls, yes; 15 phenols, no.

    1. +1 li zhi.

      —-
      I like the Clint Eastwood analogy . . . :

      From the ‘try it now’ link: If one takes the β-pentagalloyl glucose from which the ellagotannins derive and adds a 2nd gallic acid to each arm, the result is tannic acid – a promiscuous inhibitor if ever there was one – for example it is particularly known for being a polymerase inhibitor in PCR:

      https://www.ojp.gov/pdffiles1/nij/grants/249148.pdf (p. 9).

      and so requiring due consideration if expected to be prevalent in a sample to be PCR’d.

      Tannic acid isn’t unique in its family of polyphenolic compounds in having a reputation for promiscuous inhbiition. These compounds come from nature, which means their production is a product of evolution – i.e. they owe their existence to conferring a survival benefit on the plants that produce them. The question is,

      1) How do they confer a survival benefit to the plants that produce them?
      2) What answer to 1) would leave us unsurprised that this class of compounds is known for promiscuous inhibition?

  20. Vader says:

    I’m guessing the systematic names of some of these compounds would make a pretty good rap in talented hands.

  21. 11 fingerrsss says:

    Got the methyl ethyl deth
    Given me that bad breath
    Yoyo workin up to butyl
    Do not think its futile
    I got the alkanes
    Got the bad brains
    Leavin it up 2 you
    To get the brown goo!

  22. Bill says:

    Interesting that 3 out of the 4 references are from Japanese labs.

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