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Cubane to the Rescue

Medicinal chemists are interested in weird ring systems – I can’t deny it. We like them for several reasons, one of which is that we’re always looking for variations on structural themes that might affect the metabolism or absorption of our drug molecules. And the fact that these variations can lead to new patentable chemical space is not to be minimized, either. This is why you see so many cyclopropyls and cyclobutyls, azetidines and oxetanes in the med-chemi literature, and why new reactions to work with them get our attention.

So have a look at this new paper in Angewandte Chemie. They’re taking what is truly a small ring system – cubane, which is shaped exactly the way you’d figure – and substituting it into various biologically active structures. Cubane itself was first synthesized back in the 1960s by Philip Eaton, and it wasn’t a particularly easy task. Since then, I’d guess that the bulk of the literature on the ring system has come from two fields of chemistry: the theoreticians, looking at how different substituents affect the strained bonds in the ring, and the energetic materials folks, looking to pack that already high-energy structure with even more payload. Octanitrocubane is a fine example of that, densely functionalized with enough bang to the gram to send you briskly down the stairwell to avoid it.

But there are other reasons to work with this ring system. Eaton himself speculated in 1992 that cubane might serve as an isostere for a phenyl ring in many compounds, which at first sounds a bit odd. But keep in mind that aryl rings like that have a goodly amount of electron density above and below them – from that perspective, they’re chunkier than they look, and the spacing across opposite corners of a cubane molecule is about right as well. This latest paper puts that hypothesis to the test in what I think must be the most comprehensive way yet. (Examples have appeared in the literature from time to time, and there may well be some more out in patents, but I don’t recall a direct test like this one before). As the authors here say, “This apparent lack of interest in cubane presumably follows the incorrect assumption that such compounds are esoteric, unstable, or synthetically intractable“.

Well, they’re not easy, but they’re doable, for sure. In this case, of the molecules in which a cubane was worked in for a phenyl, two of them were more active (the derivatives of leteprinim and diflubenzuron), and two were equipotent (the cubane analogs of SAHA and benzocaine). Attempts to swap in a cube for one or both phenyls in benzyl benzoate (an acaricidal agent) let to lower potencies, though. These tests were done all the way to to in vivo (for example, in xenograft models with the SAHA analog), which makes the overall case pretty strong.

Overall, the cubane derivatives are slightly more lipophilic than the phenyls, which makes sense just by eyeballing them. Metabolically, the ring system appears very stable – those hindered tertiary carbons are not very reactive. Cubane itself (as mentioned above) is thermodynamically rather elevated, but it’s quite stable, because there are really no easy ways for the structure to rearrange and break down. That’s probably helping it out with the p450 enzymes as well. Some of the same CSIRO team from Australia reporting these results have also developed a large-scale synthesis of cubane 1,4-dicarboxyl systems, so the objection of “well, you can’t get any intermediates” may be disappearing as well.

A last note: the paper is dedicated to Philip Eaton, on his 80th birthday. I’m glad that he’s getting a chance to see his work getting some traction in medicinal chemistry!

 

 

31 comments on “Cubane to the Rescue”

  1. Peter Kenny says:

    There are similarities between cubane and cyclopropane in that both are strained and both are less keen than an average saturated hydrocarbon to yield a hydrogen atom. I first became aware of cubane’s potential during my first visit to CSIRO in 2010 and have fond memories of trips to the Clayton site. Since that visit, I’ve been looking for opportunities to deploy cubanes (maybe even get it to detonate inside a T cruzi?). From what I recall, you’re more restricted with substituents with cubanes in that amines tend to rearrange.

    1. Mark Thorson says:

      You want to assassinate Ted Cruz? Be sure he’s standing next to Trump when you do it.

      1. Peter Kenny says:

        I think there will be more than one Chagas disease researcher who will find this connection (which I’d never previously considered) to be most droll. The next question is whether we can extract novel natural products from Donald’s ‘hair’?

        1. Pennpenn says:

          Implying that controlling parasite has anything natural about it…

  2. Anon says:

    I suspect this will be more (only?) useful for patent busting than gaining any new drug activity. Sad.

    1. Isidore says:

      I am not sure I agree with “sad”, if the result of such “patent busting” is the development of new drugs, which if not better have at least similar efficacy to ones already approved, The increased competition should lead to lower costs for consumers, which is a not a bad thing.

      1. Anon says:

        So spending money to effectively copy something that already exists for patients is a good thing?

        I call it a waste of money that could be better spent developing meaningful improvements.

        1. Isidore says:

          It’s called free enterprise. Companies can spend their shareholders’ and investors’ money as they see fit. If shareholders or investors don’t like it they will make their views known, either by voting their shares or turning off the money spigot.
          In any case, I am not convinced that the only reason of looking at cubane is to circumvent IP. In my 25+ years experience in biopharmaceutical R&D, I have found that the motivation of looking at NCEs is to try and do better in terms of efficacy and/or safety than what’s available, without violating someone’s patents. If what one ends up with is no better than what’s out there but there is new IP, what would you have a company do, stop development? That would be a waste of money.

        2. Hap says:

          There might be meaningful improvements – you don’t really know until you make one. The hope, I think, is that the analogs won’t be simple clones (because then insurance companies probably won’t pay for them and it’ll take a lot of advertising for people with enough money to buy them) but that they might be more active or more stable (so that you might be able to use lower dosages).

        3. DH says:

          “I call it a waste of money that could be better spent developing meaningful improvements.”

          A new but equally effective treatment that costs substantially less than an existing one (or that drives its cost down) *is* a meaningful improvement.

          1. Anon says:

            Not if you look at the big picture. Those patient cost savings due to lower price merely come from what the original pharma would have made. It’s no different to Chinese companies that copy original IP and sell it cheap. Yes, it’s good for customers and patients, but spending more money just to copy existing product benefits and sell them on for cheap, destroys value overall. It’s like monkeys fighting for each other’s bananas rather than growing their own. If everyone did that the entire system would rapidly decline as no value is added.

        4. Bobby Shaftoe says:

          “I call it a waste of money that could be better spent developing meaningful improvements.”

          Dear Monday Morning Quarterback: It would be great to have your ability to know in advance what efforts would produce meaningful improvements.

          “I would have double-bagged it.” Brett Favre (https://www.youtube.com/watch?v=ZoEGYFzS0jA)

          “Half the money I spend on advertising is wasted; the trouble is I don’t know which half.” John Wanamaker

          1. Anon says:

            Dear Tuesday Morning Twat, nobody knows until they explore and discover something new. It’s called innovation. Try it.

  3. luysii says:

    Cubane is stable for the same reason that an explosive mixture of hydrogen and oxygen is stable.

    1. Hap says:

      Except the list of conditions to which cubane is unstable is a lot shorter than the list for a mixture of H2 and O2. They’re both stable because they don’t have an easy way to a lower energy state, but H2 and O2 can get to there with a spark or a flame or static electricity, all of which are pretty common, while cubane doesn’t have an easy way out at all. It’s sort of like [1.1.1]propellane, but that has relatively low-energy decomposition pathways, while cubane doesn’t.

  4. Anchor says:

    Not in the same league as in trifluoromethyl groups containing drugs (CETP inhibitors) but cubyl group drug(s) perhaps may have longer PK as well. What’s next? Perfluorocubyl, Deuterium cubyl analogs etc? I agree in part with anon @ 10.45.

  5. Anonymous Researcher snaw says:

    Since I’m not a chemist, I had no idea such a thing existed let alone was first synthesized in 1964. I can well believe that wasn’t easy: 90 degree bond angles! The things we don’t know….

    1. Mark Thorson says:

      Triatomic rings are even more strained, and they have uses. Cyclopropyl compounds are sometimes used as one of the components of binary nerve agents. Epoxide rings (two carbons, one oxygen) are very common components of curing chemistries for adhesives and plastics. Maybe similar compounds could be used in a pro-drug — like maybe two mostly inert components (one with the highly strained ring) that react together within the human body to create the active form. I’ve never heard of a two-part pro-drug, but there might be some reason to do it. For example, you swallow one part and get injected with the other part, so the active form only shows up in the lining of the GI tract. Or you inject one part in the bloodstream and the other part in the CSF, so the active form only shows up in the endothelium of the CNS vasculature.

      1. a. nonymaus says:

        Like cyclopropyl rings, cubanes might have interesting metabolism-triggered ring opening reactions. The classic example is tranylcypromine, which undergoes ring-opening to form a covalent adduct with the enzyme. So, all we need are drugs that form methylenecubyl radicals once in the target protein or bound to the right DNA.

    2. Ursa Major says:

      Strictly speaking, the bond angles in cubane are greater than 90º (and those in cyclopropane are greater than 60º) because the electron density lies outside the straight line between the atoms. https://en.wikipedia.org/wiki/Bent_bond

  6. Denton Hoyer says:

    The increasing use of strained carbocyles in medicinal chemistry may be due to lower rates of metabolism compared to linear alkanes. The H atom abstraction energies should be higher with the strained systems due to higher ground state energies of the radicals. While this seems counterintuitive to our regular notions of “reactivity’, it makes perfect sense to the cytochrome P45O enzymes.

  7. anon electrochemist says:

    Cubane analogue narcotics hitting the street in 3…2…1..

    1. anonymous says:

      I would much rather see Cubane analogue psychedelics. The psychedelic drug area has really languished lately and almost every psychedelic belongs to the phenethylamine, tryptamine, or lysergamide classes. The Cubane ring has the potential to introduce a new class of psychedelics. Cubane analogues of the phenethylamines would be the natural option to go with here. However, in the phenethylamine class of psychedelics, there are three main sub-classes – 2,5-dimethoxyphenethylamine, 2,6-dimethoxyphenethylamine, and 3,5-dimethoxyphenethylamine. In each of these sub-classes, introducing a small lipophilic substituent at the 4-position leads to psychedelics.

      Out of those phenethylamine sub-classes, the methoxy groups (and the 4-position substituent) have to be placed somewhere on the Cubane ring. Based on some 3D overlays I have done, the 2,5-dimethoxyphenethylamine sub-class is most compatible with a Cubane analogue. Here, the Cubane analogue would have the methoxy groups at the 2 and 7 position, with an additional substituent at the 8-position.

  8. dave w says:

    How available is cubane (as the pure hydrocarbon)? I’m not having much finding a source for a modest quantity (10 g?) with the usual online sort of online searches – there seems to be a brand of shoes with the same name, for one thing, and even after filtering out these “interfering hits”, most of what’s left seems to be to chemical catalog sites of the “stuff we wish we sold” persuasion. Any suggestions?

    1. Paul Savage says:

      We made some unsubstituted cubane as an internal NMR standard (DOI:10.1071/CH10107) because the carbon and proton resonances are around 48-49 ppm and 4.03 ppm respectively — well away from the usual areas of interest. The synthesis roughly followed Eaton’s protocol, first making the 1,4-dicarboxylate, which we routinely make on a kilo scale, followed by a double Barton radical decarboxylation. Drop me a line and we can talk about it.

  9. As2O3 says:

    anon electrochemist: Exactly what I was thinking, surprised no one in China has synthesized methcubanophetamine yet…

    1. Mark Thorson says:

      If you were doing good business making that stuff, you’d probably keep a low profile as long as you could. Which brings up a question — when the Feds nab a sample of the new drug, how long would it take for them to figure out it’s got a cubane group? Not exactly what you’re expecting.

  10. gippgig says:

    Anyone looked at ladderanes? Because of their rigidity, if they could be synthesized with specific substituents at specific positions it might be possible to custom design extremely specific and tight-binding ligands.

    1. David Rogers says:

      Check out anammox bacteria, only recently discovered, that feed on ammonium (NH4+). They build their internal cell walls using ladderane-containing lipids to reduce permeability to reaction intermediates hydrazine and hydroxylamine (don’t want those bad boys anywhere near your DNA…). Cool stuff!

  11. Father Minkey says:

    I justa started to follow dis nblog and my English my bea bit how you say- skeetchy. But tda Pope papa Franscesco, when we study chemistry as once stronga young men he once say to me

    You musta love all Gods molecules- eben da Square ones!

  12. ppjm says:

    Just wait for the hypercubane derivatives to take medicine into the fourth dimension…

Comments are closed.