OSA Meeting Friday February 19th 2021

[danaklug]

Meeting Feb 5th 2021 at 2pm UK time at https://ucl.zoom.us/j/92800004715. This page follows on from #54 .

Recording is here.

On the call:

1. Screening

a) Potency Results are in for the latest round of screening! Lori's N-alkylated compounds:

Note in the above the structure for 980 is slightly wrong and should have a methoxy.

MSSA Results

b) Human Cytotox Underway in the lab of Andreas Schatzlein. This is also to test the metal-binding potential of the 2-pyridyl system. Updates will be at issue #3 .

Alex to present results!

Some discussion of the tox data for NEU compounds has taken place at #3.

2. Synthetic Chemistry Update from @danaklug

3. in vitro PK Hypha results are in at #50 and will be discussed there. No action currently needed. Update Feb 15th. Sample likely ready March 1st.

4. Community updates a) Newsletters. Second newsletter has been sent and is available here.

5. Mechanism of Action Results received via email and have been shared here. Discussion at #15 and #53.

Action on @edwintse to ensure the data are also installed on Labarchives and linked to Github, to ensure we don't lose such crucial files.

Action: Compile results of literature searches on targets of interest (mquo1, purD) and whether there are biochemical assays available.

6. ELN @danaklug or @edwintse to try again (Action) Labarchives' molecule sketching facility to see if the ELN page is Google-able. i.e. sketch a molecule from OSA using the drawing facility, and check each day to see if it is indexed. ELN pages on which strings have been manually pasted are indexed (@mattodd checked this). Can we do away with manual strings pasting? Separately, @mattodd found that the OSA molecule spreadsheet is not indexed. @drc007 said he would check this out (Action).

AOB

• (ongoing -> install in wiki as a way of working) @mattodd also reminded people to keep an eye on sites such as Enamine, Manifold and Mcule, to check whether any molecules might be commercially available. We should always try to make the challenging molecules in the lab, and buy the others. Action on @edwintse to include this in wiki somewhere logical.

Actions

• [ ] ACTION ITEM: Dana and Ed to look into whether manual strings are still needed in Labarchives, or whether molecule sketching facility is sufficient.
• [ ] ACTION ITEM: Ed to outline on wiki how we should keep in mind searches for commercially-available molecules from various suppliers, in parallel to the in-house synthetic chemistry.
• [ ] ACTION ITEM: Chris to look into why the OSA molecule sheet is not Google-indexed.
• [ ] ACTION ITEM: This meeting to be posted on YouTube.

[MFernflower]

A few possible mods of 983:

LoriMods.zip

[MFernflower]

(Apologies for the repost I ended up merging two posts into one!)

This oxetane is cheap and might make for an interesting N-alkyl side chain! @mattodd @danaklug @loriferrins @drc007

I assume the N-alkyl compounds are make like this???

[MFernflower]

@mattodd @danaklug @loriferrins @drc007 All of the N-alkyl compounds have a para-F - we know that when you removed the para group from compounds that are NOT N-alkylated the potency falls - but we have no data on what happens to N-alkylated compounds! - if we can get away with removing the para group on these N-alkylated compounds we can win back some water solubility. (this requires the commercially unavailable but easy to make phenyl isocyanide)

[lferrins]

@MFernflower I am not sure that I follow what you mean by removing the para-fluoro leading to improved solubility? Do you mean to replace that piece? One could imagine replacing the phenyl with saturated rings etc which may impart improved solubility?

We are currently exploring the inclusion of polar groups in the alkyl chain to improve solubility and stability of the series and I'm more than happy to share these with OSA as we make them!

[MFernflower]

@lferrins I was referring to replacing the para-fluorophenyl moiety with a normal phenyl moiety (that is replacing the F on 983 with H) - since this helps with solubility.

could you share the structures of the polar chain compounds however?

[drc007]

@MFernflower @lferrins Personally I'd focus on introducing an ionisable group onto the alkyl chain, a primary amine might be useful.

[MFernflower]

Carboxylic acid might be possible - ethyl chloroacetate SM is cheap:

@drc007

[lferrins]

(Apologies for the repost I ended up merging two posts into one!)

This oxetane is cheap and might make for an interesting N-alkyl side chain! @mattodd @danaklug @loriferrins @drc007

I assume the N-alkyl compounds are make like this???

Hi @MFernflower we have the oxetane on our target list and will happily share :)

[MFernflower]

@lferrins the oxetane with or without the ring methyl?

[lferrins]

@MFernflower Without the additional methyl. As drawn in the bottom scheme.

[MFernflower]

That would be wonderful as that brominated oxetane is quite costly in the UK!

I asume your alkylations work in a similar fashion to what I posted?