Breaking Convention with Sulfoximines – from Lab Oddity to Clinical Candidate

In 2013 a bold decision taken by Lücking et al[1] to incorporate a sulfoximine group into a lead series overcame all of the fundamental issues of the project and lead to the discovery of BAY 1000394 as a clinical CDK inhibitor (Fig 1) – who would have thought it?

The sulfoximine strategy was just one of the concepts that the team from Bayer explored to remove carbonic anhydrase (CA) activity whilst maintaining CDK activity. Fortuitously, the inclusion of the sulfoximine moiety (BAY 1000394) abolished CA activity completely and also improved many of the pharmacokinetic properties of the lead (Fig 1).

Scott 1

Fig 1: Initial HTS hit (1); para-sulfonamide (2); clinical pan-CDK inhibitors ZK304709 and BAY 10003941

Perhaps Lücking et al could have been forgiven for not pursuing sulfoximine approach – when reading this paper I’ve got to ask myself a) “would I have thought of that?”; b) “would I have gone to the trouble of making the sulfoximine and how would I have made it?”; c) “why would I make the sulfoximine?”; d) “are there any sulfoximines on the market today?”………..

  1. “Would I have thought of that?”

Short answer – No.

Long answer – I don’t think I had ever heard of a sulfoximine prior to reading this paper.  If somebody had drawn the structure on my fumehood perhaps I would have been sceptical about the functional group being drug-like.  Reading into the subject, it seems that sulfoximines were discovered recently (in terms of functional groups)[2] and that sulfoximine chemistry has been carried out by a handful of research groups, making it quite a niche area.  Traditional applications of sulfoximines have been centred on their use as chiral auxiliaries and ligands for asymmetric catalysis.2 So maybe it’s not too surprising that I would not have thought of that.

  1. “Would I have gone to the trouble of making the sulfoximine and how would I make it?”

OK, let’s assume I said yes to a).

Sulfoximines are not commercially available so ‘analogue bashing’ might be slow as this is unlikely to be a one-stepper! As sulfoximine chemistry has been (until recently) a niche area, synthetic methods have been limited and have various safety concerns.  One method that forms in-situ hydrazoic acid from the reaction of sodium azide, diphenyl sulfoxide and polyphosphoric acid has triggered an explosion in the past.[3]  If this was the only method then maybe I would not have bothered to make the sulfoximine.

Luckily over the last decade new and safer synthetic strategies have been established and are outlined in a recent paper by Tota et al who also report the first direct synthesis of NH-sulfoximines from sulfides[4] (Fig 2).  Work like this has helped to make sulfoximines more synthetically tractable.

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Fig 2. Strategies and conditions for preparation of sulfoximines from sulfides4

  1. “Why would I make the sulfoximine analogue?”

Fortunately, Lücking has composed a mini-review on sulfoximines[5] and summarises nicely the chemical properties and versatility of the sulfoximine functional group (Fig 3).  The sulfoximine group is asymmetric at sulfur, stable, small, hydrophilic and offers another point of diversification at the nitrogen when compared to the sulfone analogue.5 BAY 1000394 exemplifies why the sulfoximine anlalogue should be made in cases where the sulfonamide analogue is active but requires further iteration to improve PK properties and off-target profile.

Scott 4

Fig 3. Sulfoximines and their chemical versitility5

  1. “Are there any sulfoximine drugs on the market today?

Short answer: No. However, in 2013 the EPA approved the first commercially available insecticide containing the sulfoximine moeity, Sulfoxaflor, to Dow Chemical Corporation.5

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Fig 4. Dow Chemical Corporation’s Sulfoxaflor5

Long answer: Although there are no sulfoximine drugs on the market at the moment, at least three have reached the clinic.  All are kinase inhibitors for the treatment of cancer (Fig 5).5 BAY1143572 (Atuveciclib) is the first highly selective inhibitor of CDK9 to reach the clinic.  Guess what – it is another recent contribution by Lücking and co.[6]

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Fig 5. Clinical sulfoximinesfor the treatment of cancer5

Recently, Sirvent and Lücking have incorporated the sulfoximine group into a range of marketed drugs with promising results in terms of improving PK properties whilst maintaining activity.2 Studies such as those outlined above are helping to raise the profile of sulfoximine chemistry, further developments in synthetic methodology and an increase in commercial sulfoximine building blocks would accelerate the likelihood of seeing the sulfoximine group in a drug molecule.2 Watch this space.

Blog written by Scott Henderson

[1] U. Lücking et al.  ChemMedChem 2013, 8, 1067

[2] J.A Sirvent and U. Lücking;  ChemMedChem 2017, 12, 487

[3] G. Satzinger, P. Stoss, Arzneim.-Forsch. 1970, 20, 1214

[4] A. Tota et al. Chem. Commun., 2017, 53, 348

[5] U. Lücking. Angew. Chem. Int. Ed. 2013, 52, 9399

[6] U. Lücking et al.  ChemMedChem 2017, 12, 1776.


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