It’s a common problem: you find a
fragment that binds to your target and want to grow it to improve affinity. A search
for commercial analogs comes up empty, so you look into modifying the hit, only
to discover that you’ve got a six-step synthesis on your hands. Or worse;
perhaps there is no precedent at all. The chemical literature is replete with
total syntheses of complicated natural products, but seemingly simple fragments
are often not well-represented. Last year, researchers from Astex exhorted
chemists to develop synthetic routes for attractive fragments, and in a recent paper in Org. Biomol. Chem. David
Rees and colleagues take up their own challenge in the case of dihydroisoquinolones.
Dihydroisoquinolone itself is a
nifty little fragment. It has just 11 atoms, cLogP = 1.0, and its solubility is > 5 mM in aqueous buffer. Its cis-amide
moiety can serve as a hydrogen bond donor and acceptor, and the adjacent phenyl
ring provides a bit of grease for interacting with hydrophobic protein residues.
The researchers built on existing
methodology using a rhodium catalyst to introduce polar groups (such as
hydroxymethyl and dimethylamino) at the R position. Depending on the nature of
the R group, regioisomers in which the substituent ends up at the 4-position
could sometimes also be isolated.
The methodology is robust and tolerates
air, moisture, and various substituents. The alkene starting material is easy
to come by, and the aromatic starting material is easy to make. By varying this,
the researchers could generate 6- or 7- substituted dihydroisoquinolones,
though 5- and 8- substituted versions seem harder to access. The team was also able
to use other aromatics as starting materials, including thiophene, thiazole,
and pyridine.
Thus, if dihydroisoquinolone
comes up as a hit, this paper will allow you to quickly explore most of the
vectors. So how often does this fragment show up? It is not clear why some
fragments, such as 7-azaindole and 4-bromopyrazole, show up again and again,
while others languish so lazily in the library that they might as well not even
be there. We’ve highlighted at least one case where a dihydroisoquinolone was a useful hit.
Practical Fragments would love to know your experience. Do you have
dihydroisoquinolones in your library? How often do they show up as hits? And
what other fragments do you find that are in need of better synthetic routes
for further exploration?
Posts
6 comments:
Thanks for this excellent summary! One of the reasons we wrote this publication was to share with the synthetic organic chemistry community the challenges we face in FBDD. We would love to see more organic chemistry publications that are FBDD-friendly. For example:
•synthesis of compounds with fragment-like MW, clogP, solubility, binding groups;
•synthetic methods for fragment-to-lead elaboration eg selectively functionalising a fragment at several different carbon atoms whilst keeping a key polar binding group intact.
These aspects are frequently challenging and time consuming for our FBDD projects. We’d like to engage with academics who are thinking of applying their synthetic methodology expertise to Fragments.
I can’t recall if we put any dihydroisoquinolines into the AZ GFSL05 generic fragment screening library but if they had been available we certainly would have done so since ‘adjacent HB donor-acceptor’ was a substructural theme that we used in the library design and also for acquisition of compounds (e.g for screening against kinases). I can’t get at the CSD right now but the axial/equatorial preference of substituents at C3 would be interesting (C2 substituent in N-acylpiperidine tends to go axial and I’ve pushed this in the past for fragment design). Achieving an axial substituent preference with minimal steric footprint is a design tactic that should be of interest to ‘3D fragment’ advocates which we touched on here. There are some interesting differences between cyclic and acyclic amides. For example, N-methylation of an acyclic secondary amide tends to lead to an improvement in aqueous solubility but for cyclic amides no significant effect is observed for secondary amides. Slide 23 in this presentation may be if interest.
Dr. Rees,
If you wish to engage, it may be better to not hide your work behind publisher paywalls
apologies for my silly comment - I see that access is free once registered with the RSC.
Alexander V. Statsyuk
Rees said: "These aspects are frequently challenging and time consuming for our FBDD projects. We’d like to engage with academics who are thinking of applying their synthetic methodology expertise to Fragments."
I am pushing this idea as well to the traditional "total synthesis" groups. PPI inhibitor fragments are even worse: hydrophobic (i.e. many C-H bonds), and many RINGS. Both are considered challenges in the synthetic chemistry (see Nutlins and their analogues in clinical trials: cyclohexane ring with 5 stereogenic centers). Chemical biology groups cannot afford to develop "total" syntheses of these compounds, and SAR/Growth is a huge challenge, which translates into lower publication rate.
My dream is that FBDD community will come up with the "universal" list of fragments (Enzyme active sites and PPI interfaces), and then push for NIH initiative to charge total synthesis community to develop all kinds of "dump and stir" coupling methods to functionalize fragments at every site via assymmetric C-C, C-Het, or other Atom-Atom coupling bonds: a) sp-sp, sp-sp2, sp-sp3, b) sp2-sp, sp2-sp2, sp2-sp3, c)sp3-sp, sp3-sp2, sp3-sp3, d) C-O, C-N, C-S, C-P, C-Si, C-You Name The Atom.
When thinking about universal screening libraries, it’s worth remembering assays differ in the weakness of binding that they can detect and quantify. This means ‘universal’ that may depend on the technology for detecting fragment binding because being able to detect/quantify weaker binding allows you to use a smaller number of fragments in a generic library.
David’s suggestions for extending scope of synthetic fragment articles prompts questions about how this thinking might be extended to other areas like X-ray crystallography. Rather than just publishing a protein structure, a crystallographer might publish a number of structures with the interaction potential of the protein mapped out using a series of highly soluble fragments. The key question is what is the best way to publish useful fragment-based contributions without having results for a full study. This discussion reminded me of a couple of blog posts I did on FBDD in academia a while back and I’ll share them here and here.
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