SCIENCE/TECHNOLOGY
Peptidomimetic Molecules Show Biological Activity Against Cancer, AIDS inhibitors, regulators of im mune response, and opioidPotential anticancer drugs like analgesics. target end of Ras protein Two presentations from a symposium on computa tional-chemistry-assisted HS drug discovery, cospon"^ Η Ο sored by the Divisions of Protein Ν Computers in Chemistry and of Chemical Informa Rebecca Rawls, C&EN Washington tion, showcased some of the breadth and promise of 211th ACS National Meeting work on these compounds. Organic chemist An drew D. Hamilton, phar macologist Said M. Sebti, and their coworkers at the University of Pittsburgh eptidomimetic compounds—mol are using the peptididomiecules that have the side-chain fea metic approach to produce tures and the general shape of pep candidates for a new class tides but with few, if any, actual peptide of anticancer drugs. They bonds in their backbones—make up one target the Ras protein, a of the promising new classes of potential key component in the sig drugs. Researchers in many sessions in naling pathway of normal Biologically active inhibitors of Ras farnesylNew Orleans presented data on com cells that breaks down in transferase, an enzyme that recognizes and pounds of this class that show promise many forms of cancer. Mu cleaves the four terminal peptides of the Ras pro in uses as varied as anticancer drugs, tated forms of the Ras pro tein (top), include mimic that replaces the middle human immunodeficiency virus (HIV) tein are found in 30% of two peptides with 2-phenyl-4-aminobenzoic acid human cancers and in 95% (middle) and one that replaces all three terminal of pancreatic cancers. peptides with a carboxybiphenyl group (bottom). "The molecules we've designed or their deriva tives can cross cell membranes and dis tachment of a 15-carbon farnesyl lipid rupt the processing of oncogenic Ras group) at a cysteine residue that is the protein inside cells," Hamilton said. fourth residue from the protein's carAs its function is currently under boxyl terminus. The reaction is cata stood, normal Ras protein is one of the lyzed by an enzyme, Ras farnesyltransintermediates in a signaling pathway ferase (FTase), which recognizes and that enables cells to recognize and re binds to the four-peptide end segment spond to external growth factors. In mu of the Ras protein. tated forms of Ras protein, this growth "FTase represents an Achilles' heel in signal gets stuck in the "on" position, the signal transduction pathway," Ham Hamilton explained, and the cell re ilton said. "Disruption of the membrane sponds with uncontrolled growth. translocation of mutated Ras should in To transmit its signal, however, Ras hibit its signaling function and eliminate must first associate with the cell's plas a molecular switch that has been stuck ma membrane, which requires modifi in the on position." The Pittsburgh researchers have cation of the protein to increase its hydrophobicity. The protein is made been attempting to develop inhibitors more lipophilic by farnesylation (at- of FTase by preparing a series of pepHamilton: disrupt oncogenic Ras processing
• Attaching side groups ofproteins tononpeptide scaffolds can make stable molecules that more easily cross cell membranes
NewOdeans P
APRIL 8,1996 C&EN
37
SCIENCE/TECHNOLOGY
Smith: designing nonpeptide scaffolds
tidomimetics in which the key features of Ras's terminal tetrapeptide are replaced by stable, nonpeptide subunits. They have replaced the two central amino acids in the tetrapeptide with a hydrophobic spacer such as 2-phenyl4-aminobenzoic acid or all three terminal peptides with a carboxybiphenyl group. The peptide mimics retain the ammonium, carboxylate, and thiol groups of the original tetrapeptide, but they have very different intervening spacers. By comparing the biological activity of these different peptide mimics with computer modeling of their lowenergy conformations, the researchers can begin to infer what features are necessary for tight binding to the active site of FTase, even though the crystal structure for that enzyme hasn't yet been determined. "It's comforting that we can still make very potent inhibitors of this enzyme without knowing its crystal structure," Hamilton said. The mimics are biologically active. The Pittsburgh team has shown that some of their compounds inhibit FTase in vitro, selectively disrupt oncogenic Ras processing and signaling in whole cells, and function in two animal model systems. In one of these animal models, the researchers implanted human lung carcinomas under the skin of mice. In untreated animals, the tumors grew more than sevenfold during the 26-day test. By contrast, those treated with the inhibitors grew only slightly. And the animals showed no signs of ill health or weight loss that would sug38
APRIL 8,1996 C&EN
Peptidomimetics based on HIV-1 protease inhibiter tide backbone is replaced by a 3,5-linked polypyrrolinone. G$H$ Now, the group has synthe sized the third structural ele BocHN, ment—a bispyrrolinone that CHH in the solid state self-assem bles into a helix. The helix-forming peptide NH-Displaced pyrrolinone mimic is an N-methyl bispyr rolinone that was initially constructed as part of a study of the solution conformation BocHN. CNB of the 3,5-linked pyrrolinone scaffold, Smith explained. The methyl group was add ed to interfere with intramo Peptide model lecular hydrogen bonding. Although further work re Çe^s mains to be done with the system, it holds promise as a BocHN possible design tactic for con structing a variety of helices. Among the molecules con Carbonyl-displaced pyrrolinone structed by the University of Pennsylvania group using the 3,5-pyrrolinone scaffold B o c * ~ COC(CH$)3 are some that mimic both parallel and antiparallel βMerck's peptide-based inhibitor of HIV-1 sheets in the solid state as protease (center) serves as model for polypyrwell as β-strands in non-hy rolinone mimics. The nitrogen-displaced drogen-bonding solvents, mimic (top) is more easily transported across Smith said. The β-sheet struc lymphocyte membranes than the original ture is important in drug de peptide and shows activity when given oralsign because proteolytic en ly. Computer modeling studies suggest that zymes such as aspartic acid the carbonyl-displaced mimic (bottom)— which has yet to be synthesized—may also and serine proteases bind show activity. both substrates and inhibi tors as β-pleated sheets. One of the Pennsylvania gest the inhibitors are toxic, Hamilton group's 3,5-linked pyrrolinones is an orally active inhibitor of HIV-1 protease said. A particularly promising feature for with good potency, based on prelimi potential drug applications is that the nary assay results obtained by collabo mimics are more effective at inhibiting rators at Merck Research Laboratories. the growth of cells containing mutated The pyrrolinone scaffold appears to Ras protein than of normal cells. The improve transport of the molecule reason for this selectivity is not under- across the membranes of lymphocytes compared to the corresponding pep stood, Hamilton noted. At the University of Pennsylvania, an tide. In a collaboration with Lawrence ongoing collaboration between chemis- C. Kuo and Zhongguo Chen at Merck, try professors Amos B. Smith III and the Pennsylvania group has solved and Ralph Hirschmann has been trying to refined the X-ray crystal structure of design and synthesize nonpeptide scaf- this orally active inhibitor cocrystalfolds that mimic the three basic elements lized with HIV-1 protease. of the secondary structure of peptides Smith and Hirshmann are also trying and proteins—β-turns, β-pleated sheets, to construct a second type of peptididoand helices. Over the past several years, mimetic polypyrrolinone with the the researchers and their collaborators β-pleated-sheet structure. The new mol have made mimics of β-turns, using ecules would be based on a 2,5-linked both carbohydrate scaffolds and a ste polypyrrolinone scaffold. The chemists roid framework. They have also made a have an efficient protocol to construct β-pleated-sheet mimic in which the pep the basic pyrrolinone building blocks for
this scaffold, Smith said. They are now working to make these polypyrrolinones and study their conformational behavior and biological properties. In polypyrrolinones, five-membered pyrrolinone rings replace conventional amino acids as the repeating unit in peptide-like polymers. A 3,5-linkage of these subunits displaces the enaminone nitrogen from the polymer backbone. By contrast, a 2,5-linkage leaves the ni trogens in the backbone but displaces the carbonyl carbons. In each case, the NH groups and the carbonyls remain
where hydrogen bonding to the NH of the protein is particularly important. The Pennsylvania group chose to make the nitrogen-displaced 3,5-linked polymer first because computer model ing predicted that its backbone would be more stable against nucleophilic attack. Computer modeling by Paul Sprengeler at Pennsylvania, however, predicts that, once synthesized, the carbonyl-displaced 2,5-linked pyrrolinones should have a greater tendency to assume the extended linear conformation needed to form pleated-sheet structures. •
able to form intramolecular hydrogen bonds with neighboring polypyrrolinone strands, thereby helping to in duce the extended strand conformation, Smith explained. In many ways, the 2,5-polypyirolinones should complement the 3^-linked poly mers, Smith suggested. For example, the nitrogen-displaced polypyrrolinones could be exploited to interact with macromolecules known to form important hy drogen bonds with the carbonyls in the peptide backbone and the carbonyldisplaced pyrrolinones used in cases
Chemists devise diverse strategies for environmentally benign syntheses 211th ACS National Meeting
New (Means Stephen C. Stinson C&EN Northeast News Bureau everal additional ways have been devised recently to synthesize com pounds in an environmentally friendly manner. One approach uses water as a solvent. A second approach employs no solvent at all. And a third approach is to replace stoichiometric amounts of metal reagents with small amounts of metal catalysts. New variations on these themes were shared by speakers at a symposium on Environmentally Benign Organic Syntheses and Process es, sponsored by the Division of Or ganic Chemistry. But chemists must also be wary of an overoptimistic view of such approach es. Though water seems surprisingly amenable to more reaction types than chemists once imagined, there will al
S
ways be cases where only an organic solvent will do. And in all reactions slat ed for scale-up, the winning approach will always be the one that is most eco nomical overall. The pioneer chiefly responsible for the renaissance of water as a solvent in or ganic preparations is organic chemistry professor Ronald Breslow of Columbia University. It was a quarter century ago that Breslow found that Diels-Alder re actions actually go faster in water, be cause the hydrophobic effect speeds up the combination of the nonpolar reactant molecules. Another innovator who is exploring the possibilities of water is organic chemist Chao-Jun Li, assistant profes sor of chemistry at Tulane University in New Orleans. Li combines aqueous organic chemistry with ingenious new reaction concepts. In work with gradu ate student Yue-Qi Lu, for example, Li wanted to invent a new method to make five-membered rings, a common task in syntheses of both natural prod ucts and other compounds. Li imagined a simple combination of a two-carbon fragment and a three-carbon
Li: focus on aqueous organic chemistry fragment to make the ring. Each frag ment would have a plus charge on one end and a minus charge on the other. Just put the cations together with the an ions, Li figured, and the ring would be bound to form. Li knew, of course, that such intermediates do not come readily to hand, and that he would have to find their equivalents. The Tulane chemists chose to test the idea with the reaction between ethyl Continued on page 42
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APRIL 8, 1996 C&EN
39
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Continued from page 39 chemistry professor Dong-Li Chen of acetoacetate (which contains the in Zhengzhou University in China, Li tended two-carbon fragment) and used indium powder in water to cata 2-methylene-l,3-dichloropropane lyze reaction of 1,3-dibromopropene (which has the three-carbon equiva with benzaldehyde. The indium medi lent). In the first step, an aqueous base ates a sequence of bromine activations catalyzes alkylation of the α-carbon of and allylic shifts to form the product acetoacetate by one chloromethyl equivalent to allylic double attack, 1,3-digroup on the propane compound. In phenyl-2-vinyl-l ,3-propanediol. the second step, indium mediates cou Yet another aqueous organometallic pling of the second chloromethyl technique Li described at the New Or group to the β-carbonyl group of aceto leans meeting is the expansion of rings acetate in water so lution to close the ring and form the Anion-cation equivalents lead to rings desired cyclopentane product. Θ ® C I H 2 C X c / CHXI In this way, Li uses Θ C0 C H Base an organoindium in C H , C ' \ ~CUH / 2 2 5 termediate in water CHo ® 2 to accomplish reac Ethyl acetoacetate 2-Methylene-1,3tions much like those dichloropropane of Grignard, organolithium, or zinc re COoCoHc j agents. But in addi ,/ © CH Indium I tion to surviving in CH CIH2C water, these organo Θ CH indium species solve 2 another problem that Note: ® and 3 a r e conceptual equivalents and not actual charges. tends to arise with dicarbonyl compounds such as acetoacetate. This problem is the Reaction sequence simulates allyl dianion tendency for other organometallic re agents to abstract a Indium , hydrogen atom from 1,3-Dibromopropene the active methylene group rather than add In across the carbonyl double bond. Br In another thought experiment, Li reflect Br ed that because diH5C6CHO Indium carbanions are so ΗΛ useful in organic syn thesis, it would be OH especially good to In have a dianion with both negative charg 5 6 es on the same al OH lylic carbon atom. Then the same car OH bon atom could at tack first one, then 5 6 H5C6CHO another molecule of a HcQ carbonyl compound. OH It is easier to draw such a dianion on 1,3-Diphenyl-2-vinyl1,3-propanediol paper than to make it. But working with visiting organic H
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42
APRIL 8,1996 C&EN
C
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Clean reaction yields three-membered rings
Photolysis gives one product in solvent... ο
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by two carbon atoms. This technique is useful in natural product syntheses be cause unfavorable entropy changes make rings larger than six atoms hard to put together. For example, starting with a substi tuted cyclopentanone, Li attaches a 4-bromo-2-buten-l-yl group to the 1-position. Stirring the resulting com pound with indium powder in water results in an organoindium intermedi ate that interconverts between two allylic forms before attacking the carbonyl group intramolecularly. The final product is a cycloheptanone. Li cited similar expansions of six-, seven-, eight-, and 12-membered rings, each by two carbon atoms.
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And finally, Li reported a rutheni um-catalyzed method to shift the posi tion of functional groups in molecules. Although useful in organic synthesis, such isomerizations can result in loss of functionality, as when an olefinic alco hol rearranges to a ketone. In particu lar, Li finds that 2 to 4% of dichlorobis(triphenylphosphine)ruthenium(II) in water isomerizes homoallylic alco hols like l-phenyl-3-buten-l-ol to 1-phenyl-l-buten-3-ol. His coworkers in this project are Chen; Dong Wang, who is a visiting chemist from the Chinese Acad emy of Science, Beijing; and graduate student John X. Haberman. In addition to investigators who dis cussed water as a solvent in organic
chemistry, others told the symposium they had dispensed with solvents en tirely. Organic chemistry professor Donald C. Dittmer of Syracuse Univer sity simply grinds up the reactants in a mortar. Dittmer's reaction is the reduc tion of 2,3-epoxides of alkyl p-toluenesulfonates by telluride ions. Working with graduate students Yongmei Wang and Bin Chao, he combines tellurium powder, sodium hydroxymethanesulfinate, potassium hydroxide, and a sul fonate ester in the mortar. The sodium hydroxymethanesulfinate, which is made by reaction of formaldehyde with sodium dithionite (Na2S204), reduces tellurium to tellu ride. One sulfonate ester substrate that
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Environmentally benign reaction uses no solvent ' OS0 2 C 6 H 5 CH 3 Epoxygeraniol p-toluenesulfonate
the Syracuse group uses is the enantiomeric epoxide that one gets on subjecting geraniol to the Sharpless asymmetric epoxidation. Teiiuride reduces this sulfonate ester to linalool and is itself reoxidized to tellurium metal. The Syracuse researchers do use some solvent, adding diethyl ether in the workup to leach linalool from the sludge. But the tellurium mixture can be reused with the addition of more sulfinate reducing agent, Dittmer emphasized. Yet one more way to dispense with solvent is to combine reactants in the solid state. Chemistry professor John R. Scheffer of the University of British Columbia, Vancouver, seeks to do this by making salts of one reactant with an amino group and another reactant with an acidic group like carboxyl. In this way, the two molecule types crystallize lying close enough to one another for reaction, the ionic interaction making them compatible. One example Scheffer noted is photolysis of a cyclopentanone with both a cyclopentene and an acetate group attached. In solution with no sensitizer, the product is a seven-membered ring fused to a five-membered ring. But when Scheffer forms the solid carboxylate salt with a basic sensitizer, the product of the solvent-free photolysis is a tricyclic system. Still another way to do organic synthesis without a solvent is in a microwave oven. Product manager Jean Luc Lenoir of Prolabo, Mercerville, N.J., described the performance of his company's newly introduced Synthewave 402 focused microwave unit. One example Lenoir cited is conversion of cyclohexanone to caprolactam. The operator combines cyclohexanone, hydroxylamine-O-sulfonic acid, and silica in the 250-mL reactor vessel of the oven. The intermediate cyclohexanone oxime-O-sulfonic acid splits out sulfuric acid, which catalyzes the Beckmann rearrangement to the lactam. Though reactions catalyzed by meth-
Tellurium HOCH 2 S0 2 Na
Linalool
ylrhenium trioxide (MTO) require organic solvents and absolutely anhydrous conditions, the small amounts of rhenium compound needed and the clean reactions it catalyzes may qualify such reactions as environmentally benign also. Much knowledge of its chemistry is owing to efforts of inorganic chemistry professor Wolfgang A. Herrmann beginning in the early 1990s at Munich Technical University in Germany. Indeed, Herrmann devised the synthesis by which most chemists today make MTO. In the U.S., chemistry professor James H. Espenson of Iowa State University, Ames, has also been mining this quarry extensively; he reported his latest results at the New Orleans symposium. He has previously found that MTO catalyzes reaction of ethyl diazoacetate with Schiff bases to form aziridines—three-membered rings comprised of two carbon atoms and one nitrogen—and with aldehydes and ketones to give epoxides [/. Org. Chem., 60, 7090 (1995)]. Now in work with postdoctoral fellow Zuolin Zhu, he finds that olefins react to give cyclopropanes. For example, styrene yields 81% of ethyl 2-phenylcyclopropanecarboxylate. Also, MTO catalyzes reactions of organic azides with aldehydes to make the very Schiff bases that are the starting materials of the aziridine syntheses. On another front, Espenson has explored MTO-catalyzed oxidation of aromatics by hydrogen peroxide to quinones. This work was foreshadowed by that of Herrmann, who has used MTO to catalyze oxidation of 2-methylnaphthalene to 2-methy 1-1,4naphthoquinone, which is vitamin K-3. Working with graduate student Josemon Jacob, Espenson got quantitative yields of 2,3-dimethylbenzoquinone from o-xylene, the 2,6-dimethylquinone from ra-xylene, and the 2,5dimethylquinone from p-xylene, with no other products and no attack on the methyl groups. •
