Here’s a paper in J. Med. Chem. that will have you adding another structure to the (long) list of Things to Watch Out For. The authors (from the University of Minnesota) report a screen that returned a series of furylquinolines as hits. Ones first reaction on seeing several structures from the same chemical series hit in a screen might be “Hey! SAR!” or (depending on how many times, or how recently) you’ve been burned, you might say “Hey! What do those things have wrong with them?”
In this case, what these structures have wrong with them is the furan ring. Furan is just not a group that shows up in medicinal chemistry very often, a notable exception in the horde of five-membered ring heterocycles that otherwise permeate the field. It has a reputation (earned) of being metabolically unstable, and as this example shows, it can be unstable to plain old ambient oxygen, much less the oxidative power of metabolic enzymes. The team found this out the hard way, retesting their own stock and then re-ordering commercial material, and finding these both repeating in the assay. But a freshly synthesized batch was inactive, and that’s when you squint at the assay results and go “Oh, crap”. Many of you can probably guess what’s coming next: as the freshly made material sat in DMSO solution, it magically began to pick up increasing activity over time. Ah, yes.
A closer look showed that the furan ring was doing a 4+2 cycloaddition with oxygen, and the resulting intermediate (basically a secondary ozonide) falls apart in various entertaining ways, including Baeyer-Villager chemistry. You get acids, aldehydes, lactams, and more, and some of these are likely Michael acceptors as well. The “SAR” was merely due to everything in the series falling apart into broadly similar piles of rubble. You’d have to figure that there are other substituted furans out there that are doing much the same thing in screening collections as we speak.
I’ve been there! And so has pretty much everyone else who’s had enough experience in dealing with primary screening data. This whole situation illustrates the fine line that you have to walk along. You need to be alert to the possibility of structure-activity relationships emerging from your data, of course (what kind of medicinal chemist are you if you aren’t?) But you also need to be alert to the possibility that you’re looking at false positives – because what kind of medicinal chemist are you if you aren’t? Accepting everything in the screening data at face value is a path to heartbreak and wasted effort, but the opposite approach (assuming that everything is crap) won’t get you anywhere, either. Just because you can screw things up in one direction doesn’t mean that you can’t screw them up in the opposite one – that’s one of the basic principles by which I conduct my scientific life – and the rest of my life, too, come to think of it.
When it comes to screening data, I do have a few structures that I rule right out (one beast that featured a quinone, a 1,4-diaminoaryl, and several free phenols all in the same structure comes to mind). Beyond that kind of thing, there’s a list of “Show Your Papers!” structures that I regard as “likely to be false positives”, and these furanylquinolines are now on it. These get labeled with stickers like “should probably work on other stuff first” and “make sure that the biologists don’t get too attached”. It should be fairly straightforward to show that these things are acting badly, if you’re alert to the possibility. (Resynthesis is one way, as with the paper under discussion, but the good old fashioned “run it through a plug of silica gel” can work wonders, too, and is usually much faster). Then come the “haven’t seen anything like that before, so I don’t know if it acts funny or not” compounds, which have to be dealt with impartially, and finally the “looks OK to me” set, which have to dealt with in the same way, because not everything that looks OK to me is, in the end, actually OK, dang it all.
It would be a lot easier and faster if we med-chem types could run our steely gaze down a long list of screening hits and say, with confidence, which ones (if any!) are the right things to spend time, money, and effort on. We can do that up to a point, of course, but that point isn’t nearly as far along the line as we like to think. Or like to have others think. . .