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New Reactions And Where They’ll Come From

Here’s a new paper calling for expanding the medicinal chemistry synthetic toolbox. There have been calls like this before, of course, but those weren’t wrong, either. It’s not hard to figure out how we’ve ended up where we are, though (links added to replace footnotes in the below paragraph):

The limited set of reaction types used in medicinal chemistry can be rationalized by the use of several criteria in their selection. The first criterion is the availability of starting materials and reagents. The second is the ease of synthesis (such as short reaction times, moderate temperatures and high yields with limited by-products). Indeed, analysis of the synthetic methodologies used over the past 240 years in more than 6.5 million organic reactions indicated that key parameters, such as reaction time, temperature, pressure and solvent, are biased by anthropogenic factors. For example, half of the reactions were complete within <3 hours, and >90% of reactions were run at atmospheric pressure, typically between −80 °C and +200 °C. Furthermore, medicinal chemists are often reluctant to make difficult-to-synthesize molecules without compelling precedence or predictions, and the strength of computer-aided design is still largely geared towards prioritizing lists of compounds and designing libraries rather than predicting a single optimal compound. Consequently, chemists may prefer to focus on simple reactions that can efficiently cover a lot of ground and, indeed, this is what is observed when analysing what is actually made in medicinal chemistry laboratories.

Those last links are blogged about here and here, and see here as well. The authors mention the problem of new reaction robustness (tolerance of a wide range of functional groups, or at the very least testing for such tolerance). That makes you reluctant to try some new method out of the literature as well, because there’s no telling how your (often more polar and/or complex) molecule will handle it. As the paper points out, medicinal chemists are indeed biased towards robust reactions, things that (in our own experience) will tend to deliver products instead of failing in interesting and puzzling ways.

That’s the thing: the current state of synthetic organic chemistry in the medicinal labs is actually the result (for the most part) of pretty rational choices. We’re trying to make the most diverse compounds in the shortest period of time, using the reactions that we think are most likely to work. So you get a lot of workhorse transformations, and you get a completely understandable bias towards chemistries that you know you can radiate out from using a big set of diverse building blocks that you already have on hand. None of this is stupid in the least.

But it’s not necessarily the optimum, either. It really would be desirable to have more sorts of reactions in the “workhorse” category, and to have scaffold-generating reactions that generate interesting starting points that are under-represented now. Over the years, various companies have made deliberate efforts toward this sort of thing (I know; I’ve been on some of them), but my impression is that it’s quite an uphill climb to make a real change in a typical screening collection. Importantly, though, the larger vendors of building blocks and intermediates have been making similar efforts, looking for commercial advantage.

This new paper goes into detail about the way that new software and automated hardware might make a change as well: synthesis programs don’t have the biases we do, and can extract reactions out of the literature that the average chemist might not have noticed, is reluctant to try, or hasn’t realized yet has been developed to a useful point. And automated methods for reaction discovery and optimization can clear out a lot of underbrush on the scope and robustness fronts, leading to validation of new techniques much faster than letting time do its usual work. This isn’t going to happen next week, or next month, but it is coming on. These tie into the hardware-driven search for new reaction conditions and types, too – flow chemistry, photochemistry, high-pressure chemistry, electrochemistry and biocatalysis (among others) are sources of transformations that you just can’t do with the usual reactions in the usual flasks and vials, and the automated forms of these things can fill out the example table to where a bench chemist can trust them. The machines are even more biased towards robustness than we humans are; we have common interests for sure.

It’s true that new chemical matter is not necessarily a rate-limiting step in drug discovery. But that’s drug discovery as we practice it now. As we get into newer modes (binders instead of functional molecules, for protein degradation, etc., small-molecule/biomolecule hybrids, targeting things like disordered proteins, intracellular condensate and so on) we could probably use all the help we can get. Anyone who’s tried a number of screening campaigns will know of some high-value targets that never seem to turn up anything useful. One possibility is that there’s nothing useful to turn up. But given the size of druglike chemical space, and the tiny amount of it that we’ve explored so far, I’m not sure that that’s the way to bet, either. . .anyway, don’t you want to start a project with something other than a kinase inhibitor scaffold or some Suzuki/amide combination? Sure you do!

16 comments on “New Reactions And Where They’ll Come From”

  1. AC says:

    I’m a bit wary about synthesis planning programs although I suppose if you treat them as automated literature trawlers (keeping in mind the good ol’ caveat of garbage in, garbage out) they can be useful. Automated reaction discovery/optimisation is definitely something that will add a lot of value though, and is precisely the area that machines excel at (repetitive menial work). I look forward to the day I can simply type in a set of reaction conditions to screen, and a robot does all the work for me while I have a relaxing weekend then come in on Monday to look over the results of 4,096 different reaction conditions.

  2. Anon says:

    Only selected successful reactions are reported in a handful of journals. We mostly don’t know what fails, how they fail and what the products are. Good luck with the machines!

  3. cynical1 says:

    The article is behind a pay wall but I would like to put forth that the pharmaceutical industry has always rewarded chemists on the number of compounds they made and not on the ingenuity involved in either their synthesis nor whether their analogs answered key questions surrounding the SAR on a project. I watched many chemists get promoted for repeatedly making inactive compounds over and over again simply because the chemistry was easy. And the chemists who made lots of easy analogs were the ones that were retained during layoffs and promoted. What does the industry expect when it rewards the chemist who makes a 100 dead amides with a seat in the comfy chair?

    This is not revelation. It really is not too hard to figure out why there’s a paucity of synthetic diversity out there. What the pharmaceutical industry doesn’t want the world to know is what their key strategy has been for decades: “Even a blind squirrel finds a nut once in a while.”……….just not many.

    1. anon the II says:

      What he said! This is the order in which people are rewarded.

      1. Make one compound that goes into clinic
      2. Make a ton of crappy compounds
      3. Make a few well thought out and challenging compounds that don’t make it to the clinic
      4. Make a few crappy compounds.

      Unfortunately, when it’s layoff time, the line is drawn between 2 and 3. Unless you’re older, then you’re hosed regardless.

      1. cynical1 says:

        Yep……….I was old.

  4. An Old Chemist says:

    cynical and anon the II: I have witnessed it over tens of years that managers (‘the bean counters’) reward chemists with high productivity (easy to make compounds even when they are worthless)! These productive chemists (who are good at prep-HPLC only) do Suzuki, make amides and ureas, most of the times. They leave behind prep-HPLCs in a poor shape for the next user. Managers love these chemists because when they present the progress of the project to their managers (mostly MBAs and biology majors) they produce Powerpoint slides overloaded with neatly drawn structures, company code numbers and the biological data, they come out great. These MBAS and biologists do not understand anything about chemistry!!! The med chems doing good chemistry and making clever logical analogs gets pushed out to the process chemistry groups. Needless to remind you that pharma industry’s top managers think that process chemists are just scale up people, who take procedures from ancient journals and scale them up like robots!…. ‘have been there, got the T-shirt!!!

    1. Nick K says:

      My experience, FWIW, is that the best chemists were in Process, while there were plenty of hacks and self-promoters in Med Chem.

      1. Med chemist says:

        This might be true on some level. But to be a proficient med chemist means you need to be good at designing and executing synthetic routes without any pre-existing precedent, especially if a molecule has a well thought out hypothesis irrespective of what can be easily made. You also have to be good at switching gears at a moment’s notice. There is something to be said about getting a previously unknown, well thought out molecule into a bottle…

        1. An Old Chemist says:

          @Med Chemist: But the chemistry that these good med chems use to make the novel structures often yields the novel compounds in <5% yield. This is no good chemistry, and any chemist can do that. Most of the times (if not always), these novel compounds are synthesized (isolated) by using a known reaction, and placing all the component reactants (often without accurate weighing) in a sealed tube, heating overnight, and characterizing the hoped desired product by LC/MS, followed by a prep HPLC, collecting tens ans tens of tiny fractions! I am not impressed by this kind of chemistry!!!

  5. Thanks for highlighting the paper Derek. It is available via RedCube. The link is https://rdcu.be/5jzN

  6. Anonymous says:

    “anthropogenic factors” I used to explain some published experimentals to junior colleagues that way. Set up and start a reaction at ~4 PM; come back at 10 AM = 28 hours, not that it needs 28 hours, but that’s when the researcher came back; in our hands, set it up and start at 11 AM but it’s done by 5 PM. In our hands, another reaction is over in 4 hours; literature 72 hours = weekend skiing or at the beach!

    1. Anon says:

      How many reactions that are relevant to industry are time sensitive?? Maybe a handful.

      1. Dr CNS says:

        So what? The experimental section of a synthesis paper is supposed to describe what you did to get the product. Unless it is stated, I don’t expect the reaction conditions conditions to be optimal.

  7. Anonymous says:

    Oops. 4 PM to 10 AM = 18 hours, not 28 hours.

  8. Inconvenient truther? says:

    Thank you Derek for posting this, and seeding the discussion. An different view to share, which isn’t intended to be direspectful, but provoke thought. Designing and executing synthetic routes makes one at best, a proficient organic chemist, not a medicinal chemist. True medicinal chemistry requires a knowledge of pharmacology, biochemistry, toxicology, anatomy, and human physiology. I’ve encountered way too many self proclaimed medicinal chemists who lack knowledge in these critical areas. Strength in organic chemistry does not equate to medicinal chemistry, and challenges in organic chemistry does not mean weakness in medicinal chemistry. I am not in the least concerned about the ability to make molecules, tool boxes, etc. – synthesis has been done quite well for 200+ years, and the chemists in pharma are exceptionally good at making compounds. The mindset and ‘culture’ of what is considered medicinal chemistry is of more concern, beyond any toolbox. Personally, would like to see more knowledge and emphasis on understanding mechanism of action of a disease, and making and evaluating a FEW well chosen compounds evaluated in pharmacologically relevant models. For the record, former medicinal chemistry group leader from industry, but now in academic medicine at a major medical center (but with a respect for chemistry and what pharma is capable of doing). Getting off the soap box now, and thank you for reading…

  9. Reviewer #3 says:

    A 2+2 photo-cycloaddition is not photocatalysis, just photochemistry

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