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Mix-and-Match Natural Products

A lot of people in med-chem and chemical biology would like to have more natural-product-like features in their libraries of organic compounds. But realizing that idea is not so easy. Natural product structures, er, naturally tend to be more complex, with a lot of functionality and stereochemistry compared to the sorts of things you usually find in compound libraries. These features are usually chemically intensive, giving you a choice of a lot of structural variety or a lot of compounds, but not both at the same time.
There have been many efforts to get around this problem, among them diversity-oriented synthesis. DOS does tend to make complex compounds, but they’re often out in their own area of chemical space, “unnatural products” that probably don’t partake of whatever evolutionary advantages natural products have accumulated. Now there’s another solution, courtesy of boronate chemisty. Martin Burke at Illinois has been working on adapting MIDA boronates to produce libraries of natural product modules and side chains, ready to be stapled on to whatever other structures you might have.
This Nature Chemistry paper has details of this approach as applied to polyene structures. There’s a power-law distribution to these things that makes it all feasible:

. . .we decided to ask the question, how many bifunctional MIDA boronate building blocks would be required to make most of the polyene motifs found in nature? To find the answer, we devised a general retrosynthetic algorithm for systematically deconstructing these motifs into the minimum total number of building blocks. This analysis generated the intriguing hypothesis that the polyene motifs found in >75% of all polyene natural products can be prepared using just 12 MIDA boronate building blocks and one coupling reaction.

They’ve had to do a good amount of synthetic optimization to get this to work – the more straightforward conditions had compatibility problems. But it seems as if they’ve got some protocols now that will allow the various MIDA and pinacol boronates to work together orthogonally, and they’ve synthesized several natural product test cases to demonstrate. The polyenes make up between 1 and 2% of all the known natural products (>2800 of >238,000), but the idea is to extend this plan into other structural classes:

It is stimulating to consider how many building blocks would be required to access most of the remaining 99%. Although the answer to this is not yet known, the strategy demonstrated herein, that is, systematically identifying common motifs and transforming them into bifunctional building blocks compatible with iterative coupling, provides a roadmap for pursuing this problem. For example, we have identified 12 additional common structural motifs that are collectively present in more than 100,000 natural products. Half of these motifs have already been transformed into bifunctional halo MIDA boronates that are now commercially available. To achieve the same goal with some of the others will require solutions to frontier methodological problems, which include new chemistry to make and stereospecifically cross-couple Csp3 boronates.

I look forward to seeing these realized. This chemistry looks to provide a lot of interesting new compounds, and it could also answer some questions about natural products themselves. What, for example, would the screening hit rates and activity profiles be like for a large library of almost-natural products, things with the same biophysical properties and functional motifs as the rest of natural product space, but without the evolutionary fine-tuning?

11 comments on “Mix-and-Match Natural Products”

  1. PorkPieHat says:

    The problem with DOS, at least at first, is what do you do when you need to analog in places on the molecule that the DOS chemistry was not developed for? Great for hits, not so great for optimization. It looks like this approach at least aims to make structures related to NP motifs.
    BTW, am I the only one who is encountering problems with accessing the comments sections on blog posts here? Weird. Hit and miss, those comments sections are.

  2. The Aqueous Layer says:

    Burke is a pretty impressive guy. Wonder how long he remains at UIUC…

  3. ADCchem says:

    The problem here is the structurally interesting molecules in his paper like Natamycin, Hemicalyculin A, and Enacycloxin IIa would be difficult to synthesize in a library setting because of the complexity connected to the polyene.
    While his method is great for the synthesis of simple polyenes it won’t get you to rapamycin in 4 steps either and therefore may prove to have less biological relevance than advertised.

  4. Anonymous says:

    Has anyone tried using polymers of amino acids? All the machinery exists to make any sequence you want, as long as you want, and the products have already been shown to perform virtually every function in the natural world, including getting through the gut and blood brain barrier in some cases. Quite nifty, actually. Perhaps worth considering more seriously instead of trying to reinvent the wheel.

  5. Phil says:

    @4 Yes, peptide therapeutics have been investigated for quite a while now.
    http://pubs.acs.org/cen/business/83/i11/8311bus1.html
    More recently, aptamers (polyoligonucleotides) have caught some attention. These can also be made by biological machinery.
    http://www.nature.com/nrd/journal/v9/n7/full/nrd3141.html

  6. partial agonist says:

    #4, peptide libraries?
    Yes, it’s been tried over and over again for 35+ years. Poor stability/ PK properties seem to be the main issues and why it became relatively uncommon

  7. SP says:

    #4- My phage, let me display it to you.

  8. Anonymous BMS Researcher says:

    @Anonymous: as @Phil and @partial agonist say, peptide libraries have been tried many times. It had been hoped that a variant called “stapled peptides” might get around some of the issues. Unfortunately, there are issues with stapled peptides as well:
    http://pipeline.corante.com/archives/2012/12/17/stapled_peptides_take_a_torpedo.php

  9. Anonymous says:

    @5-8: I was referring to folded proteins, not short peptides, because that’s what nature uses. Nature doesn’t use short peptides for all the same reasons we now avoid using them.

  10. Phil says:

    @9&10: Many folded proteins are used as therapeutics. The first one that comes to mind is the now infamous erythropoetin alfa or EPO (it’s what Lance Armstrong and other cyclists used to dope their red blood cell levels). It’s made essentially as you describe, by expressing the protein in cells and then harvesting it.
    Again, it’s been of interest for some time now and has both pros and cons.

  11. Phil says:

    @9&10: Many folded proteins are used as therapeutics. The first one that comes to mind is the now infamous erythropoetin alfa or EPO (it’s what Lance Armstrong and other cyclists used to dope their red blood cell levels). It’s made essentially as you describe, by expressing the protein in cells and then harvesting it.
    Again, it’s been of interest for some time now and has both pros and cons.
    And, as a matter of fact. Nature uses plenty of short peptides – for instance, as neurotransmitters.

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