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Silicon In Drug Molecules, Revisited

Here’s an update to a post from last year about silicon in drug-like molecules. The Denmark group at Illinois has investigated a range of silicon-containing heterocycles, providing both synthetic routes into the (mostly unknown) structures, and looking at some basic pharmaceutically relevant properties.

There’s a lot of work in this paper on the synthetic procedures, both to prepare these compounds and to investigate their chemistry. What it tells you is that (as you would have figured) that C-to-Si is a nontrivial switch in the fume hood, because the chemistries involved can be quite different. For instance, that first core on the list does N-alkylation and N-acylation reactions just fine, but when you try to do metal-catalyzed N-C couplings on it, things go to pieces (protodesilylation and other decomposition reactions). Protodesilylation in general was something that had to be looked out for, with attention paid to solvent choice and temperature in the reaction conditions.

Another theme that comes up several times is that the nitrogens, when exposed to base, can be significantly more prone to oxidative side reactions than expected (even fairly simple reductive amination reactions had to be performed under inert atmosphere, although they were successful then). Metalation reactions were also tricky. Some of them worked just fine and reacted as expected with a range of electrophiles, while others would work with some partners but not others. But some of them just fell apart immediately on attempts to form the anions (such as C2 of the second compound on the list shown), and the only way to find that out was to try them.

Overall, the group was able to prepare an impressive range of functionalized derivatives of these cores, almost all of which are shots into unknown territory. How, then, do such compounds behave? Their cLogP values are almost invariably higher than their carbon analogs, but as usual when you move into unusual structure space, it would be interesting to have some experimental values to make sure that that some of this just isn’t a problem with the calculations.

Comparing the Si and C matched pairs in assays, there seems to be no difference in P-gp transporter behavior in vitro, for starters. There was a slight trend towards more instability against CYP enzymes, but this wasn’t universal (and was also species-dependent, with the rat enzymes being more vigorous. (That’s often the case; rats have a reputation for having more strongly oxidizing liver enzymes, which I’ve always attributed to their rather broad definitions of suitable food). Inhibition of these enzymes didn’t show much of a trend one way or another.

The second compound on the list above and its carbon analog were compared in rat PK experiments as well (oral and i.v.) Intravenous behavior was fairly similar – the Si compound had slightly higher clearance and slightly higher volume of distribution. As for p.o. dosing, the Si compound is significantly more bioavailable, although it has a lower Cmax. Overall AUC was pretty much the same, though. And even though it had greater instability to the rat enzymes, it had a twofold great half-life in vivo, which makes you think plasma protein binding. So this is only one point, but taken with the other Si compounds in the literature, it seems as if they fall inside the normal range of variation that you see with all-carbon compounds – there’s nothing intrinsically weird about them from a pharmacokinetic/metabolic standpoint.

That brings up what I mentioned in my past last year, though: perhaps it would be better for silicon-containing drugs if there were something unusual about them. Admittedly, that could also be “unusually bad”, but overall, it’s harder to make the case for moving to silicon if the effects of doing so are (a) not huge and (b) not all that predictable. You’re already in that zone with carbon analogs, most likely, so why bother? The paper itself has this to say:

This lack of success in the pharmaceutical industry may be attributed to two key factors: (1) an absence of general and accessible synthetic methods for the construction of appropriately functionalized silicon-containing molecules and (2) ineffective approaches to the utilization of silicon, of which the “carbon/silicon switch” is the most common. 

I think that second point is what we’re talking about. “Ineffective approaches to the utilization of silicon”, from another angle, means “lack of a good reason to use it at all”. If some effective uses for it can be found – and they may well be out there, who knows? – then things will change. But not until then. If the late-stage silicon switch doesn’t necessarily get you anything, it’s true that you’re going to have to look earlier (good activity in a silicon-containing compound that isn’t replicated by its carbon analog), and this work is an attempt to provide a host of new Si-containing chemical matter towards that end.

What would go a long way to answering the overall question would be if someone were to produce a library of (say) ten or twenty thousand diverse silicon-containing drug-like structures and their exact carbon analogs, and do some high-throughput screening campaigns (variously targeted, cellular, and phenotypic) to see how they behave. But no one’s going to go to that trouble just yet, for just the reasons described (an absence of ways to make such things and an absence of compelling reasons to make them). The chicken and egg question remains.

45 comments on “Silicon In Drug Molecules, Revisited”

  1. b says:

    Their chemical behavior in a flask doesn’t bode well for their chemical behavior in a living flask with millions of reactions. Maybe their only use is in a patent busting exercise.

  2. mallam says:

    There’s always the patent consideration, make a mimic of someone else’s blockbuster, to get a slice of a big pie. I’d also like to see how Si for C analogues perform as antibacterials and formation of resistance.

  3. Matthew Statham says:

    The silanediol group is by far the most interesting silicon switch for the hydrated carbonyl or amide. Alternatively silicon in a ring prevents aromatisation potentially blocking off a potential metabolism route.

    1. Perhaps no person has done more to explore the Si/C switch than Reinhold Tacke. His silicon analog of haloperidol prevents aromatization, a source of toxicity for the drug. A great deal of very important work on comparative metabolism has been published. This is a good lead reference: https://doi.org/10.1124/dmd.109.028449

  4. John Wayne says:

    I’ve played with silanes from time to time, and it hasn’t ended up in a lead molecule yet. In my experience you almost always pick up significant amounts of lipophilicity (often a full log, and those were measured logD’s.) This has the usual effects on other properties, so I’ve had this in my back pocket for the rare event wherein I need to make something greasier, but don’t want to add a lot of atoms. Also, patent-busting; always good for that.

    1. AR says:

      “and those were measured logD’s”

      People measure LogD’s!?!?

  5. pk says:

    Has anybody looked at RSiF3 or RSiF2R’ as bioisosteres? Seems a better option than the RSiMe2R’ which must be adding a lot of grease.

    I also wonder if the oxetane equivalents could be interesting.

    1. AVS-600 says:

      Despite the famously high thermodynamic stability of the Si-F bond, silyl fluorides are usually pretty kinetically labile in an aqueous environment. It would likely be hard to keep those from converting to silanols in vivo.

      1. DrOcto says:

        Given that silane diols polymerise at high concentration, silane difluorides are interesting as prodrugs for this same reason.

  6. TMS says:

    One advantage that organosilicon compounds have is in reactivity. For example a chloromethylsilicon compound is far more reactive to nucleophilic substitution than a neopentyl halide. This renders certain silicon containing targets more accessible than their carbon containing counterparts.

  7. Design Monkey says:

    By and large, those tetraalkyl silanes are just a somewhat fatter and greasier, than C analog, lipophilic group. That is not the most needed or useful functionality in med chem. Silane diols as transition state analogs and thus enzyme inhibitors might have some chance and usefulness, if the luck plays out. But just siliconized grease blob – nope, not really needed anywhere.

  8. Anon says:

    “This lack of success in the pharmaceutical industry may be attributed to two key factors: (1) [the limitations of silicon chemistry]; and (2) [more limitations of silicon chemistry]”.

    Clearly said by a complete academic with no clue of the industry. There are many issues limiting the industry’s success, but silicon? I have never heard something so ridiculous!

    1. Anon2 says:

      Scott Denmark is a lot of things but he’s also one of the world’s leading authorities on silicon chemistry. He’ll make more consulting in an afternoon to a pharma company than most posters here will make in a month. I’d say he has a clue.

      He also introduced Derek at a talk by saying blogs are stupid.

      1. Anon says:

        Just like Michael Cohen then?

    2. Marcus Theory says:

      Pretty sure he meant lack of success *of silicon-containing compounds* in the pharmaceutical industry….

    3. Derek Lowe says:

      That’s somewhat out of context, thanks to me. He just means “the lack of success of silicon-containing drug structures in the pharmaceutical industry”.

    4. anonymouse says:

      Silo mentality?

    5. Bla says:

      Well done on deliberately misunderstanding an obvious quote to make a snipe at academia. Got turned down for tenure, did you?

  9. Peter Kenny says:

    I found hexadecane/water logP values of 3.66 (neopentane) and 4.37 (tetramethylsilane) and am sure that the corresponding octanol/water logP values have been measured. Molecular surface area is greater for tetramethylsilane than for neopentane on account of the longer Si-C bond and this can be considered the cause of hexadecane/water logP differences. The zip archive for the article that I’ve linked as the URL for this comment includes some measured alkane/water logP values.

    Replacing C in marketed drugs with Si is unlikely to prove to be a panacea. First, you’ll still need to do the clinical trials. Second, the Si-drugs will still be exposed to generic competition when the original drugs come off patent. There may be ways forward if an Si-drug shows significant benefits in clinical trials but it will need to do something special.

  10. BernYeKidneys says:

    Organosilicon metabolites?

    Ow, my Loops of Henles!

    1. Mark Thorson says:

      That was my first thought. How do you piss away all that glass?

  11. Noni Mausa says:

    Help a biochemistry onlooker here, but when I think of adding silicon based analogs to a living carbon based organism, my first thought is a precipitation of quartz throughout the luckless critter. Obviously, this is not YOUR first thought, since you all seem to accept the possibility of an Si based molecule being useful in pharma, someday, somehow, and therapeutic fossilization has not appeared anywhere in this discussion. But if such an analog were ever proposed for a drug use, I predict it would be a PR difficulty of some considerable size.

    1. Derek Lowe says:

      Quartz is definitely a low-energy state, but there’s a pretty high activation barrier to get there (in the same way that all the aluminum foil doesn’t burn off to give us piles of alumina).

    2. John Wayne says:

      I’m savoring the term ‘therapeutic fossilization,’ thank you very much for contributing it. It seems more ‘James Bond villain’ than Pharma project, but hey … these days most people can’t tell the difference. Let’s do it.

      1. Noni Mausa says:

        Aww, twarnt nothin.

  12. MrXYZ says:

    As a note, there is a silicon compound that is almost FDA approved. ZS-9 (AstraZeneca) is a sodium zirconium cyclosilicate that is a potassium chelator used to treat high potassium levels (hyperkalemia). It was almost approved a few years ago but had some manufacturing issues flagged by the FDA, which I think have been solved. While this is a somewhat different beast than what you are describing as silicon-containing drugs (this is not an organosilicon compound and it doesn’t bind to either protein or nucleic acid targets), it does nicely illustrate the point about using silicon only if there is a compelling reason to do so. Zirconium too!

    1. Anonymous says:

      A few groups studied silicates and organosilicates for aluminum chelation. Some Alzheimer’s patients do show higher levels of Al in their plaques and tangles so it was thought that Al might be a contributor to some cases of AD. Fasman showed that A-beta 1-42 could be switched from random coil to beta-sheet with Al(+3) and back to random coil by addition of sodium silicate. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC42741/ No drugs yet.

      You can buy food grade silica gel for nutritional use from places like GNC and Amazon. People have been eating large amounts for a long time. I don’t think it’s known to be harmful. ORGANOsilicates are another matter. They can go places silicate does not.

      I haven’t updated this search in several years, but there were no known metabolic enzymes that process “Si” itself. Organosilicons can get chewed up on their carbon parts. (I think there are transport proteins for silicates or ways to get them into plant structural components.)

  13. Mark Thorson says:

    Note that the MSDS on most silanes mentions cataracts as a risk factor. Apparently, they can infiltrate and disrupt the lens of the eye.

    1. b2 says:

      Just curious, do you have any example MSDS of this?

      1. Mark Thorson says:

        I first ran across this with (3-Aminopropyl)trimethoxysilane, which is a common silane coupling agent.

  14. MoMo says:

    Denmarks’ work is quite remarkable in catalysis and mechanism in organic reactions-I doubt Pharma wants him for his Silicon expertise.

    Although it does foster the notion of creating a company that uses DELs and AI for generating Si-Drug Mimetics.

  15. Dr. McCoy says:

    Dammit Jim, I’m a doctor, not a bricklayer!

  16. Dominic Ryan says:

    For Si to be useful in a patent, or ‘patent busting’, remember that it has to actually do something different and useful. The H/D switch changes PK in a ‘non-obvious’ manner for IP. Si/C would have to do the same. The idea of blocking aromatization is very interesting but can you think of a structure where you are replacing a methylene or methine, where that H might get pulled off, with an Si-H and have it be more stable in all ways?

  17. loupgarous says:

    My student job with the Louisiana Tech Center for Biomedical Engineering and Rehabilitation Science, beyond its primary brief of building custom electronic gadgets for the research and rehab sides of the shop and writing tech and operating manuals for the stuff we built under Federal grants also included sending off those little postcards in professional journals and compiling a library of catalogs – of every conceivable technical product, because… you never know.

    This blog reminded me of the catalog of organosilicon chemicals Petrarch Chemicals sent us (UCT bought their rights to their entire line, and still sells them as “Petrarch Specialty Chemicals”).. Even back in the mid-1980s, Petrarch was sunnily optimistic that swapping Si for C would give the world useful and lucrative biochemicals and pharmaceuticals. Skimming the catalog, I was mainly impressed at how many of the interesting silicon analogues carried warnings about causing cataracts. I’m also persuaded by Noni Mausa that formation of quartz, sand, or literal geodes (in radiology, it means a cyst of hyaluronic acid encapsulated by bone) are dreadful possibilities. Even less manageable gout than boring old uric acid crystals.

    The catalog Petrarch sent us was pretty thick, so if UCT’s kept producing the entire Petrarch library, it may be a start on Derek’s “library of (say) ten or twenty thousand diverse silicon-containing drug-like structures”. Commercial off-the-shelf… well, I’m sure you med-chem guys want to make all that yourselves, but it’s something to think about.

  18. Paul says:

    This compound got into Phase I in man: MDL 73,745 (2,2,2-trifluoro-1-(3-trimethylsilylphenyl)ethanone): Clinical Experience with MDL 73,745; Pharmacokinetics, Pharmacodynamics, and Clinical Tolerance in Normal Volunteers https://link.springer.com/chapter/10.1007/978-1-4615-8149-9_24

  19. Istvan Ujvary says:

    In the world of pest control agents, an often ignored topic, there is a silicon-based inhabitant: flusilazole, a triazole-containing silane. This fungicide is a close bioisostere of flutriafol, another SBI used in agriculture.
    http://www.fao.org/fileadmin/templates/agphome/documents/Pests_Pesticides/Specs/Flusilazole08.pdf
    Simeconazole likewise:
    https://www.rsc.org/Merck-Index/monograph/m9943/simeconazole
    And don’t forget about the extremely toxic silatranes!
    http://pubs.rsc.org/en/content/articlelanding/2011/cs/b925899j#!divAbstract
    BTW: In BIOSTER database I have listed over 150 Si-containing substances with documented bioactivity.

    (I have tried to post this comment several times without much success. Apologies for duplicates.)

    1. Bill Moberg’s Flusilazole was the first organosilane produced for its biological activity (fungicide in the triazole class). The second – and the only other – is silafluofen, a pyrethroid insecticide (https://doi.org/10.1002/ps.2780280308).

      1. Istvan Ujvary says:

        Yup, Scott! I have missed that one. Damn.
        So there have been 3 organosilane pest control agents marketed:
        The fungicides flusilazole and simaconazole, and the insecticide silafluofen.
        I have just gone through the formula index of ‘The Pesticide Manual 13th’ (2003) and noticed organostannanes: the fungicide azocyclotin and the acaricide cyhexatin, both probably still in use.

        1. Istvan Ujvary says:

          It turns out that I missed silthiofam, that is dimethyl-N-prop-2-enyl-2-trimethylsilylthiophene-3-carboxamide, used for antifungal seed treatment in cereals. So silafungicides in crop protection abound.
          Terminal TMS-analogues of terbinafine?

      2. Dominic Ryan says:

        I randomly just came across this a Si analog of ketoprophen. The abstract suggests in vivo data but perhaps not (I don’t have access to the paper in Saudi Pharmaceutical Journal, issue 1, page 1, 1993: Ketoprofen, one of the potent non-​steroidal anti-​inflammatory agents, was synthesized by using a Friedel-​Crafts acylation with BzCl of a trimethylphenylsilane deriv. of 2-​chloro-​N,​N-​dimethyl-​2-​(phenylthio)​acetamide as a key step. A sila-​analog of ketoprofen, 2-​m- and -​p-​(dimethylphenylsilyl)​propionic acid, was synthesized from dimethyldiphenylsilane in a similar manner and evaluated for anti-​inflammatory activity. Authors are from Kyoto: M. Hikeda…

    2. Design Monkey says:

      Toxic silatranes are just cage convulsants – GABA chloride cahnnel blockers. Phenyl silatrane was proposed as rat poison in USSR, but did not really pan out. Nothing especially magical about silicone role there either, yes, it allows relatively easily synthesize those things (mix triethanolamine with appropriate trichlorosilane in a rusty bucket and you have your silatrane), but the same and even easier you can make tetramine (tetramethylenedisulfotetramine).

    3. Design Monkey says:

      Aaaand speaking of silatranes and (sort of) drugs, chloromethyl silatrane acts as hair growth agent. It is being sold commercially in Russia, though it is unclear about its actual status – is it registered drug (seems not) or they are pushing it as “supplement” (which would be rather freaky case, but not much of wonder, given the general style of “supplement” business and Russia in particular)

  20. anon says:

    A dumb question-Assuming that silicon based drug is on the horizon, can we use fluoridated water? Hehe…

  21. Yajun Zheng says:

    This discussion reminds me of the sterol C14 demethylase inhibitor, flusilazole (DPX-H6573), an organosilicon fungicide invented by DuPont for preventing fungal infections on fruits and vegetables.

  22. pedro says:

    great post

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