Scripps Institute scientists cut cost of making complex steroids


LA JOLLA — A barrier to making an important class of steroid drugs has been cracked by researchers led by a renowned chemist at The Scripps Research Institute.

Phil Baran and colleagues invented a practical way to make large quantities of complex steroid compounds used to treat heart failure and being studied for their antiviral and anticancer properties.

The discovery promises to make new drugs more practical and lower their cost -- an important consideration when the expense of new drugs is as much an issue as their effectiveness.

The study was published online Thursday in the journal Science. The research was funded by Leo Pharma, a Danish drug company that plans to use the technology to make new drugs, said Baran, the study's senior author. Hans Renata, a graduate student in Baran's lab, was the first author.

These complex steroids are made naturally by plants and marine organisms like starfish and coral, but human chemists have been challenged to duplicate nature's cleverness. Baran is known for taking on such challenges. A Baran-led team discovered an easier and cheaper way to tweak potential drugs; the research was published in November in the journal Nature.

In the Science paper, Baran's group describes a "quasibiomimetic" strategy for making the molecules, called polyhydroxylated steroids.

"We show how you can use simple 'massaging' of a normal steroid skeleton and by applying two interesting principles for synthesis ... you can get the functional groups of the molecule to talk to each other, instead of acting like isolated units," Baran said. "The routes to approach molecules like this in the past have been extremely cumbersome and cost-prohibitive, and basically impossible to make in any other way than to isolate it from an organism."

The target was ouabagenin , a drug for congestive heart failure.

"It's the most polyhydroxylated steroid that there is on Planet Earth," Baran said. Polyhydroxylated refers to the attachment of a molecule of oxygen and hydrogen, called a hydroxyl group, to another molecule. The more hydroxyl groups, the harder it is to build the molecule, at least for humans.

Among its benefits, the new process requires about half the chemical steps of an earlier process developed in 2008. That's important, because each step in producing a drug decreases efficiency, thus raising cost, Baran said. Moreover, while some drugs can be synthesized in minute quantities with older processes, the practical inability to make them in large quantities means they can't be commercialized.


