MFernflower
commented
3 years ago @danaklug Interesting paper - https://pubs.rsc.org/en/content/articlelanding/2020/gc/d0gc02722g#!divAbstract
Closed mattodd closed 3 years ago
MFernflower
commented
3 years ago @danaklug Interesting paper - https://pubs.rsc.org/en/content/articlelanding/2020/gc/d0gc02722g#!divAbstract
Meeting June 18th 2021 at 2pm UK time at https://ucl.zoom.us/j/92800004715. This page follows on from #74 and #75.
Recording is here.
On the call: @mattodd @danaklug @edwintse @flavioemery @Giada-chem @MFernflower Jyoti Chauhan, Bruno Quiroga
a) Potency
Screen has been completed at #76. Discussion points:
Controls look fine.
Metabolite inactive (enhances importance of the clearance rate, since going to inactive).
Benzimidazoles are inactive, so don't need to pursue. Can still go in paper, obviously.
N-linked, N-methylated compounds: one (OSA1000) with excellent potency, likely to need a repeat eval. Based on previous data from @loriferrins the ideal alkyl group on the N is bigger/longer, rather than methyl. @MFernflower suggested removing the ring OMe. Action: search to see whether @loriferrins NEU team have analogs of OSA1000 already, to explore that core a little more.
Is there a point in the inactive (vs gram-negative bacteria) benzimidazoles going into the DNDi assay? @edwintse tasked with liaising with @loriferrins to set this up if the structures are non-duplicative.
@loriferrins and team have started the N-alkylation chemistry in #68 with Jyoti Chauhan (NEU, postdoc) and Bruno Quiroga (NEU, undergrad). Jyoti gave a short presentation: aiming for isobutyl and tert-butyl on the N. Getting some bis-alkylation byproducts, and trying to resolve this. Could use alternative alkylating agents, or reductive alkylation. Possible for alkylation on alternative sites (e.g. pyridine) too. Attempts are continuing. Post slides below.
@flavioemery pursuing the "homology series" shown here. Aiming for 5-6 compounds to be sent to UCL.
@Giada-chem is synthesising the key intermediate for her series exploring the aromatic amines in the northwest position (Suzuki then Buchwald-Hartwig), shown in #66.
@danaklug doing one-pots shown in #66. Using different heterocyclic aldehydes. Doing purifications. Aim to explore replacing the 2-pyridyl. Expect to need to N-alkylate. There is some activity already - if they had proven to be inactive, these one-pots would be less interesting, but they look OK. @flavioemery mentioned that most formylpyrroles are very reactive and may need to be handled carefully e.g. as dilute solution.
Jyoti asked about removing the 5-membered ring in the east of the molecule where the metabolism is happening. @danaklug was making attempts at doing that chemistry in (where are the structures shown?). Would also remove the metabolic liability.
b) Parallel DNDI assay Compounds have arrived in DNDI lab. Results on way?
c) Human Cytotox Discussion last time following update by Alex. There is tox observed for all compounds. It is not yet a red light for the series. There is no "gold standard" cytotox model for antibiotic dev. It is possible we could look at red blood cell haemolysis. It might be interesting to try to establish why tox is happening, to learn more about potential MOA. @mattodd to forward issue re apoptosis to Alex V, who may investigate a possible DNA binding mechanism. Alex will complete the table she presented, to obtain a publishable data set. Interim conclusion: we cautiously continue. We have funding for one more in vivo PK analysis from Monash.
Synthetic Chemistry Updates described above.
in vitro PK Metabolite successfully purified and identified (@edwintse data deposited where?), and assessed for potency (inactive). This needs to be installed on the wiki, then this item can be removed.
Community updates a) Newsletters. Third newsletter needs to be written by @mattodd. Focus on S2.
Mechanism of Action @mattodd has reached out to Lee Graves to ask if MoA experiments can resume.
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). <-- @drc007 can we remove this, or are further actions needed?
Previous guest appearance by Isabelle Giraud who described, with @drc007, how to auto-import the OSA Master List into Datawarrior. Action: install on wiki a simple how-to for how to visualize OSA molecules, and filter to this series.
AOB
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