Metal scavenging

 

Can biological assay results be trusted if your sample is contaminated with Pd?

Jun 27, 2022 8:14:09 AM / by Tim Jones

I recently read an interesting paper from Graham Wynne and his many collaborators at the University of Oxford and CEMAS describing just how much residual palladium (Pd) is making its way through the standard purification processes employed by medicinal chemists.

As a former medicinal chemist, I’ll hold my hands up here and admit that this was not something I ever really considered, despite having served some time as a process chemist and understanding some of the disdain often jokingly referenced when first critiquing the “Medchem route”.

The goal during early – stage discovery is to introduce diversity late in the synthesis and therefore libraries utilizing Pd chemistry are very attractive and can leverage the whole range of Pd-Palladium catalysed cross-coupling reactions, hydrogenations or carbonylations. So what’s the problem with this approach? Well, as referenced in the paper, metal impurities can interfere with biological assays and lead to either inactive targets being erroneously pursued, or active hits being discounted. A big waste of time basically.

The paper goes on to highlight that the usual techniques of flash or HPLC purification of crude mixtures containing Pd impurities, do NOT effectively remove the metal to an acceptable level (below 100pm). However, a quick treatment with a metal scavenger, such as ISOLUTE® Si-TMT, post flash purification will reduce Pd levels to below 100 ppm in 100 % of the examples, and to below 50 ppm in 87 % of trials.

The findings of this study lead the authors to suggest five considerations that should be made when using Pd chemistry in late-stage synthesis:

1. Pd scavenging reagents and procedures should be used following column chromatography purification and before the reaction product is used in a subsequent process or assay.

2. Quantification of residual palladium should be undertaken more routinely to verify the lack of metal contamination, in particular, for compounds used to make important project decisions. We suggest that the appropriate maximum level of palladium in reaction products destined for testing in biological assays of any type should be 100 ppm.

3. Consideration should be given to the use of reagent combinations or catalysts with potential for leaving lower impurity levels, such as encapsulated metals or catalysts with high turnover numbers (TONs).

4. Evidence that residual Pd levels have been quantified and shown to be within acceptable limits should be provided for any compounds that have been synthesized using a reaction sequence where Pd-catalysed reactions have been used in the final or penultimate step and for which biological screening data are being generated.

5. Journal editors should consider requiring authors to either provide appropriate trace-metal analytical data for compounds where it may impact the study as a whole or acknowledge that they have considered the potential impact of trace residues and deem it not to be a relevant factor for their work. (Many approving authorities for late stage pharmaceuticals care very much about the amount of trace metal impurities in products). Authors and readers of patent applications should similarly be aware of the potential impact of trace-metal impurities, including Pd, because their use is also prolific therein.

These are all great points to consider and point one is clearly a problem that Biotage work up products can address. Medicinal chemists regularly use some form of polymer supported reagent, packed into an SPE column for free basing or concentrating a product after reverse phase purification. Why not make the treatment of the purified product with a metal scavenging resin a regular part of the workflow?

Learn more about the scavengers used in this blog post, just follow the link below!

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References: Chatzopoulou, Maria & Madden, Katrina & Bromhead, Liam & Greaves, Christopher & Cogswell, Thomas & Da Silva Pinto, Solange & Galan, Sebastien & Georgiou, Irene & Kennedy, Matthew & Kennett, Alice & Apps, Geraint & Russell, Angela & Wynne, Graham. (2022). Pilot Study to Quantify Palladium Impurities in Lead-like Compounds Following Commonly Used Purification Techniques. ACS Medicinal Chemistry Letters. 13. 10.1021/acsmedchemlett.1c00638.

Topics: palladium, screening, Oxford, Si-TMT, biological assays, Pd, medchem, impurities, Wynne, CEMAS

Tim Jones

Written by Tim Jones

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