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30th January 2014 @ 05:02

Hi,

This week I am starting my honours project at USyd with Mat Todd and Alice Williamson. I’ll be working on the OSM project, specifically focussing on the Series 4 Triazolopyrazines.

Alice has been looking into synthesising the trifluoromethyl form of the below compound since the difluoro form is particularly difficult to make.

My first task was to search PubChem and ChEMBL for similar compounds to see if anyone else had made any. I plugged MMV669844 into PubChem first, adjusting the similarity down to >80% before obtaining any results. 127 compounds were found (example here), and other than two analogs of the above structure (added by Chris Southan for ease of comparison), they all looked rather different.

I then searched for MMV669844 in ChEMBL, this time adjusting the similarity down to >70% before finding any similar structures. The compound with the highest similarity (79.77% similarity) can be seen here.

This compound was also quite dissimilar, and a scan of the rest of the compounds in both PubChem and ChEMBL didn’t yield any compounds with any greater similarity to MMV669844. Series 4 are therefore quite a unique set of molecules as there are no known compounds at 80% similarity or above. Note that this corroborates with a search that Chris Southan performed back in December 2013 detailed on his blog here.

Joanna

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21st January 2014 @ 22:32

I have conducted a literature search using SciFinder to see if there is an existing straightforward method for the direct carbonylation of chloropyrazine. Finding such a method would be very useful because 6-chloropyrazine-2-carboxylic acid is a key intermediate in the synthesis of series four amides. It will need to be made in large quantities and in such a way that avoids lengthy experimental procedures and the purchase of expensive compounds.

Methods for the synthesis of 6-chloropyrazine-2-carboxylic acid have already been proposed (see Carbonylation Project - Appeal for a collaborator) and are currently being tested.

 The reaction literature search was conducted as follows:

1) I used the ‘Reaction Structure’ search tool in SciFinder.

carbonylation_0.PNG

2) I drew out the carbonylation reaction I wished to investigate.

carbonylation_1.PNG

I then searched using the search type ‘Allow variability only as specified’. As this did not return any results, I then selected ‘Substructure’ instead.

carbonylation_2.PNG

3) This search method was used for the following carbonylation reactions:

Reaction 1.

Reaction 2.

Reaction 3.

All searches for Reactions 1. and 2. returned either no results or unhelpful ones. However, the ‘exact’ and ‘substructure’ searches of Reaction 3. yielded some patented and literature methods which may be of interest:

Possible Methods of Carbonylation from SciFinder Search.docx

In addition, from the answer set result for the ‘exact’ search for Reaction 3., I selected ‘Similar reactions’ and found other experimental procedures of note.

carbonylation_6.PNG

These are summarised here:

Possible Methods of Carbonylation from SciFinder Search_2.docx

Also, I stumbled across another possible reaction pathway in this paper (DOI: 10.1039/C2NJ40791D). The reaction is outlined on p. 400 and is as follows:

This paper, Paladium-catalyzed carbonylation of N-heteroaromatic chloride, may also be of interest.

Linked Posts
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20th January 2014 @ 03:54

Hi,

 

Today I started what will be a six week Summer Scholarship research project at the University of Sydney with Mat Todd and Alice Williamson. I’ll be working on Series Four, with particular focus on the amide compounds.

 

I’m just about to start the fifth and final year of my Bachelor of Science (Adv.)/Bachelor of Arts degree. Aside from the courses I’ve taken as part of my chemistry major, I’ve done some other chemistry research projects. These have included work on metal-organic frameworks for use in carbon dioxide capture materials and an investigation into the physical properties of ionic liquids.

 

Although I do not have a med-chem background, I was drawn to the idea of a project based upon open source research. For me, the idea of a collaborative approach, as opposed to a secretive one in which it is impossible for scientists to share experiences and draw from others’ strengths, was very appealing.

 

I’m very excited to begin.

18th January 2014 @ 23:21

I've just noticed a problem with SMILES that makes we wonder whether we ought to be using it at all for this project. Comments welcome in case I've missed something. (Those with OpenID's or Google accounts can easily login and comment below, or I will link this post on G+ here)

OSM recently had a meeting. Several of the compounds inherited in Series 4 contain a difluoromethyl group, which is a pain to make. We were wondering whether we could synthesize a compound with a trifluoromethyl on it instead, since those should be much easier to make (Action Item is here). It appeared, via quick searches in the meeting, that no such compound had been made. The R = CH3 was known. I therefore needed to make sure that the R = CF3 was not known, and, as a control, to see whether the R = H compound was known.

 Substitution Analysis

I therefore went to the spreadsheet of knowns in this series, which contains SMILES strings for all the compounds. In Chemdraw I constructed the strings for each compound and searched the sheet, coming up a blank. OK, I thought, we should make these compounds. But then I happened to notice that the strings I had generated actually looked *nothing* like the strings in the sheet (compare the red strings below). So I copied one of the strings from the sheet and pasted it into Chemdraw, giving me the structure with circles in the aromatic rings. It seemed to matter how you drew the structure. "Surely not" I laughed, but on quick inspection, I can see that others have known about this for some time. This in itself means we should stop using SMILES for this project. This is astonishing, given how widespread is the use of SMILES in medchem. Not to downplay the inherent difficulty of dealing with variations in how molecules are represented, but we can't live with this kind of ambiguity if we are searching compound databases.

 Smiles comparison

But it gets worse. I copied the SMILES string from the sheet and generated a structure in Chemdraw. I then used that structure to generate a new SMILES string from within Chemdraw, which is different to the original string. It seems as though the nature of the string is dependent on which software is used to generate it? Can that be right?

 Smiles generation

Luckily there are other means. Chris Southan has been at pains to point out the benefits to the consortium of using InChI and InChiKey. As you can see above (blue and green respectively), those perform just fine, and are immune to the way the compound is drawn. Unless there are any objections, shall we move to InChiKey from this point on? Is there a benefit to using SMILES in e.g. similarity searching? 

(comment below or here) Chemdraws of schemes are below if you want to play. Author of this post: Mat Todd.

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14th January 2014 @ 22:26

Hi there! I'm Carmen, an undergraduate student starting work on the OSM project, and will be taking this chance to introduce myself and some of my work. 

I've just finished my second year of B. Sc. (Adv) at the University of Sydney, and will be spending six weeks of my summer break working with Dr Mat Todd and Dr Alice Williamson on a USYD School of Chemistry Summer Scholarship. Currently, my project is to help wrap up Series 3 by synthesising some of the last proposed compounds for testing and assisting with collating the data for the whole series. 

What drew me to the OSM project was both its medical relevance in tackling a major infectious disease, and its unique open source format driving towards that goal. It's an exciting opportunity for both learning about synthetic medicinal chemistry and engaging with the open source structure, where everything I do is accessible for anyone to view or join in. I've done short projects with other research groups, but this is definitely a completely new experience to me, and will likely lead to some better habits and record keeping on my end! 

My past couple of days can be summed up as getting familiar with the lab, learning about the different platforms for communication in the project (and acquiring a whole new bundle of accounts) and writing up proper ELN entries, and of course, some chemistry on the side. 

Anyway, that's enough from me for now. Looking forward to working with everyone! 

Cheers,
Carmen Tran (CT)