C&EN REVISITS 2003 C&EN reporters step back in time to look at several RESEARCH ADVANCES from a decade ago to see what became of them, and to review some notable stats from that year COMBINATORIAL CHEMISTRY: EXTENDING NATURE’S STRUCTURE INVENTORY
make up almost one-fifth of the nearly half-million compounds in the compound library at the Broad Institute of Harvard and Massachusetts Institute of Technology, where he directs the Center for the Science of Therapeutics. A number of drug leads have been found by screening the Broad library, including a candidate for treating malaria, an agent that could help diabetics by preventing premature death of insulin-producing cells, and a molecule that interferes with lipid uptake and could be used to probe cholesterol metabolism. Other combinatorial techniques for creating natural-product-like libraries include biology-oriented synthesis devel-
oped by Herbert Waldmann of the Max Planck Institute of Molecular Physiology, in Dortmund, Germany, and coworkers. In this approach, structural modifications relevant to a specific disease or biological Ten years ago, Stuart L. Schreiber of Harfunction are used to construct bioinspired vard University and coworkers reported a compounds. technique for making natural-product-like In another example, Thomas Kodadek compound collections that featured an of Scripps Research Institute Florida and unprecedented diversity of structures. Glenn C. Micalizio, now at Dartmouth These so-called libraries were designed College, developed a way to synthesize to serve as a pool of promising bioactive chirally and conformationally constrained molecules for drug discovery and biomedicompounds resembling natural products cal research (Science 2003, DOI: 10.1126/ made by bacterial polyketide synthase science.1089946). Fast-forward a decade, enzymes—a class of compounds that disand a number of drug leads have emerged plays antibiotic and anticancer properties. from such libraries. And Paul J. Hergenrother and BB1 BB2 The 2003 technique was not the first coworkers at the University of BB1 BB2 to synthesize diverse collections of comIllinois, Urbana-Champaign, pounds—researchers had already developed a way to start with σ1 𝛔1, 𝛔2, BB2 BB2 been generating libraries for drug actual natural products and BB BB1, BB2 2 discovery for about a decade. The chemically modify their rings approach was instead a versatile and functional groups to creσ2 BB BB1 BB1 1 variation on a set of techniques Schate new molecules. BB1 BB2 reiber had previously labeled “diversityIn a further extension of BB1 BB2 oriented synthesis.” combinatorial chemistry, The early versions created many difWaldmann, his colleague ferent compounds “combinatorially” by Kamal Kumar, and coworkers developed ADDING UP DIVERSITY A decade adding sets of building blocks to coma reaction cascade method in which a seago, Schreiber and coworkers used mon molecular skeletons. But the comquence of transformations in a single pot a combinatorial synthetic approach, mon skeletons displayed the building efficiently leads to a family of compounds like the one above, to make a library of blocks in limited numbers of spatial oricalled centrocountins. These natural1,260 natural-product-like compounds entations, restricting the diversity that product-like compounds affect the stabilbased on the six skeletons shown below. could be attained. ity and formation of centrosomes and In the reactions, skeletal information In their 2003 variation, Schreiber and mitotic spindles inside cells and have elements (σ) react and combine with coworkers replaced some of the building anticancer effects. core structures (squares). BB = building blocks with “skeletal information eleWaldmann points out that big pharma block, Ac = acetyl, Ar = aryl group, and M ments,” which are molecular compocompanies understand the relevance = macrobead solid support. nents that react and combine with of natural-product-inspired Ar O Br O common skeletons to transform libraries from academic them into varied core struclabs and are incorporatBB2 BB2 BB2 BB1 O O tures. This approach boosted ing them into their corpoBB1 O OH the achievable molecular dirate libraries. “I could have MO O BB1 MO versity considerably, producdistributed my in-house library MO ing compounds even more of about 10,000 natural-productBr O Ar like the complex compounds inspired compounds several BB2 found in nature. times over in the past BB2 BB1 Schreiber says comdecade or so,” Waldmann O BB1 O BB O BB OAc 1 2 O MO MO pounds made by diversisays. “Interest is always OAc MO OAc ty-oriented synthesis now high.”—STU BORMAN CEN.ACS.ORG
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SCIENCE
COURTESY OF JAY SWITZER
ART IN SCIENCE: SURFACE FEATURES MAKE CAPTIVATING IMAGES From a variety of microscope images, analytical spectroscopy techniques, and computer graphics, scientists often find that their work is more than just science—the illustrations they create can be astonishing. In 2003, C&EN’s year-end Chemistry Highlights feature included two captivatX-ray diffraction pole figures of two chiral copper oxide films electrodeposited on a gold substrate are nonsuperimposable mirror images, showing that the films are enantiomeric. ing graphics that when viewed today give one pause to wonder what became of the research and offset printing. gered by the flip of a switch: Applying a that created them. Langer says several of his potential to the gold substrate attracts the One of the figures is colleagues have followed carboxylate tips down to the surface, hiding a schematic drawing up on the technology the hydrophilic carboxylate groups and exdepicting the behavior in novel ways, includposing the hydrophobic alkyl chains. of a self-assembled ing making asymmetric “There has been quite a bit of follow-up monolayer of alkanethiol nanoparticles. work from many groups, including my own molecules that could be made to Joerg Lahann, now a research group,” Lahann says. “I think it’s reversibly stand or collapse by professor at the University of fair to say that paper sparked a new direcapplying an electrical poMichigan, Ann Arbor, led tion for active and autonomous materitential (Science 2003, DOI: the MIT team that created als. The paper has been cited more than 10.1126/science.1078933). the surface by wetting a 600 times by now, and it is still regularly At the time, the switchgold electrode with an referenced.” In addition to switchable able surfaces, created by serial alkanethiol capped by a monolayers, Lahann’s group has developed inventor Robert S. Langer carboxylate end group. different approaches to making switchable of MIT and coworkers, The transition between surfaces, including magnetically switchMIT researchers created this selfwere thought to be useful assembled alkanethiol monolayer straight (hydrophilic) able particle arrays that change color. for microfluidics, drug A second eye-catching figure from 2003 that reversibly stands or collapses and bent (hydrophobic) delivery, electro-optics, with the flip of an electrical switch. alkanethiols was trigstems from research to create solid chiral
IN HINDSIGHT C&EN looks back at the chemical enterprise and how it has changed since 2003.
2003 Nobel Prize in Chemistry:
Peter Agre and Roderick MacKinnon, for discoveries concerning ion and water channels in cell membranes Percent of women chemistry faculty at top 50 institutions in 2003:
12.0% In 2011 : 17.4% a
Academic chemistry R&D spending in 2003c:
$1.23 billion In 2012 : $1.75 billion a
Top-selling pharmaceutical by U.S. retail sales in 2003:
Lipitor
(atorvastatin)
Unemployment rate for U.S. chemists in 2003:
3.5% In 2013: 3.5%
Median base salary for all chemists in 2003:
$80,000 In 2013 : $74,400 b
Schools spending the most on chemistry R&D in 2003c: #1 University of California, San Francisco #2 University of California, Berkeley #3 University of Texas, Austin In 2012a: #1 California Institute of Technology #2 Rutgers University #3 Georgia Institute of Technology
Most-cited Journal of the American Chemical Society paper from 2003: Joseph Wang and coworkers, “Solubilization of Carbon Nanotubes by Nafion Toward the Preparation of Amperometric Biosensors,” (DOI: 10.1021/ ja028951v),
961 citations
a Most recent year for which data are available. b Figure accounts for inflation. c Institution fiscal years. SOURCES: NSF WebCASPAR database, ACS salary and employment surveys, Bureau of Labor Statistics, Nobel Foundation, Drugs.com, SciFinder, Open Chemistry Collaborative in Diversity Equity
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optically monitoring the progress of DNA sequencing. “We knew the fundamental limitation in fluorescence-based sequencing would be background noise caused by other nucleotides,” says Stephen W. Turner, founder and chief technology officer of Pacific Biosciences, who was on the team that invented the zero-mode waveguides. “We needed to reduce the observation volume.” Turner and his Cornell colleagues tried several approaches. “Most of them worked to some degree, but the zero-mode waveguide worked so well and was so much better and simpler than the others that it was the hands-down winner,” Turner says. The technology is now the heart of Pacific Biosciences’ PacBio RS II sequencing instrument. Each waveguide in a These reaction cells for the disposable PacBio RS II PacBio RS II reaction cell serves as a tiny vessel for a DNA-se- DNA sequencer 150,000 quencing reaction. Single contain zero-mode polymerase enzymes are waveguides immobilized in a wave(holes not visible). guide, which provides
the University of Washington. “That, along with the long read lengths, is enabling its utility in niche applications such as accurate assembly of microbial genomes with high or low GC content, as well as accurate assembly of challenging regions of mammalian genomes.”—CELIA ARNAUD
Record-breaking surface areas, exceptional pore sizes, and cavernous internal channels are properties that thrust metal-organic framework (MOF) materials into the scientific spotlight just over a decade ago. Researchers quickly predicted that these porous crystals—built from metal ions or metal clusters bridged by organic linking groups—would prove useful for gas separation and storage and other applications. Then in 2003, a team led by Omar M. Yaghi, now at the University of California,
a window to observe sequencing in real time by precisely following the incorporation of fluorescently labeled nucleotides. The prototype device had a few thousand waveguides, but today’s PacBio RS II uses reaction vessels with 150,000 waveguides that can be monitored simultaneously. The combination of the waveguide and specially designed DNA polymerases allows sequence read lengths that are thousands of base pairs long—some longer than 30,000 base pairs, which is the most among DNA sequencers. Other sequencing devices sometimes have trouble working through DNA regions containing a lot of guanine and cytosine (GC) bases, but not the PacBio RS II. “The place where PacBio is truly amazing is its lack of GC bias,” comments Jay Shendure, associate professor of genome sciences at
Berkeley, reported that a zinc-based MOF could reversibly store a few percent by weight of hydrogen at room temperature and more at lower temperatures (Science 2003, DOI: 10.1126/science.1083440). That development was considered a step toward the practical use of hydrogen as a fuel for electric cars, and it sparked a flurry of activity by scientists working on hydrogen storage, which continues today. A hydrogen uptake as high as 10% by weight has been reported for a copper-based MOF at high pressure and cryogenic temperature. Researchers today have synthesized thousands of MOFs and related types of framework compounds and demonstrated that many of them are useful for storing and purifying gases, separating hydrocarbons, capturing carbon dioxide from
MATERIALS CHEMISTRY: METAL-ORGANIC FRAMEWORKS GO COMMERCIAL
PACIFIC BIOSCIENCES
surfaces, which can be used as enantioselective catalysts or for sensing chiral molecules (Nature 2003, DOI: 10.1038/ nature01990). The two images, created in the lab of Jay A. Switzer at Missouri University of Science & Technology, are graphical representations of X-ray diffraction data. The peaks are stereographic projections— so-called pole figures—showing the crystal orientation of enantiomeric copper oxide films electrodeposited on achiral gold substrates. Switzer’s team used right- or lefthanded tartrate molecules in the deposition solution as templates to orient the films with right- or left-handed chirality. Since 2003, Switzer’s group has deposited chiral copper oxide on different substrates and shown that the enantiospecificity can be enhanced by etching the films using chiral etchants (J. Am. Chem. Soc. 2007, DOI: 10.1021/ja073640b). “I am sad to announce that I have not formed a start-up company and made billions of dollars—yet,” Switzer informs C&EN. Switzer’s lab is still working on electrodeposition of metal oxide and metal hydroxide films, with an eye toward developing oxygen-evolving catalysts for splitting water to produce hydrogen (Chem. Mater. 2013, DOI: 10.1021/cm400579k) and to make switches for solid-state memory devices being designed for smartphones and tablet computers (ACS Nano 2013, DOI: 10.1021/nn4038207).—STEVE RITTER
DNA SEQUENCING: ZERO-MODE WAVEGUIDES TURN 10 A decade ago, researchers at Cornell University reported an analytical device, which they called a zero-mode waveguide, for using light to detect single biomolecules in samples of any concentration. That device was remarkably simple—just an array of nanometer-scale holes in a metal film on a fused-silica surface (Science 2003, DOI: 10.1126/science.1079700). Today, that unpretentious device is the basis of the DNA-sequencing technology from Pacific Biosciences, based in Menlo Park, Calif. Waveguides are devices that are used to direct light and sound waves—optical fibers are one example. Zero-mode waveguides are so named because the holes, which serve as the waveguides, are smaller than the wavelength of light used, so the light doesn’t pass through the holes. From the beginning, the Cornell team’s waveguides were intended to be used for
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BASF (BOTH )
exhaust gas streams, mediating catalytic reactions, and soaking up uranium from seawater. Most of the reports—especially ones detailing the structures and compositions of new MOFs—come from academic research groups. But MOFs are no longer just academic curiosities. A few companies, including Sigma-Aldrich, now sell lab quantities of MOFs. And BASF makes a handful of the compounds on a ton scale, although commercial applications for them remain scarce. “We manufacture double-digit-ton quantities of some MOFs per production run,” says BASF Senior Vice President Ulrich Müller. He adds that the company’s manufacturing capabilities have already been optimized, so no additional development work is needed; the company is just waiting for demand to pick up. One application for BASF’s MOFs is to boost the storage capacity of natural gas fuel tanks for vehicles such as buses. The
BASF now manufactures a few types of MOFs on a multiton scale at its facilities in Germany (above). The porous crystals are starting to be used in commercial applications, including sorbent materials that increase the gas storage capacity and driving range of natural-gas-burning vehicles, such as this truck (left).
extreme surface area of a MOF—thousands of square meters per gram—and its ability to adsorb methane and other natural gas molecules mean that cylinders packed with MOFs can store roughly twice as much natural gas as unfilled cylinders.
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The technology has been road tested on passenger vehicles and large trucks. Müller has been closely following MOF developments coming out of academic labs since the end of the 1990s. Yet these materials continue to amaze him. “It’s fascinating to see the way tuning and tweaking the metals and linkers can lead to new materials with properties that would have been unimaginable just a few years ago,” Müller says. Translating some of these newer materials into real-world applications seems inevitable, he adds. But as with any new technology, Müller concedes, commercialization takes time.—MITCH JACOBY
