What compounds to make or buy?

[kym834]

Hi All,

Now that we've got the first round of biological testing back, time to consider what we might like to synthesis next :)

I (@kym834) still have the 2-methyl, 3-methyl and 4-methyl compounds below on my list to synthesise

SMILES 2-methyl: CC1=CC=NC(NC2=NC(C3=CC=CC=C3C)=CS2)=C1 3-methyl: CC1=CC=NC(NC2=NC(C3=CC=CC(C)=C3)=CS2)=C1 4-methyl: CC1=CC=NC(NC2=NC(C3=CC=C(C)C=C3)=CS2)=C1

John from IMSA (sorry I don't know the handle) has also put down some compounds they would like to synthesis, see below. They will be exploring the removal of the methyl group and the nitrogen atom from the 2-amine ring system while maintaining the 2-pyridyl and will also explore this with the 2-methoxy (the second best from our batch of molecules that were tested in vitro

SMILES (Clockwise from top left) 1: C1(C2=CSC(NC3=CC=CC=N3)=N2)=CC=CC=N1 2: CC1=CC=CC(NC2=NC(C3=CC=CC=N3)=CS2)=C1 3: COC1=CC=CC=C1C2=CSC(NC3=CC=CC=N3)=N2 4: COC1=CC=CC=C1C2=CSC(NC3=CC(C)=CC=C3)=N2

@AndyBishopSevenoaks and @PaulMcKeatingSevenoaks - I know you are still keen to work on some compounds to. I think we could explore some more molecules which will build on the compounds John is working on. Could look at removing the nitrogen and methyl group (1) and other substitutions on that ring at the 2, 3 and 4 positions (2). Other areas we could explore are modification of the amine linker or substitution at the 5 position of the thiazole ring rather than the 4 (3).

[mattodd]

Great @kym834 (and huge kudos for updating the wiki, by the way). I reckon for the moment we keep that 2-pyridyl N (could always add to that ring elsewhere) and maybe alter something else in the structure. I like your suggestions. @AndyBishopSevenoaks - what do you say? Looks like these are nice targets for the class? @kym834 do we know which of the proposed structures would be novel according to SciFinder?

[MFernflower]

I might as-well throw my hat into the ring:

@mattodd @kym834

Des-methyl-MMV0006357 (compound 1 in the image) is commercially available: https://mcule.com/MCULE-6813619596/

[kym834]

@mattodd, for the suggested compounds (1) - comes up on SciFinder with ~25 references, the synthesis and characterisation data is in a paper that looks at a bunch of these compounds as targeting agents for von Hippel-Lindau Deficient Renal Cell Carcinoma Cells. They mostly focus on the 4-pyridyl compounds but a few 2-pyridyl in there too (DOI: 10.1021/jm901457w)

(2) - looking at different R groups on the amine ring system (2) there are a few on SciFinder but almost all of them have every low references, 1- 5 in most cases. Happy to look further into those.

(3) - just did a quick search on SciFinder putting the 2-pyridyl ring at the 5 position and got no results, for the phenyl group at this position got some results so that one isn't novel. I also did a quick search with any atom at either the 2, 3 or 4 position on the phenyl ring and only got results which also had further modification to the other ring system for all 3 options so will be some novel compounds to explore here.

[MFernflower]

@kym834 Could you run the compounds I proposed through sci finder? I do not have access to that software

[kym834]

@MFernflower, sure! It is currently undergoing maintenance until 1am eastern time but I'll take a look once it's back up and running. I know that: (1) This one is the same as the first compound John is looking at; not novel. Comes up on SciFinder with 10 journal articles and 15 patents which have reference it. and (3) We've already made this one; it was novel

[kym834]

2, 4 and 5 are novel. No results in SciFinder when searched for their structures. Also nothing on PubChem for these 3 compounds.

[MFernflower]

I think it would be interesting to see what methylation of the free secondary amino group (compound 4) would do to the potency - but I think these would need to be made by you instead of the BG students as it's likely going to involve methyl iodide

@kym834

[MFernflower]

@kym834 Another possible idea is ring expansion:

That compound can be synthesized from a commonly sold perfume ingredient called Oranger Crystals

https://pubchem.ncbi.nlm.nih.gov/compound/2-Acetylnaphthalene#section=Depositor-Supplied-Synonyms

[MFernflower]

@kym834 @mattodd This compound actually has a decent CLOGP but no clue where you would buy acetylcyclohexane

[kym834]

@MFernflower agree that it will be interesting to explore alkylation of the N, and yes probably not suitable for students. I think starting with methylatoin and ethylation and seeing what we get out of that. Of course can also look at changing the linker to an amide etc as well. I also thought about looking at the quinoline as an additional expansion on the first set of compounds we have tested. Similar to your suggestion above but also keeps the nitrogen in the ring which I think is important.

Once I've finished with the 2,3 and 4 methyl analogues I'll decide which ones to look at next so keep adding suggestions here :)

[MFernflower]

I'd figure you could probably make compound 4 by throwing MMV0006357 into a vial with methyl iodide and MeCN and maybe some heating but I've been wrong before

I might worry about quaternization of the two nitrogenous ring systems but I defer to @qsimpson

[PaulMcKeatingSevenoaks]

Are we thinking that potential derivatives of compound 2 might be worth our students exploring?

Very willing...

[MFernflower]

The para fluorinated compound (compound 3 on my sheet) might not be a bad choice since the starting material P-fluoroacetophenone is cheap @PaulMcKeatingSevenoaks

[kym834]

@MFernflower and @PaulMcKeatingSevenoaks We'e already made the p-fluoro. I just realised that in my comment above it has automated it to ascending numbers so it had 2 when it should be 3! I've edited so that now it to correct. Just to clarify: (1) Also on John's list - not novel (2) novel (3) We've made this one already (MYOS_00185_00_01) - it was novel (4) novel (5) novel

[MFernflower]

@kym834 Another possible idea is to do the classic methyl ---> trifluoromethyl swap on the aminopyridine portion of the molecule:

[PaulMcKeatingSevenoaks]

OK. We can have a look and a think. Might be expensive for us to get (enough of) suitable starting materials that are safe / allowed in school! #4 #5 are so similar it's very tempting to try to find a route to them.

@kym834 @andybishopsevenoaks

[kym834]

@PaulMcKeatingSevenoaks @AndyBishopSevenoaks Let us know. If there are some that are safe but a little expensive, we might be able to easily make them in the lab and send them to you :)

As we haven't started exploring compound 2, which Andy mentioned above, there is heaps of flexibility such that hopefully you find some that are suitable for in school.

[PaulMcKeatingSevenoaks]

@kym834 @andybishopsevenoaks

We've been considering the thiazole

and substituting at the amine with a halogenated (chloro or bromo) pyridine derivative like:

Then a substitution at least to put the ethyl group on the amine (compound #5) - but not sure about using methyliodide in school.

Or a different pyridine derivative to work towards the methoxy (compound #2).

So then it's just the apparatus to physically do it and a suitable solvent!!