OpenSourceMalaria:GSK Amino-thienopyrimidine Series: Difference between revisions
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===Preamble=== | ===Preamble=== | ||
This page describes | This page describes a sub-project of the Open Source Drug Discovery for Malaria consortium. Background to how the project works can be found on the page that describes the first branch of the project: [[OSDDMalaria:Story so far]]. | ||
All experimental work in this branch of the project is described on an [http://malaria.ourexperiment.org/aminotpseries open lab book]; status updates for the project are posted on The Synaptic Leap website, for example [http://www.thesynapticleap.org/node/343 here]; and some discussions take place on the consortium's [https://plus.google.com/u/0/114702323662314783325/posts Google+] page and [http://twitter.com/osddmalaria Twitter] feed, which may be followed. All contributions are welcome, ideally in the public domain, though existing members may be contacted offline if absolutely necessary e.g. at [[User:Matthew Todd]]. | |||
All experimental work in this project is described on an [http://malaria.ourexperiment.org/aminotpseries open lab book]; status updates for the project are posted on [http://www.thesynapticleap.org/node/343 | |||
===The Origin of this Antimalarial Drug Candidate and Our Approach=== | ===The Origin of this Antimalarial Drug Candidate and Our Approach=== | ||
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---- | ---- | ||
=== | ===Analogs=== | ||
TCMDC 135294 is part of a series with one other member, [https://www.ebi.ac.uk/chemblntd/compound/results/9373/1/molweight/asc/mini | TCMDC 135255], shown below: | TCMDC 135294 is part of a series with one other member, [https://www.ebi.ac.uk/chemblntd/compound/results/9373/1/molweight/asc/mini | TCMDC 135255], shown below: | ||
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InChI=1S/C19H15N5OS/c20-18-17-15(21-11-22-18)10-16(26-17)12-5-4-8-14(9-12)24-19(25)23-13-6-2-1-3-7-13/h1-11H,(H2,20,21,22)(H2,23,24,25) | InChI=1S/C19H15N5OS/c20-18-17-15(21-11-22-18)10-16(26-17)12-5-4-8-14(9-12)24-19(25)23-13-6-2-1-3-7-13/h1-11H,(H2,20,21,22)(H2,23,24,25) | ||
A list of commercially available compounds with similar structures to the one I'm trying to synthesise were identified with much help from Iain Wallace. If you're reading this and are interested in donating samples of these compounds, | A list of commercially available compounds with similar structures to the one I'm trying to synthesise were identified with much help from Iain Wallace. If you're reading this and are interested in donating samples of these compounds, please contact someone on the project. | ||
Misc possible industry sources of compounds: | |||
*[http://pubs.acs.org/doi/abs/10.1021/jm0510979 Boehringer thienopyridines]. [https://plus.google.com/u/0/b/114702323662314783325/114702323662314783325/posts/K5SqH5M9RcN Contacted]. Need other way in! | |||
*[http://www.tuberculosisjournal.com/article/S1472-9792(09)00051-1/abstract Southern Research Institute]. Contacted April 1 2013. Replied April 2 to say they did not have the compounds available. | |||
* | |||
Iain Wallace created a cytoscape file which details purchaseable compounds related to the two series that I am trying to make. The file can be found [http://malaria.ourexperiment.org/in_silico_prediction/2962/Purchaseable_chemical_space_around_TCMDC_135294_TCMDC_134395.html here], and Cytoscape can be downloaded for free [http://www.cytoscape.org/ here] (one will need to activate the chemviz plugin, which can be activated from within Cytoscape). The results of this work, in the form of a list of purchaseable compounds, can be found [http://www.emolecules.com/cgi-bin/rene/visitor.cgi?h=57e58914e7d2d8d6e5ddefe72863813331479a3c7b9b5974 here] | Iain Wallace created a cytoscape file which details purchaseable compounds related to the two series that I am trying to make. The file can be found [http://malaria.ourexperiment.org/in_silico_prediction/2962/Purchaseable_chemical_space_around_TCMDC_135294_TCMDC_134395.html here], and Cytoscape can be downloaded for free [http://www.cytoscape.org/ here] (one will need to activate the chemviz plugin, which can be activated from within Cytoscape). The results of this work, in the form of a list of purchaseable compounds, can be found [http://www.emolecules.com/cgi-bin/rene/visitor.cgi?h=57e58914e7d2d8d6e5ddefe72863813331479a3c7b9b5974 here] |
Revision as of 21:25, 1 April 2013
GSK Thienopyrimidine Series
Introduction
Preamble
This page describes a sub-project of the Open Source Drug Discovery for Malaria consortium. Background to how the project works can be found on the page that describes the first branch of the project: OSDDMalaria:Story so far.
All experimental work in this branch of the project is described on an open lab book; status updates for the project are posted on The Synaptic Leap website, for example here; and some discussions take place on the consortium's Google+ page and Twitter feed, which may be followed. All contributions are welcome, ideally in the public domain, though existing members may be contacted offline if absolutely necessary e.g. at User:Matthew Todd.
The Origin of this Antimalarial Drug Candidate and Our Approach
In 2010, GlaxoSmithKline (GSK) released chemical and biological data pertaining to some 13,500 compounds that displayed potent antimalarial activity in vitro (Nature paper). Medicinal chemists at the Medicines for Malaria Venture (MMV) identified two compounds present in this dataset which they believed to be excellent antimalarial drug candidates. These two compounds had the combination of a drug-like profile (polar, low molecular weight, amenable to structural variation), high poteny, low cytotoxicity, no known intellectual property issues, and to the best of their knowledge they were not the subject of antimalarial research anywhere else in the world.
This page details the development of one of these two compounds: the so-called "aminothienopyrimidine" compound. The MMV has developed a set of compound progression criteria and we will use these to inform our drug discovery efforts. The high throughput nature of the GSK screen generates the possibility of an erroneous hit, and thus the first step mandated by the MMV criteria is to compensate for this by evaluating the re-synthesised hit in vitro, to confirm antimalarial activity. The synthesis of analogues is also desired, so we may obtain a preliminary structure-activity relationship (SAR) of the compound.
Known Data
The first structure in this series, | TCMDC 135294, has the following structure:
| ChEMBL 581088 link.
| ChemSpider link.
SMILES: Nc1ncnc2cc(sc12)c3cccc(c3)S(=O)(=O)N
PubChem: [1]
InChI=1S/C12H10N4O2S2/c13-12-11-9(15-6-16-12)5-10(19-11)7-2-1-3-8(4-7)20(14,17)18/h1-6H,(H2,13,15,16)(H2,14,17,18)
Of all structures on the GSKTCAMS that have the aminothienopyrimidine moiety, this molecule has the most attractive ALogP value and the lowest molecular weight (search performed by Jim Cronshaw 5/8/12 on ChemblNTD).
Experimental Work
Synthesis
A proposed synthesis for this hit compound was drawn up, and is shown below:
It was envisioned that the hit compound could be generated using this convergent strategy. The thienopyrimidine scaffold was to be synthesised from the commercially available formamide and methyl 3-aminothiophene-2-carboxylate. The use of trivial heterocyclic chemistry was thought to be sufficient for the introduction of an amine at the 4-position of this scaffold, before the substitution at the 6-position by a halogen was to proceed using lithiation/halogenation. Meanwhile, the benzenesulfonamide moiety was to be generated by transforming the commercially available 3-bromobenzenesulfonamide into the relevant boronate ester. The thienopyrimidine scaffold (A) and benzenesulfonamide boronate ester (B) would then be united using a Suzuki coupling.
The results of this synthetic effort are described hereinafter.
Construction of the thienopyrimidine scaffold
It was found that the desired ring closure of formamide and methyl 3-aminothiophene-2-carboxylate could not proceed in the conditions tested. This ring closure was instead carried out using formic acid and ammonium formate in lieu of formamide. Steps 2 and 3 proceeded without controversy to give the aminothienopyrimidine scaffold.
Completion of the halogenated aminothienopyrimidine scaffold
Substitution at the 6-position of this aminothienopyrimidine scaffold could not - in our experience - be carried out. Protection of the free amine at the 4-position was found to be a successful strategy for introducing the halogen at the 6-position, however, this method gave low yields. Using the chlorinated thienopyrimidone (X) in a lithiation/halogenation was found to be the most synthetically tractable way of introducing the desired functionality whilst maintaining workable yields (~50%). An amine was introduced at the 4-position using ammonium hydroxide solution in a sealed tube (120 °C).
Alternative Synthetic Strategies
The step that involves n-BuLi would best be avoided, and if a more direct route of arriving at the Suzuki coupling step could be discovered, that would take a potentially dangerous and difficult step out of the synthetic route.
One possibility, involving NIS and an ionic liquid such as 1-Butyl-3-methylimidazolium tetrafluoroborate (which our lab doesn't have, but which is available from Aldrich in catalytic quality from $247/5g), is found below:
[doi:10.1016/j.tetlet.2011.03.010 DOI]
[dx.doi.org/10.1139/V09-125 Here] is another alternative, where the direct iodonation of arenes can be carried out using oxone and NaI. Whether or not this would work in my compound, given selectivity issues, is something that I'll have to investigate.
This paper shows a method of direct halogenation of thiophenes. This uses [Bis(trifluoroacetoxy)iodo]benzene, which we don't have lying around, but which can be bought from Aldrich for $136/10g. The reactivity of thiophenes vs pyrimidines is something I'll have to look into. UPDATE: I've read Clayden et al. (2012, p 727) and I'm informed that pyridine is, generally speaking, terrible at electrophilic aromatic substitution reactions. My understanding is that pyrimidine has the same reactivity as does pyridine, so there shouldn't be any selectivity problems with any of these reactions (a result that was perhaps anticipated by the BuLi reaction proceeding at the alpha position on the thiophene ring in the first place).
--- July 9th.
The BuLi reactions have literature precedent. Heffron (2010) acheives a very similar reaction, albeit with protection of a pyrimidine position (which doesn't seem to be reacting in my case anyway). Snegaroff (2009) uses (TMP)3CdLi to acheive the metallation/iodination. This less harsh base can be used at rt. This author discovered the reagent, so they are probably interested in self promotion. In any case, there is precedent for the lithium metallation proceeding.
--- July 18th
A post on ChemForums suggested that the sulfur might react with the iodine. According to Joule & Mills (p. 234) this won't happen. "The five membered heterocycles do not react with electrophiles at the heteroatom." and "...in pyrrole, electrophilic addition at the nitroge would lead to a substantial loss of resonance stabilisation - the molecule would be converted into a cyclic butadiene, with an attached nitrogen carrying a positive charge localised on that nitrogen atom.
--- August 26
A search performed on SciFinder at 8:57pm revealed that the meta sulfonamide is NOT novel.
Generation of the Boronate Ester
Initially, the synthesis of a boronic acid was desired however, this could not be generated on these substrates. Instead, boronate esters were generated for the para- and meta-substituted boronate esters of interest.
Thiophene Starting Material Synthesis
Additionally, the thiophene available from Sigma Aldrich for $159/10g can be made from the following synthesis.
Analogs
TCMDC 135294 is part of a series with one other member, | TCMDC 135255, shown below:
| ChEMBL639249 link.
| ChemSpider link.
SMILES: Nc1ncnc2cc(sc12)c3cccc(NC(=O)Nc4ccccc4)c3
InChI=1S/C19H15N5OS/c20-18-17-15(21-11-22-18)10-16(26-17)12-5-4-8-14(9-12)24-19(25)23-13-6-2-1-3-7-13/h1-11H,(H2,20,21,22)(H2,23,24,25)
A list of commercially available compounds with similar structures to the one I'm trying to synthesise were identified with much help from Iain Wallace. If you're reading this and are interested in donating samples of these compounds, please contact someone on the project.
Misc possible industry sources of compounds:
- Boehringer thienopyridines. Contacted. Need other way in!
- Southern Research Institute. Contacted April 1 2013. Replied April 2 to say they did not have the compounds available.
Iain Wallace created a cytoscape file which details purchaseable compounds related to the two series that I am trying to make. The file can be found here, and Cytoscape can be downloaded for free here (one will need to activate the chemviz plugin, which can be activated from within Cytoscape). The results of this work, in the form of a list of purchaseable compounds, can be found here
A list of the above compounds in .csv format, with InChi, InChiKey, SMILES and eMolecules identifiers, can be found here.
These compounds, and relevant data, are shown below:
OLD DATA NOW IRRELEVANT. REFER TO NEW DATA BELOW:
Two compounds have since become unavailable from Enamine. These are commercially available but with a less strict similarity search on emolecules. http://www.emolecules.com/cgi-bin/rene/visitor.cgi?h=c22c97319d83c434da71f7f53149d7d2aaf0fe3014125ab4
Synthesis of new analogues
This image presents some strategies for assessing SAR's on the aminothienopyrimidine core.
References
Brown, G. B.; Baker, B. R.; Bernstein, S.; Safir, S. R., BIOTIN. II. 3,4-trans-DIAMINOTHIOPHANE. The Journal of Organic Chemistry 1947, 12 (1), 155-159.
Castenado, G.; Dotson, J.; Goldsmith, R.; Gunzo, J.; Heffron, T.; Mathieu, S.; Oliveo, A.; Staben, S.; Sutherlin, D.P.; Tsui, V.; Wang, S.; Zhu, B.; Bayliss, T.; Chuckowree, I.; Folkes, A.; Wan, N.C. (Genentech, Inc., USA; Piramed Limited). Thienopyrimidine and furopyrimidine derivatives as phosphoinositide 3-kinase inhibitor and their preparation, pharmaceutical compositions and use in the treatment of cancer. World Intellectual Property Organisation 2008073785 A2, 2008; SciFinder Scholar AN 2008:735944 (accessed 2/2/2012).
Son, J.B.; Jung, S. H.; Choi, W.I.; Jung, Y.H.; Choi, J.Y.; Song, J.Y.; Lee, K.H.; Lee, J.C.; Kim, E.Y.; Ahn, Y.G.; Kim, M.S.; Choi, HG.; Sim, T.B.; Ham, Y.J.; Park, D.; Kim, H.; Kim, D. (Hanmi Holdings Co., Ltd., S. Korea; Korea Institute of Science and Technology; Catholic University Industry Academic Cooperation Foundation). Preparation of thienopyrimidine derivatives for use as protein kinase inhibitors. World Intellectual Property Organisation 2011093684 A2, 2011; SciFinder Scholar AN 2011:971406 (accessed 3/2/2012).
Woodward, R. B.; Eastman, R. H., Tetrahydrothiophene ("Thiophane") Derivatives. J. Am. Chem. Soc. 1946, 68 (11), 2229-2235.