Patents Represented by Attorney Donald G. Lewis
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Patent number: 6476190Abstract: Processes for the preparation of modified proteins comprising the coupling of a first peptide segment having a haloacyl group at the N-terminus thereof with a second peptide sequent having a carbonylthiol group at the C-terminus thereof are disclosed. Novel modified proteins produced by the process are also disclosed.Type: GrantFiled: December 29, 1998Date of Patent: November 5, 2002Assignee: The Scripps Research InstituteInventors: Stephen B. H. Kent, Martina Schnolzer-Rackwitz
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Patent number: 6462193Abstract: Hydroxyazepanes display inhibitory activity with respect to glycosidase, with Ki values from-moderate to low micromolar range. Benzyl and 3,6-dibenzyl derivatives of hydroxyazepanes display inhibitory activity with respect to HIV protease. These compounds are synthesized either by chemoenzymatic or chemical methodologies.Type: GrantFiled: August 23, 1999Date of Patent: October 8, 2002Assignee: The Scripps Research InstituteInventors: Chi-Huey Wong, Francisco Moris-Varas
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Patent number: 6462054Abstract: Potent inhibitors of fatty acid amide hydrolase (FAAH) are constructed having Ki's below 200 pM and activities 102-103 times more potent than the corresponding trifluoromethyl ketones. The potent inhibitors combine several features, viz.: 1.) an &agr;-keto heterocylic head group; 2.) a hydrocarbon linkage unit employing an optimal C12-C8 chain length; and 3.) a phenyl or other &pgr;-unsaturation corresponding to the arachidonyl &Dgr;8.9/&Dgr;11.12 and/or oleyl &Dgr;9.10 positions. A preferred &agr;-keto heterocylic head group is &agr;-keto N4 oxazolopyridine, with incorporation of a second weakly basic nitrogen. Fatty acid amide hydrolase is an enzyme responsible for the degradation of oleamide (an endogenous sleep-inducing lipid) and anandamide (an endogenous ligand for cannabinoid receptors).Type: GrantFiled: March 27, 2000Date of Patent: October 8, 2002Assignee: The Scripps Research InstituteInventor: Dale L. Boger
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Patent number: 6441186Abstract: Epothilone A, epothilone B, analogs of epothilone and libraries of epothilone analogs are synthesized. Epothilone A and B are known anticancer agents that derive their anticancer activity by the prevention of mitosis through the induction and stabilization of microtubulin assembly. The analogs of epothilone are novel. Several of the anlogs are demonstrated to have a superior cytotoxic activities as compared to epothilone A or epothilone B as demonstrated by their enhanced ability to induce the polymerization and stabilization of microtubules.Type: GrantFiled: September 4, 1997Date of Patent: August 27, 2002Assignee: The Scripps Research InstituteInventors: Kyriacos C. Nicolaou, Yun He, Sacha Ninkovic, Joaquin Pastor, Frank Roschangar, Francisco Sarabia, Hans Vallberg, Dionisios Vourloumis, Nicolas Winssinger, Zhen Yang, N. Paul King, M. Ray Finlay
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Patent number: 6423834Abstract: Aureobacterium barkerei strain KDO-37-2 (ATCC 49977) and KDO aldolase (EC 4.1.2.23) isolated therefrom are disclosed. The KDO aldolase is further disclosed to have a broad substrate specificity with respect to its reverse reaction, i.e. the condensation of aldoses with pyruvate to form a wide range of 2-keto-3-deoxy-onic acids, including 2-keto-3-deoxy-nonulosonic acid, 2-keto-3-deoxy-octulosonic acid, 2-keto-3-deoxy-heptulosonic acid, and 2-keto-3-deoxy-hexulosonic acid. In particular, 3-deoxy-D-manno-2-octulosonic acid (D-KDO), a vital component of lipopolysaccharides found in the bacterial outer membrane may be synthesized from D-arabinose and pyruvate in 67% yield. Additionally, protected forms of the KDO aldolase products, e.g. hexaacetyl 2-keto-3-deoxy-nonulosonic acid and pentaacetyl 2-keto-3-deoxy-octulosonic acid, may be decarboxylated to form the corresponding 2-deoxy-aldoses, e.g. 2-deoxy-octulose and 2-deoxy-heptulose respectively.Type: GrantFiled: February 9, 1999Date of Patent: July 23, 2002Assignee: The Scripps Research InstituteInventors: Chi-Huey Wong, Takeshi Sugai, Gwo-Jenn Shen
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Patent number: 6380394Abstract: Novel analogs of epothilone A, epothilone B, and epothilone C are synthesized by Stille coupling thazole-stannanes to macrolactone intermediates. The synthetic epothilone analogs selectively prevent mitosis in cancer cells through the induction and stabilization of microtubulin assembly. Selected synthetic epothilone analogs are demonstrated to have greater bioactivity than their corresponding native compound.Type: GrantFiled: June 22, 1998Date of Patent: April 30, 2002Assignee: The Scripps Research InstituteInventors: Kyriacos C. Nicolaou, N. Paul King, M. Ray Finlay, Yun He, Frank Roschangar, Dionisios Vourloumis, Hans Vallberg, Francisco Sarabia, Sacha Ninkovic, David Hepworth, Tianhu Li
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Patent number: 6368839Abstract: Antibodies that catalyze the aldol reaction are generated by immunization with a reactive compound that covalently traps a Lysine (Lys) residue in the binding pocket of the antibody by formation of a stable vinylogous amide, i.e., a covalent antibody/hapten complex. The resultant catalytic antibodies employ a catalytic mechanism which mimics the catalytic mechanism employed by natural class I aldolase enzymes.Type: GrantFiled: November 16, 1999Date of Patent: April 9, 2002Assignee: The Scripps Research InstituteInventors: Carlos F. Barbas, III, Richard A. Lerner, Juergen Wagner
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Patent number: 6350905Abstract: Osmium-catalyzed aminohydroxylation reactions are accelerated and expanded in scope by the use of olefinic substrates having ionic groups, either anionic or cationic. The use of ionic groups on olefinic substrates also extends the aminohydroxylatable positions of unsaturations to include &agr;,&bgr;, &bgr;,&ggr;, and &ggr;,&dgr; positions, with respect to such ionic groups. A mechanism for the disclosed acceleration and extension is provided.Type: GrantFiled: August 20, 1999Date of Patent: February 26, 2002Assignee: The Scripps Research InstituteInventors: K. Barry Sharpless, Valery Fokin
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Patent number: 6329497Abstract: Analogs of sandramycin (1) are synthesized and shown to have cytoxicity against various tumor cell types. The relative cytotoxic properties of the sandramycin analogs are approximately parallel tp their relative DNA binding affinities. An exception to this generalization is compound (4) which completely the sandramycin chromophore phenol. Although typically 4-10× less potent than sandramycin against leukemia cell lines, compound (4) proved to be 1-10,000× more potent against melanomas, carcinomas, and adenocarcinomas exhibiting IC50 values of 1 pM-10 nM. This activity places compound (4) amongst the most potent agents identified to date.Type: GrantFiled: December 3, 1999Date of Patent: December 11, 2001Assignee: The Scripps Research InstituteInventor: Dale L. Boger
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Patent number: 6310209Abstract: The present invention relates to a method for the synthesis of the dihydroindole C-ring found in CC-1065/duocarmycin analogs.Type: GrantFiled: July 10, 2000Date of Patent: October 30, 2001Assignee: The Scripps Research InstituteInventor: Dale L. Boger
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Patent number: 6307018Abstract: Disclosed herein is a process whereby oligopeptides are ligated to form ligation peptide products. In the first step, two starting oligopeptides are ligated to form an intermediate having an amino-thioester linkage. In the second step, the aminothioester linkage undergoes a rearrangement to form a peptide having an N-substituted amide linkage. In an optional third step, the N-substitution of the amide linkage is chemically removed to form a native peptide linkage.Type: GrantFiled: June 22, 1999Date of Patent: October 23, 2001Assignee: The Scripps Research InstituteInventors: Stephen B. H. Kent, Tom W. Muir, Philip E. Dawson, Steven J. Bark, Lynne Canne Bannen
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Patent number: 6294374Abstract: Three monoclonal aldolase antibodies, generated against a &bgr;-diketone hapten by reactive immunization, catalyzed rapid and highly enantioselective retro-aldol reactions providing ent-9a-k by kinetic resolution. Compounds 9a, 9g and 9k were resolved in multi-gram quantities using 0.005-0.0004 mol % antibody catalyst. Enantiomerically pure starting materials, 9a-k, are useful synthons for the construction of epothilones A-E (2-6) and their analogs including 13-alkyl derivatives. Previously, the use of compound 9a as a synthon was reported in the preparation of epothilones A-D, 2-5. To further expand this synthon-based strategy, syntheses of epothilone E, 6, 13-methyl epothilone C, 7, and their trans-isomers have been achieved starting from enantiomerically pure thiazole aldols 9g and 9a, respectively, prepared by large-scale antibody catalyzed resolutions.Type: GrantFiled: October 8, 1999Date of Patent: September 25, 2001Assignee: The Scripps Research InstituteInventors: Subhash C. Sinha, Richard A. Lerner, Carlos F. Barbas, III
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Patent number: 6271400Abstract: An process for epoxidizing diversely functionalized olefins by oxorhenium catalysis employs conditions which control water concentration. By controlling water concentration, one can maximize monoperoxo complex formation and increase turnover which subsequently reduces diol side products obtained from epoxide ring opening and increases the yield of the desired epoxide product. The optimal range of water concentrations is 0.50-80.0 mol %. Using less than 0.5 mol % water does not result in practical turnovers and 1.0 equivalent of water (or more) is detrimental to the lifetime of the active catalytic species formed.Type: GrantFiled: October 23, 1998Date of Patent: August 7, 2001Assignee: The Scripps Research InstituteInventors: K. Barry Sharpless, Andrei K. Yudin
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Patent number: 6271384Abstract: Onium salts of taxo-diterpenoid-Cn,2-O-aza-arenes form water soluble self-assembling nanostructures above a critical aggregation concentration. The onium salt of aza-arene includes a delocalized charge which renders derivatized taxo-diterpenoids amphoteric, enhances their solubility in water, and promotes self-assembly of water soluble nanostructures, e.g., helical fibular structures and spherical micellular structures. These same onium salts of taxo-diterpenoid-Cn,2-O-aza-arenes are employed as water soluble prodrugs. For example, taxol-2′-methylpyridinium tosylate (MPT) is characterized by an elevated aqueous solubility, rapid activation by serum protein, good stability in most other aqueous solutions, formation of a protein:taxol intermediate and good retention within the circulatory system. The toxicity of the activated form is comparable or greater than underivatized taxol. Furthermore, taxol-2′-MPT can be synthesized by a simple one step reaction between taxol and 2-fluoro-1-MPT.Type: GrantFiled: April 13, 1998Date of Patent: August 7, 2001Assignee: The Scripps Research InstituteInventors: K. C. Nicolaou, Wolfgang Wrasidlo, Rodney K. Guy, Emmanuel Pitsinos
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Patent number: 6262271Abstract: A series of bioactive analogs of (+)-CC-1065 (1) and the duocarmycins 2 and 3 are synthesized. The bioactive analogs include either iso-CI or iso-CBI (6 and 7) as a DNA alkylation subunit. Conjugated to the DNA alkylating subunits are a variety of DNA binding subunits. The bioactive analogs maintain their DNA selectivity and display enhanced reactivity.Type: GrantFiled: April 12, 2000Date of Patent: July 17, 2001Assignee: The Scripps Research InstituteInventor: Dale L. Boger
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Patent number: 6255088Abstract: Enzymatic sulfations of biomolecules catalyzed by 3′-phosphoadenosine-5′-phosphosulfate (PAPS) dependent sulfotransferases are enhanced by coupling the sulfation reaction an enzymatic regeneration of PAPS. The PAPS is enzymatically regenerated from its hydrolysis product 3′,5′-diphosphate (PAP) using recombinant aryl sulfotransferase as the catalyst and aryl sulfate as the substrate. Biomolecules capable of enhanced sulfation by this method include carbohydrates, oligosaccharides, peptides, proteins, flavonoids, and steroids. When enzymatic sulfation and substrate regeneration steps are coupled, the desulfated aryl group produced in the regeneration step has a spectroscopic signature that can be employed for monitoring the progress of the sulfation of the biomolecule.Type: GrantFiled: September 10, 1999Date of Patent: July 3, 2001Assignee: The Scripps Research InstituteInventors: Chi-Huey Wong, Michael D. Burkart
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Patent number: 6252094Abstract: Cyclic chemical switching method is employed for solubilizing and desolubilizing taxo-diterpenoids with respect to aqueous solvents. 2-Halogenated onium salts of aza-arenes are employed to derivatize taxo-diterpenoids so as to alter their solubility in aqueous solvents. The onium salt of aza-arene includes a delocalized charge which imparts polarity and aqueous solubility to taxo-diterpenoid derivatives. Solubilization is achieved in a one step derivatization with the onium salt of 2-halogenated aza-arenes. Desolubilization is achieved by contacting onium salts of taxo-diterpenoid-Cn,2-O-aza-arenes with serum protein to displace the 2-O-aza-arene and form a soluble protein:taxo-diterpenoid intermediate. This protein:taxo-diterpenoid intermediate then dissociates over time to provide a bioactive taxo-diterpenoid. These same onium salts of taxo-diterpenoid-Cn,2-O-aza-arenes are employed as water soluble prodrugs. The toxicity of the activated form is comparable or greater than underivatized taxol.Type: GrantFiled: February 4, 1999Date of Patent: June 26, 2001Assignee: The Scripps Research InstituteInventors: K. C. Nicolaou, Wolfgang Wrasidlo, Rodney K. Guy, Emmanuel Pitsinos
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Patent number: 6232450Abstract: A new class of N-linked Lewis and LacNAc analogs of are synthesized and shown to be effective inhibitors of human fucosyltransferases. In a high yielding reaction sequence the glucosamine derivative 1 was transformed to the 3-azido-2,3-dideoxy sugar 2e under excellent stereocontrol. The LacNAc analog 4d was synthesized as a single isomer in three steps starting from 2e. In a one pot procedure iminocyclitol 5 was transformed into aldehyde 6 and successfully used for reductive amination with 4c and 2f yielding trisaccharide 8a, and disaccharide 7a.Type: GrantFiled: June 7, 1999Date of Patent: May 15, 2001Assignee: The Scripps Research InstituteInventor: Chi-Huey Wong
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Patent number: 6210938Abstract: Nine efficient aldolase antibodies were generated using hapten 2. This hapten combines, in a single molecule, structural components employed for reactive immunization with structural components employed for forming a transition state analog of the aldol reaction. Characterization of two of these antibodies reveals that they are highly proficient (up to 1000-fold better than any other antibody catalyst) and enantioselective catalysts for aldol and retro-aldol reactions and exhibit enantio- and diastereo- selectivities opposite that of antibody 38C2.Type: GrantFiled: December 9, 1999Date of Patent: April 3, 2001Assignee: The Scripps Research InstituteInventors: Carlos F. Barbas, Richard A. Lerner, Guofu Zhong
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Patent number: 6204376Abstract: Libraries are synthesized with oligomeric carbopeptoids and carbonucleotoids. Carbopeptides are oligosaccharides having carbohydrate subunits linked to one another by amide bonds. Carbonucleotoids are oligosaccharides having carbohydrate subunits linked to one another by phosphodiester bonds. Carbopeptide libraries may be fabricated using automated polypeptide synthesizers.Type: GrantFiled: November 20, 1997Date of Patent: March 20, 2001Assignee: The Scripps Research InstituteInventor: Kyriacos C. Nicolaou