At the Sanofi-aventis Tucson Research Center in Oro Valley, chemists work with very small quantities of substance, in the sums of milligrams and microns.
The company's use of technology, and its ability to create and examine very small amounts of material, is crucial to the quest for "advanced lead compounds" that may become pharmaceutical products.
Through what can be dozens of steps, chemists at Sanofi-aventis use "solid-phase chemistry" to build specific chemical molecules and compounds for research.
"Some of the best solid-phase chemists anywhere" create compounds that are stored in the world-class Tucson Collection, used in Tucson-based research, or shipped for utilization at Sanofi-aventis sites across the world, according to Daniel Schirlin, vice president for discovery research for Sanofi-aventis.
Solid compounds are preferable because they're easier to manage, explains chemist Eric Wegrzyniak, a principal research investigator at Sanofi-aventis.
"As a liquid, we could not run all these reactions, and program all the sorting, without having to purify the compound at every step," Wegzryniak explained.
Compounds are cleaved to tiny polymer beads, ranging in size from 100 to 300 microns. "The bigger the bead, the more compound you can attach," Wegzryniak said.
In turn, beads are held inside tiny, permeable "nanokans," very small baskets that contain up to 8 milligrams of substance.
"The reaction occurs in the bead," Wegzryniak said. "The beads have chemical anchors we can use to attach and modify the compound."
Each bead-holding nanokan, and its larger companion Micro-X-Kan, Mini X-Kan and Macro Kan, is identified by barcode. "We always know where we are and what we do," Wegzryniak said.
The system allows chemists to use "directed sorting technology" that lets them sort multiple canisters in many arrangements, and undertake dozens of different reactions on small amounts of identical compounds at any one time.
"A sequence of reactions can be very long," Wegzryniak said. Through "directed sorting technology," a scientist doesn't require "very laborious separation at each step of the reaction." With this technology, processes are accelerated, and information retained.
"You can take a very complicated reaction scheme, and at the end derive the designated compound," Wegzryniak said. "You get to completion without cleaning at each step. It's very easy to manipulate."
Within the containers, chemists can filter, wash and clean the substances to arrive at the "target molecule." In the end, a "cleavage cocktail" kills the connection between bead and compound, leaving the desired substance. Purified compounds are placed in a finished library.
Ken Wertman, scientific director at the Tucson Research Center, provides historical context for the use of technology to create smaller "test tubes" into which compounds are placed with biological substances to identify interactions.
Wertman remembers the 96-well microtiter dish, in effect 96 very small test tubes on a small well plate that fits in the palm of your hand. With the mid-1990s came the 384-well plate, with smaller volumes of compound in each test tube. Last year, routinely, Sanofi-aventis conducted 1,536-well plate testing. "On each plate," Wertman said, "scientists could conduct 16 times as many tests as they did in 1995, and with 1/16th as much compound."
All this has required significant technological innovation. Getting smaller means getting smarter, to manage things like surface tension, evaporation and variability in the assay. "So many technical elements had to be put in place," Wertman said.
"What it has done for us," Wertman said, "is we can test 1 million compounds in about two weeks' time."
Sanofi-aventis is believed to be the only company using the nanokan system. "We have been successful in using this system," Wegzryniak said. "We couldn't do what we do without it."
"It is a quite powerful technology," Schirlin agreed.