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Meeting Recording and Minutes
21 March 2013 - 2:57am
Commenting on: OSDDMalaria Agenda, Feb 26th 2013
Minutes and Discussion: http://www.thesynapticleap.org/node/441
SOLVED-onamides - perhaps!
28 February 2013 - 5:44pm
Commenting on: Sulfonamides
As per my tweet/lab book here, it looks like I've got these to chlorinate cleanly with oxalyl chloride - so I should ask, do we want both compounds you've shown here? E.g. the ones based on glycine (NH) and sarcosine (NMe). I can make both here relatively easily, as I have a bit more of the sulfonic acid lying around.
25 February 2013 - 12:42am
Commenting on: API Form & Drug product research
If a DKR version of this process could be developed (or even using it as it is) there would be no waste in producing (R)-Praziquantel.
SAR refresh comment
12 February 2013 - 1:23pm
Sounds fine but would still suggest in the gentlest possible way that it's imprudent to assume 1) or b) untill you accumulate a substancial collated data set that defines this variance statistically. The pharmacophore work is also dependant on this as you know.
SAR refresh - good idea
9 February 2013 - 9:33pm
Sure - I'm in Sydney this week. I'll get together with the local team and get this posted. I think the % inhibition figures are mostly for low-actives, though I do think we are waiting on a very early set of numbers from the Ralph group if memory serves. We're expecting biological data for the latest set of compounds in a week or so from Vicky's group, and that may inform our discussion, so we should wait till then - if the latest compounds (near neighbour thiazolidinone set) are good-looking (since we've made them more soluble) then they become of greater interest. Let'd revisit when we know. I'm not too concerned about resubmitting IC50s, but it's something we could do if there's a consensus that this is necessary. The reasons are: 1) early figures for the first round carried out by several labs were quite consistent, meaning spatial variance (another form of temporal variance..) is low, and b) the labs doing the evaluation have these assays running all the time, meaning there is unlikely to be a lot of variability in set-up. And degradation of compounds over time could presumbly be assessed by NMR. But very happy to vote on it.
8 February 2013 - 1:06pm
Inspired by being featured with the gang in Chemistry World and PubChem pushing towards 50 mill, I would like to catch up with any searching you might think useful. Can I request an SAR update/refresh of say the "top ten" ? Just a simple table would do of SMILES, InChIKey and IC50s. If you have any outstanding "% inhbition" figures I'd suggest getting IC50s done so they are comparable. I'd also suggest re-submiting at least your top-five for IC50s, so that time-separated duplicates will provide some idea of variance.
6 January 2013 - 3:18pm
The use of sulfur trioxide pyridine is looking promising. I was wondering have you considered forming the sulfonamoyl chloride and treating this with the pyrrole? Maybe using pyridine or 4-DMAP as a nucleophilic catalyst?
So what’s going wrong?
3 January 2013 - 10:31pm
Commenting on: Williamson's attempted ether synthesis
I am no pyrrole expert, but I was wondering could your alcohol and other alkylated products be decomposing along these lines?
3 January 2013 - 12:31am
3 January 2013 - 12:30am
3 January 2013 - 12:26am
Context of late stage gametocyte assay to whole project
15 December 2012 - 2:21am
Commenting on: Late Stage Gametocyte Assay for Arylpyrroles
To see the relevance of this assay to the overall results for the arylpyrroles, see the Story So Far summary. The data provide a clear delineator between original GSK arylpyrroles and the near neighbour set (the iminothiazolidinones).
Update on the near neighbour thread...
15 December 2012 - 1:44am
Commenting on: Known Near Neighbours of Initial Tres Cantos Leads
The near neighbours were to some extent included in the project, though not all of the structures included above have, to date, been included. See the overall Story so Far for the current situation. Some of these near neighbours were very insoluble, though they did show significant late stage gametocyte activity. The compounds remain of interest.
Yes - triazole is a simple target
13 December 2012 - 10:05pm
That's right - it's a "well, why not" shot. The S/Ms are simple and the chemistry should be fine. Would be great if you wanted to take a pop at it. See my comment below about the lab book though - important to share the data.
Note that anything you make in the UK can be screened for activity there/in Europe vs. controls - no need to mail to Aus...
13 December 2012 - 10:03pm
That'd be great. Happy to use the online lab notebook to record your data? Even repeats of reactions are useful, but certainly when you get to new/trial things. You could use Matin's, or start your own. Any of the team can help with that. The chlorosulfation seems to be going, but since we don't isolate the intermediate, or at least characterise it properly, it's not clear what's going wrong.
13 December 2012 - 12:02pm
I've dropped Matin a comment as the sulfonamides look interesting: We're playing with chlorosulfonation here in Edinburgh. Given that I'm about 12,000 miles away I'll just make some of the fluoroaryl-pyrrole SM myself this weekend.
Nice, low-priority shot
13 December 2012 - 11:54am
I could tinker with this, since it seems at the moment that my time/resources are very limited. If I'm reading the context right, it would be a low-priority punt on something interesting and it looks reasonably simple - azido-aromatic, propargyl alcohol and 2-hydroxyacetamide give or take some protecting groups? I'd also be able to cut my teeth on the blogging side of things etc.
11 December 2012 - 9:48am
This is a good collation but I suggest you consolidate the SAR in more scope and detail before investing in major analoging efforts. In particular you need the assay data nailed down as best as possible. You at least should have the IC50s repeated across these series, ideally as a single batch, with technical error determinations by replicates and internal controls. Note at the moment you can't compare the apples of % inhbition at fixed conc. with the pears of IC50 curves that probably have different shapes.
10 December 2012 - 12:12pm
Well, one of the nice things here is that you've already done the commercial assessment, so we're left with what can we make and what can we otherwise acquire?
Synthesis is governed by how much time you have - I think you want to try all permutations of the coupling partners you have to hand, plus phenylboronic acid as a control. Wasn't there a urea you were looking at? Other boronates in the building?
Then can you try a SciFinder (etc) search for analogs that are not commercial, so see if anyone is making compounds like this? Perhaps you've done this recently?
We can order the two
4 December 2012 - 12:12am
We can order the two compounds for 234 (US$), they are from separate suppliers and so the postage costs as much as the compounds. Should we have a think about other molecules we might want to order alongside?