OpenSourceMalaria:GSK Amino-thienopyrimidine Series

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Contents

GSK Thienopyrimidine Series

Introduction

Preamble

This page describes the current status of one of three antimalarial drug candidates being investigated by the Todd laboratory at the University of Sydney, using an open source approach. A more thorough discussion of this approach may be found at: OSDDMalaria:Story so far. In short, this is a drug discovery project which is to be carried out using the philosophies of open source science, which will require adherance to the six laws of open source science:

1) First law: All data are open and all ideas are shared 2) Second Law: Anyone can take part at any level of the project 3) Third Law: There will be no patents 4) Fourth Law: Suggestions are the best form of criticism 5) Fifth Law: Public discussion is much more valuable than private email 6) Sixth Law: The project is bigger than, and is not owned by, any given lab. The aim is to find a good drug for malaria, by whatever means, as quickly as possible.

All experimental work in this project is described on an open lab book; status updates for the project are posted on the synaptic leap; and some discussions take place on Google+ and Twitter where convinient. All are publicly viewable and, once a member of the relevant platforms (eg: Facebook), anyone may discuss the project in the open. All discussion, suggestions, complaints and queries are welcome. If a more private avenue for discussion is required, several personal contact points are to be found at User:Jim Cronshaw and 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:

GSK Thienopyrimidine Series: TCMDC 135294
GSK Thienopyrimidine Series: TCMDC 135294

| 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

The proposed synthesis for this compound is below:

Proposed synthesis for the above compound
Proposed synthesis for the above compound

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.

Thiophene Starting Material Synthesis

Additionally, the thiophene available from Sigma Aldrich for $159/10g can be made from the following synthesis.

Proposed synthesis for the above compound
Proposed synthesis for the above compound

Analogues

TCMDC 135294 is part of a series with one other member, | TCMDC 135255, shown below:

TCMDC 135255
TCMDC 135255

| 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, feel free to contact me: Jim Cronshaw

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

Image:NewThienosFromEnamineR.png Image:NewThienosFromEnamine1R.png

Synthesis of new analogues

This image presents some strategies for assessing SAR's on the aminothienopyrimidine core.

Image:Variability.png

References

| Barker, J. M.; Huddleston, P. R.; Wood, M. L., A RAPID CONVERSION OF 3-OXOTHIOLANES INTO 3-AMINOTHIOPHENES. Synthetic Communications 2002, 32 (16), 2565-2568.

| Baykal, A. T.; Kakalis, L.; Jordan, F., Electronic and nuclear magnetic resonance spectroscopic features of the 1 ',4 '-iminopyrimidine tautomeric form of thiamin diphosphate, a novel intermediate on enzymes requiring this coenzyme. Biochemistry 2006, 45 (24), 7522-7528.

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).

| Diel, B. N.; Han, M. C.; Kole, P. L.; Boaz, D. B., Synthesis of (C-13(6)-Ring-(U))-(+/-)-benzo(a)pyrene metabolites from (C-13(6)-Ring-(U))benzene. Journal of Labelled Compounds & Radiopharmaceuticals 2007, 50 (5-6), 551-553.

| F, Duus., A study of the tautomerism of 2- and 4-ethoxycarbonylthiolan-3-ones implicating stereochemical effects of ring-substitution. Tetrahedron 1981, 37 (15), 2633-2640.

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.

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