Let's talk tool compounds. This topic has come up around here before, generally when some paper gets published from an academic group featuring a hideous molecule. Today, alas, is no exception. Feast your eyes on this one, an inhibitor of tyrosyl-DNA phosphodiesterase I.
Now, on one level, I'm sympathetic. That's an unusual enzyme, and there really aren't any decent inhibitors known for it. It's pretty hard to work out the function of an enzyme without a good inhibitor to watch the effects in living cells, and in that sense, it's good to have found something. But here comes the other hand: your compound for such a purpose needs to be a good one, or the studies you run with it risk being meaningless. "Good" is a relative term, I realize, depending on how much you're expecting the compound to do for you: enzyme assay only? Cells? Mice? But at a minimum, it should be selective for the target you're trying to figure out.
And that's where my eyebrows go up with this little beast. It's not quite a rhodanine (switch the carbonyl and thiocarbonyl if you want that), but it's not a particularly pretty heterocycle, either. This paper, which I wrote about here, looked at the promiscuity of several related heterocycles, but not this one in particular. Any time I see a thioamide group, I get worried. This very system, in fact, shows up in the PAINS paper (open access copy), which I blogged about here, warns against this whole class (see page S45 of the supplementary material).
It also warns, with good reason, against the alkylidene branching off of such rings. I know that there are drugs with such features (epalrestat, Sutent), but your chances of such compounds being real and going all the way are surely lower. Finally, we come to the triphenol. Polyphenol compounds are notorious in medicinal chemistry. They're reactive, they're unstable, they show up in all kinds of assays, and their SAR almost never makes any sense. So this compound has lots going for it.
The authors realize this, and checked the compounds against bovine serum albumin as a way to assay nonspecific protein binding. They also did some work with whole-cell extracts, and continue to feel that these "controversial scaffolds" (their words) can still be useful. (And to be fair, they're also looking at replacing the phenolic section with less nasty polar groups). But while their hearts (and their heads) are in the right place, I still worry very much about these compounds. I'd be quite interested in seeing them run across a broad panel of assays, just to see how promiscuous they really are, and I would be very careful about trusting cellular data (or anything close to it) until that's done.