Better Tools For Drugmakers

When medicinal chemists home in on a drug, they’ll often tweak the molecule’s substituents, adding an alkyl or fluoroalkyl group to boost stability or bioactivity. Now, researchers have developed a reagent tool kit that allows chemists to add 10 different alkyl or fluoroalkyl groups onto a class of molecules that have traditionally been tough to functionalize—heteroarenes (Nature, DOI: 10.1038/nature11680).

Heteroarenes used in medicine often possess limited solubility in organic solutions and can act as protein ligands. Although these properties make them good molecules for medicines, they also make heteroarenes challenging to modify, says Phil S. Baran of Scripps Research Institute, who led the research effort.

Within the past year, Baran and his team reported that zinc sulfinate salts can transfer difluoromethyl radicals to heteroarenes under mild conditions (C&EN, Jan. 16, page 30). “The demand for these reagents has been outstanding,” says Troy D. Ryba, manager of academic chemistry strategy at Sigma-Aldrich, which sells four of the zinc sulfinate salts. “They are simple to use and provide unique products, making them highly valuable tools for the chemistry toolbox.”

Now, Baran’s group has expanded this chemistry to include a total of 10 zinc sulfinate salts, thereby creating a tool kit for medicinal discovery research efforts. The reactions take place under mild conditions and are simple to perform. Using reagents from the tool kit, the team reports the synthesis of 52 compounds, only two of which had previously been reported. In one example, they use just one step to prepare a compound from material that costs $1.10 per g; that same compound currently costs $3,500 per g.

Baran acknowledges that the yields can be low for some of the transformations. But, he points out, “medicinal chemists care about time. Yield for them is about getting enough for the biological testing. If they have to spend two weeks to get a 90% overall yield, that’s far inferior to a route that will give them 20 to 30% yield in one afternoon.”

The researchers also show that the reaction can be carried out in unusual solvents, such as cell lysate and oolong tea. “I’m not advocating that anyone in the chemical universe start doing their chemistry in tea,” Baran says. Nevertheless, the tea experiment demonstrates that this chemistry tolerates an enormous amount of impurities, he notes, “which speaks to the robustness and chemoselectivity of the reaction.” It also demonstrates the innate reactivity of radicals and heteroaromatics. Despite the myriad compounds in the tea, the heteroarenes and the radicals are exclusively attracted to one another.

“I believe medicinal chemists across the pharmaceutical industry will welcome this new reagent tool kit,” comments William J. Pitts, a researcher in Bristol-Myers Squibb’s department of molecular sciences and candidate optimization. “Like any tool, it isn’t applicable in all circumstances. However, in certain instances the tool kit will greatly facilitate the generation of lead molecules with improved pharmacokinetic properties, which, in turn, can increase the chances of identifying superior drug candidates.”