could be used. Deacon predicts that ChiroTech chiral technology business "a vast reduction chemistry will in 1997, and formed a genomics subsidemerge." iary, Rapigene, in 1998. The Irvine group overcame synChiroscience has always said that conthetic hurdles in preparing the bulky solidation within the pharmaceutical incomplexes. 'When they first made dustry is essential for the critical mass [the trivalent samarium complex], necessary to build sustainable profits and that was a surprise, because for cash flow while minimizing risks, says many years they didn't think three Hugh Collum, Chiroscience's chairman, bulky ligands could be put around a who will become the new company's depsamarium center," Takats says. uty chairman. Peter Fellner, Celltech's Evans suspects that other chem- chief executive officer, will remain CEO, ists may have been generating and Chiroscience's CEO, John Padfield, From left: Evans, graduate students Gregory W. strong reducing agents as well, as is to become CEO of Nycomed AmerNyce and Robert D. Clark, and staff research they tried to make complexes with sham's imaging division. associate Joseph W. Ziller. Nyce is holding model bulky ligands. But they may have For the fiscal year ended Sept. 30, of the sterically crowded [CJCH^J^JI molecule. unwittingly dismissed their mole- 1998, Celltech had revenues of $18.6 milEvans says exploiting this property cules' quick decomposition as failures, lion and a net loss of $4.9 million. Chirocould lead to great tunability in reduc- not realizing that they might have gen- science had revenues of $65.5 million tive lanthanide inorganic chemistry. erated products of a reduction reaction. and a net loss of $27.4 million for its fisBut with this new proof of principle, cal year ending Feb. 28. The 15 lanthanides span a range of atomic sizes, and if they all could be Evans* group knows how to proceed. Celltech will issue new shares at an used in sterically crowded complexes, "It's now just a matter of making crowd- exchange ratio of 0.62 share per Chirochemists could exploit the same reduc- ed molecules and looking to see if they science share, which values Chirotion chemistry accomplished with diva- will do redox reactions," Evans says. science's shares at 293 pence (about $4.66) lent samarium with other lanthanides "But that's not trivial. Making crowded each. Chiroscience shareholders, if they that have many interesting properties. molecules is hard." accept the offer, would own about 47.6% Additionally, different-sized ligands Elizabeth Wilson of the new company, and 52.4% would be in the hands of Celltech shareholders, who still must approve the merger. Chiroscience's shares rose nearly 9%, to 282 pence per share (about Two drug discovery companies based in its leading product candidate—an MAb $4.49), following the June 15 merger anthe U.K.—Celltech and Chiroscience against septic shock it was developing nouncement. Celltech's shares dropped Group—are merging to create one of with Bayer—in May 1997 after poor about 2%, to 462.50 pence. the largest biopharmaceutical firms in clinical trial results, and its stock price Ann Thayer Europe. Each ranks among Europe's plummeted. Then in late 1997, it comtop 10 biotechnology firms in market pleted the sale of its biologies manufaccapitalization, and the new Celltech Chi- turing business to Alusuisse-Lonza for roscience will have a valuation of more about $80 million. than $1.1 billion. Although much younger than CellA key goal for the new company is to tech, Chiroscience has launched two become financially self-sustaining and products since it was formed in 1992 Great Lakes Chemical Corp. says it is coprofitable, its executives say. It will start and has been busily building its busi- operating with the U.S. Department of Jusoff with two products—the anesthetic ness. It acquired Seattle-based Darwin tice and the European Commission in inChirocaine and the analgesic dexketopro- Molecular in 1996, created its profitable vestigations of the bromine industry. The fen, both from Chiroscience—and another antitrust probe is the most recent of sev12 in development And it will have partnereral aimed at global chemical producers. ships with several major drug producers. Great Lakes says the government inCelltech Chiroscience vestigations began, at its prompting, in Celltech was the first dedicated bioat a glance the spring of 1998 soon after its new prestechnology company in the U.K. It was ident and chief executive officer, Mark P. created in 1980 with the government's Revenues: $84 million in 1998 Bulriss, came aboard and learned of "cerformer National Enterprise Board as its Net loss: $32 million tain practices that raised questions under major shareholder to capitalize on bioR&D spending: $81 million the antitrust laws." After an internal intechnology and related discoveries from vestigation, the company reported its British universities, but it hasn't been Products: Chirocaine, dexketoprofen findings to the two agencies. profitable. Its revenues are derived Employees: More than 400 in R&D largely from royalties and licensing fees 'The type of conduct at issue here is Locations: Slough, Stevenage, on technology used in the production of unacceptable and is not condoned by genetically engineered monoclonal anti- and Cambridge, England; Seattle the company nor by the current manbody (MAb) drugs. agement team," Bulriss says. Note: Based on Chiroscience fiscal year ended Great Lakes says it is disclosing its Over time, Celltech shifted its focus Feb. 28 and Celltech's ended Sept. 30. role now because the Justice Departto drug discovery. However, it dropped
Celltech to merge with Chiroscience
Antitrust agencies eye bromine industry
JUNE 21,1999 C&EN
11
n e w s of t h e w e e k ment investigation is nearing its conclusion. Under an amnesty program for cooperating companies, Great Lakes will be exempt from criminal prosecution and fines in the U.S.; it is seeking favorable treatment under a similar European Union plan. Great Lakes is one of three companies that together make 80% of the world's bromine. More than 665,000 metric tons of bromine was produced in 1997, according to SRI Consulting, Menlo Park, Calif., extracted mostly from the Dead Sea and from brine deposits found in Arkansas. Bromine is converted into flame retardants, oil well drilling fluids, biocides, and other products. Great Lakes' main U.S. competitor, Albemarle Corp., issued a statement last week saying it has not been contacted by the Justice Department or the European Commission. However, the third big producer, Israel's Dead Sea Bromine Group, confirms a European investigation and says it is cooperating with a Justice Department investigation. None of the companies is providing details on the investigation, but it is thought to be fairly limited. Two small
bromine compound producers contacted by C&EN say they were unaware of the investigation. Observers point out that Great Lakes and Dead Sea are linked by a venture formed in 1995 to jointly produce, but separately market, the flame retardant tetrabromobisphenol A in Ramat Aviv, Israel. This is not the first time the U.S. government has looked into the highly concentrated bromine industry. In the mid1980s, it investigated producers of bromine-based drilling fluids. Then in 1988, it blocked Dow Chemical's sale of its bromine business to Albemarle—then part of Ethyl Corp.—requiring Dow to first sell a calcium bromide plant to Tetra Technologies in order to maintain competition in the drilling fluid sector. The investigation is part of a wider government scrutiny of chemical industry pricing practices as a whole. Two major vitamin producers recently agreed to pay a $725 million fine to settle price-fixing charges (C&EN, May 31, page 6), and earlier government probes have resulted in fines on producers of sorbates, citric acid, and lysine. Michael McCoy
Palladium helps make C-N bonds in nucleosides Using palladium catalysts to form car- several procedures attempted, the Pdbon-nitrogen bonds, researchers at the based method alone provided the desired University of North Dakota, Grand product. Forks, have developed a procedure for 'The synthesis appears to provide a making the biologically important ami- major advance over existing methodolnoaryl nucleosides. That family includes ogy," remarks Vanderbilt University's compounds formed from carcinogenic Thomas M. Harris. A chemistry proarylamines—like those produced while fessor and molecular toxicologist, Harbarbecuing steaks—that have until now ris comments that the method offers a challenged synthesis strategies. way to produce compounds needed by The study was conducted by assis- scientists working at "developing a tant chemistry professor Mahesh K. molecular-level understanding of the Lakshman, graduate students John C. structural and mechanistic basis for biKeeler and John H. Hilmer, and under- ological effects of various types of graduate student Jocelyn Q. Martin DNA damage." [/. Am. Chem. Soc, published June 10 & ASAP http://pubs.acs. | org/journals/jacsat]. § Researchers at the 'i University of Washing- £ ton, Seattle, have inde- 2 pendently discovered and applied the method to the synthesis of a sample of an interstrand cross-linked DNA [/. Am. Chem. Soc, 1 2 1 , 5081 (1999)]. The Seat- Aminoaryl nucleoside synthesis team (from left): tle group notes that of Lakshman, Hilmer, Keeler, and Martin. 12 JUNE 21,1999 C&EN
Bromonucleoside yields arylamine derivative
RO
Ar = Aryl groups CH 3 I R = Si-C(CH3)3
RO
CH*
Treating a bromonucleoside with aromatic amines in the presence of an organopalladium compound, Lakshman and coworkers produce 2'-deoxyadenosine analogs that have substituted aryl rings at the exocyclic amino group. The reaction proceeds by way of a nucleoside-palladium intermediate, they say. The group reports high yields from its arylamination reaction. Several factors played a part in shaping the group's approach to the reaction. It's known that direct displacement reactions can kick out groups such as bromine residing at the C-6 position in the nucleoside, Lakshman explains. "But aromatic amines aren't nucleophilic enough for such a displacement," he points out, making the palladiummediated route look more promising. But why choose the brominatpd starting material over other halogenated analogs? Lakshman notes that using the fluorinated compound requires an elaborate six-step synthesis. The chloro- and bromonucleosides are much easier to prepare, he asserts. And recent studies on amination reactions of aromatic halides with palladium-ligand complexes indicate that the first step of the reaction—oxidative addition of the aromatic halide to the metal complex—proceeds much more sluggishly with chlorinated compounds than with brominated ones. "Now we're working on applying the same kind of logic used with aromatic amines to prepare adducts from metabolites of polycyclic aromatic hydrocarbons," Lakshman says. Harmful compounds in that family (present in cigarette smoke) are even more ubiquitous than arylamines, he points out. Mitch Jacoby
