Hi there, just watched Tom's Google Tech Talk and thought I'd have look around.
I worked on a project that used sulfonamides and we found the tetrazole was a good bioisostere. It may reduce the solubility as you'd have 3 aromatics in conjugation but it's a option if you want some variety or to explore how the sulfonamide contributes to binding.
Craig
Hi Matin,
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.
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. DOI: 10.1021/op300343q
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.
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.
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.
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?
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).
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.
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...
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.
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.
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.
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.
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?
Hi there, just watched Tom's Google Tech Talk and thought I'd have look around.
I worked on a project that used sulfonamides and we found the tetrazole was a good bioisostere. It may reduce the solubility as you'd have 3 aromatics in conjugation but it's a option if you want some variety or to explore how the sulfonamide contributes to binding.
Craig
Recording: http://www.youtube.com/watch?v=5XCfDPBxkcg
Minutes and Discussion: http://www.thesynapticleap.org/node/441
Hi Matin,
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.
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.
DOI: 10.1021/op300343q
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.
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.
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.
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?
I am no pyrrole expert, but I was wondering could your alcohol and other alkylated products be decomposing along these lines?
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).
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.
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...
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.
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.
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.
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.
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?