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Palladium Couplings – Inside Living Cells

I only have time for a short post this morning, but here’s a technique that I had never thought about: palladium-catalyzed drug synthesis inside the target cells. There have been a few reports of activation of prodrugs via intracellular Pd catalysis (such as this one), but it seems like a real challenge to get both components and a bio-compatible Pd catalyst into the cell at the same time and place. The earliest report in this field that I know of is from the same Edinburgh group that’s reporting this new work.

They’ve produced Pd-loaded microspheres and conjugated those to cRGD, a tumor-targeting peptide (via integrin receptors) that increases cellular uptake of the microspheres. (It’s been used for similar purposes for many other drugs and nanotech species, as those who follow that literature will know). The catalyst was internalized quite readily in the cell lines of interest, and was decreased by the appropriate competition experiments, so the first step worked as planned.

A test with a Pd-catalyzed deprotection to give a fluorescent species also worked, so the next step was to try the two reactions shown at right: deprotection of 5-fluorouracil and coupling to produce the kinase inhibitor PP-121. These reactions both took place under buffer conditions, and in the presences of  U87-MG, none of the precursors showed cytotoxicity on their own, alone or in combination (nor did the Pd microspheres). In the key experiment, the cells were exposed to the Pd-loaded microspheres, washed to remove any extracellular Pd, and then exposed to the compounds of interest. As you can see in the figure, cell viability did indeed decrease, and it decreased even more when the cells were exposed to both sets of precursors at once (as well they might).

I would still wonder if any Pd leached out into the surrounding media, though, especially as some cells began to die off, and whether some of the cytotoxic compounds were formed extracelluarly. The fluorescent experiment, though did indicate that the Pd reactions can and do take place in the appropriate cell compartments, so it’s reasonable to assume that this is happening with the drug cases as well. A further test of this technique might involve producing a therapeutic compound that is known to have such poor cell penetration that it’s inactive in such assays, but which could be broken down into cell-penetrant precursors. I have no candidate in mind, off the top of my head, but it would be a dramatic demonstration, and also point to a practical use of the technique.

13 comments on “Palladium Couplings – Inside Living Cells”

  1. anon says:

    I like this one too:
    “In Vivo Gold Complex Catalysis within LiveMice”
    http://onlinelibrary.wiley.com/doi/10.1002/anie.201610273/epdf

  2. 🍆 says:

    I remember seeing a photoredox reaction done in rats but I’m having a hard time remembering the details

  3. Antibac says:

    Let’s give credit where credit is due…

    The first real example (although the metal was Ru instead of Pd), was carried out by none other than Craig (Holywood) Streu back in 2006.

    Streu, C., and Meggers, E. (2006) Ruthenium-Induced Allylcarbamate Cleavage in Living Cells. Angew. Chem., Int. Ed. 45, 5645−5648.

  4. Major advance says:

    What if we could get cells to make natural products using nothing but visible light and CO2 for feedstock? No one steal my idea I’m sending it to NIH.

    1. John Wayne says:

      CO2? That will never work. My proposal uses syngas, a way more useful starting material.

      1. Gacy says:

        It’s what substrates crave

  5. Little buddy says:

    Im glad at least some chemists care about biology.

    “I dont care about ensymes”– Phil Baran, sardonically said in a graduate student lecture given to biology students at TSRI.

    1. BK says:

      I’m certain palau’amine will not be used in humans anytime soon as well…

    2. Bagger Vance says:

      “Go with your strengths”

  6. Rule (of 5) Breaker says:

    …and here I am using flasks to run reactions like a sucker.

  7. gippgig says:

    I wonder if cisplatin, or the cisplatin-DNA adduct, could act as an effective catalyst.

    1. Anonymous says:

      I don’t think that Pt is as common in coupling reactions as is Pd. Then, since Cl2Pt(NH3)2 is fairly easy to come by for non-medical use, and it has been extensively studied for decades, I think people would have an idea of the a priori potential for its use in these coupling reactions. And it would be among the first things to test in the synthesis lab before buying or making much more complicated and expensive stuff. THEN, since it would be fairly easy to try your suggestion (or to add as a control), I say go for it, as long as it isn’t too expensive.

  8. kjk says:

    Start with a low-toxicity chemo to wipe out most of the tumor, and then hit the stragglers with a sledgehammer? Once the primary tumor is gone, the stragglers have much less mass to spill out of the cell.

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