The Scripps Research Institute

Massachusetts Institute of Technology

University of California

The Hong Kong University of Science and Technology

K Barry Sharpless

Valery Fokin

Jiajia Dong

Luke Green

Fahmi Himo

Jeffery W Kelly

Wentao Chen

Guigen Li

Vsevold A Rostovtsev

Yun Gao

Palmer Taylor

Peng Wu

Aleksandra Baranczak

Vsevold V Rostovtsev

Larisa Krasnova

Luke R Kwisnek

James S Oakdale

Zoran Radic

M G Finn

Istvan E Marko

Tomoyuki Shibata

Hoi-Lun Kwong

Rakesh Sit

Bing Gao

Zilei Liu

Gunther Schlingloff

Hong Liu

Jonathan Clive Tripp

Brent K Blackburn

Andrei K Yudin

Lisa Wang

Jie Li

Hua Wang

A Erik Rubin

Robert Epple

Beata Tao

Ryu Oi

Declan Gilheany

Byeong M Kim

Jens Hartung

Wihelm K Amberg

Tatsuzo Ukita

Yasukazu Ogino

Yasuhiro Kawanami

Matthias Beller

Jason E Hein

Alexander V Gontcharov

Larissa Krasnova

Joachim Rudolph

Jae Uk Jeong

Han-Ting Chang

Suhua Li

Guochen Jia

Guocheng Jia

Gisela-Andrea Camacho-Hernandez

Malin Andersson

Valery V Fokin

Jonathan C Tripp

Vsevolod Rostovsev

This application describes modified amino acids and polypeptides comprising a SOF or CHCHSOF group bound to the side chain of an amino acid or amino acid residue of a polypeptide in place of a hydrogen of a hydroxyl or amino substituent thereof. Methods of covalently binding the polypeptides to receptor sites of receptor proteins are also described herein.

Sulfur (VI) fluoride compounds and methods for the preparation thereof

A high-throughput screening methods for identifying candidate anticancer medicinal agents is described herein. The candidate anticancer medicinal agents are arylfluorosulfate compounds derived from phenolic compounds. The method involves in situ generation of the arylfluorosulfate compounds in multi-well plates by reaction of phenolic compounds in DMSO with a saturated solution of SOFdissolved in a solvent such as acetonitrile, in the presence of an organic base, followed by reaction of generated fluoride ion with trimethylsilanol to form volatile trimethylsilyl fluoride. Solvents, organic base, and silyl compounds are then removed, in vacuo, to afford the arylfluorosulfate compounds suitable for biological screening in cancer cell lines without further purification.

Arylfluorosulfate compounds and methods

Thionyl tetrafluoride gas reacts efficiently with primary amines to form reactive iminosulfur oxydifluoride compounds. These dual S&#x2014;F loaded iminosulfur oxydifluoride compounds, in turn, readily react with secondary amines or aryloxy silyl ethers (ArO&#x2014;SiR), yielding the corresponding fused heteroatom-linked substrates. Iminosulfur oxyfluoride polymers also are provided by disclosed methods.

Thionyl tetrafluoride modified compounds and uses

This application describes a compound represented by Formula (I): wherein: Y is a biologically active organic core group comprising one or more of an aryl group, a heteroaryl aryl group, a nonaromatic hydrocarbyl group, and a nonaromatic heterocyclic group, to which Z is covalently bonded; n is 1, 2, 3, 4 or 5; m is 1 or 2; Z is O, NR, or N; Xis a covalent bond or &#x2014;CHCH&#x2014;, Xis O or NR; and R comprises H or a substituted or unsubstituted group selected from an aryl group, a heteroaryl aryl group, a nonaromatic hydrocarbyl group, and a nonaromatic heterocyclic group. Methods of preparing the compounds, methods of using the compounds, and pharmaceutical compositions comprising the compounds are described as well.

In alternative embodiments, the invention provides nucleophilic hydroxyimino-acetamido alkylamine antidotes that cross the blood-brain barrier (BBB) to catalyze the hydrolysis of organophosphate (OP)-inhibited human acetylcholinesterase (hAChE) in the central nerve system (CNS). The hydroxyimino-acetamido alkylamines of the invention are designed to fit within AChE active center gorge dimensions, bind with reasonable affinity, and react with the conjugated phosphate atom in the gorge. The hydroxyimino-acetamido alkylamines of the invention are also designed to possess ionization states that govern affinity and reactivity for the two linked hAChE re-activation steps. In alternative embodiments, the invention provides pumps, devices, subcutaneous infusion devices, continuous subcutaneous infusion devices, infusion pens, needles, reservoirs, ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi-chambered pump, a syringe, a cartridge or a pen or a jet injector, comprising a compound of the invention.

Centrally active and orally bioavailable antidotes for organophosphate exposure and methods for making and using them

This application describes a compound represented by Formula (I):YZX&#x2014;S(O)(X)F)]&#x2003;&#x2003;(I)wherein: Y is a biologically active organic core group comprising one or more of an aryl group, a heteroaryl aryl group, a nonaromatic hydrocarbyl group, and a nonaromatic heterocyclic group, to which Z is covalently bonded; n is 1, 2, 3, 4 or 5; m is 1 or 2; Z is O, NR, or N; Xis a covalent bond or &#x2014;CHCH&#x2014;, Xis O or NR; and R comprises H or a substituted or unsubstituted group selected from an aryl group, a heteroaryl aryl group, a nonaromatic hydrocarbyl group, and a nonaromatic heterocyclic group. Methods of preparing the compounds, methods of using the compounds, and pharmaceutical compositions comprising the compounds are described as well.

Sulfur(VI) fluoride compounds and methods for the preparation thereof

Condensation of fluoro-substituted and silyl-substituted monomers provides polymers suitable for use, e.g., as engineering polymers. A monomer composition is condensed in the presence of a bifluoride or poly(hydrogen fluoride) fluoride salt. The monomer composition contains a compound of formula F-X-F and a compound of formula (R)Si&#x2014;Z&#x2014;Si(R), and forms an alternating X-Z polymer chain and a silyl fluoride byproduct. X has the formula -A(-R-A)n-; each A is SO, C(&#x2550;O), or Het; Ris an organic moiety; n is 0 or 1; Het is an aromatic nitrogen heterocycle; Z has the formula -L-R-L-; each L is O, S, or N(R); and each Ris an organic moiety, and Rcomprises H or an organic moiety.

Polymerization of silyl- and fluoro-containing monomers

In alternative embodiments, provided are selective agonists having a high affinity for the alpha7 nicotinic acetylcholine receptor (&#x3b1;7 nAChR), assays for selectivity of nicotinic receptor subtype and ligand-gated ion channel subtype based on receptor occupation and response, behavioral assessments for reversing cognitive impairment after scopolamine treatment, enhancing memory retention over time, pharmaceutical compositions and formulations and devices comprising them, and methods for making and using them, including characterizing and efficiently assaying them for receptor subtype selectivity. In alternative embodiments, provided are substituted anti 1,2,3-triazoles compounds with high affinity, and selective binding, for the alpha7 nicotine acetylcholine receptor (&#x3b1;7 nAChR), as exemplified by 5-(1-(2-(Piperidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)-1H-indole ('IND1'), 5-((quinuclid-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indole ('IND8') and 3-(4-hydroxyphenyl-1,2,3-triazol-1-yl) quinuclidine (&#x201c;QND8&#x201d;). In alternative embodiments, provided are products of manufacture such as pumps, devices, syringes and the like comprising a compound, pharmaceutical composition or formulation as provided herein.

Selective alpha-7 nicotinic receptor agonists and methods for making and using them

This application describes a compound represented by Formula (I): (I) wherein: Y is a biologically active organic core group comprising one or more of an aryl group, a heteroaryl aryl group, a nonaromatic hydrocarbyl group, and a nonaromatic heterocyclic group, to which Z is covalently bonded; n is 1, 2, 3, 4 or 5; m is 1 or 2; Z is O, NR, or N; Xis a covalent bond or &#x2014;CHCH&#x2014;, Xis O or NR; and R comprises H or a substituted or unsubstituted group selected from an aryl group, a heteroaryl aryl group, a nonaromatic hydrocarbyl group, and a nonaromatic heterocyclic group. Methods of preparing the compounds, methods of using the compounds, and pharmaceutical compositions comprising the compounds are described as well.

Condensation of fluoro-substituted and silyl-substituted monomers provides polymers suitable for use, e.g., as engineering polymers. A monomer composition is condensed in the presence of a basic catalyst. The monomer composition contains a compound of formula F&#x2014;X&#x2014;F and a compound of formula (R)Si&#x2014;Z&#x2014;Si(R), and forms an alternating X&#x2014;Z polymer chain and a silyl fluoride byproduct. X has the formula -A(&#x2014;R-A)n-; each A is SO, C(&#x2550;O), or Het; Ris an organic moiety; n is 0 or 1; Het is an aromatic nitrogen heterocycle; Z has the formula -L-R-L; each L is O, S, or N(R); and each Ris an organic moiety, and Rcomprises H or an organic moiety.

Polymerization method and polymers formed therewith

Condensation of fluoro-substituted and silyl-substituted monomers provides polymers suitable for use, e.g., as engineering polymers. A monomer composition is condensed in the presence of a basic catalyst. The monomer composition contains a compound of formula F&#x2014;X&#x2014;F and a compound of formula (R)Si&#x2014;Z&#x2014;Si(R), and forms an alternating X&#x2014;Z polymer chain and a silyl fluoride byproduct. X has the formula -A(-R-A)n-; each A is SO, C(&#x2550;O) or Het; Ris an organic moiety; n is 0 or 1; Het is an aromatic nitrogen heterocycle; Z has the formula -L-R-L-; each L is O, S, or N(R); and each Ris an organic moiety, and Rcomprises H or an organic moiety.

Condensation of fluoro-substituted and silyl-substituted monomers provides polymers suitable for use, e.g., as engineering polymers. A monomer composition is condensed in the presence of a basic catalyst. The monomer composition contains a compound of formula F&#x2014;X&#x2014;F and a compound of formula (R)3Si&#x2014;Z&#x2014;Si(R)3, and forms an alternating X&#x2014;Z polymer chain and a silyl fluoride byproduct. X has the formula -A(-R-A)n-; each A is SO, C(&#x2550;O), or Het; Ris an organic moiety; n is 0 or 1; Het is an aromatic nitrogen heterocycle; Z has the formula -L-R-L-; each L is O, S, or N(R); and each Ris an organic moiety, and Rcomprises H or an organic moiety.

A copper catalyzed click chemistry ligation process is employed to bind azides and terminal acetylenes to provide 1,4-disubstituted 1,2,3-triazole triazoles. The process comprises contacting a solution of an organic azide and a terminal alkyne with a source of catalytic Cu(I) ion to form a 1,4-disubstituted 1,2,3-triazole, wherein the source of Cu(I) ion comprises Cu(II) and a metal capable of reducing Cu(II) to Cu(I). In some embodiments, the metal capable of reducing Cu(II) to Cu(I) is selected from the group consisting of Al, Be, Co, Cr, Fe, Mg, Mn, Ni, and Zn.

Copper-catalysed ligation of azides and acetylenes

A copper catalyzed click chemistry ligation process is employed to bind azides and terminal acetylenes to provide 1,4-disubstituted 1,2,3-triazole triazoles. The process comprises contacting an organic azide and a terminal alkyne with a source of reactive Cu(I) ion in human blood plasma to form by cycloaddition a 1,4-disubstituted 1,2,3-triazole. The source of reactive Cu(I) ion can be, for example, a Cu(I) salt, Cu(II) ion in the presence of a reducing agent, or copper metal.

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La Jolla, CA, United States of America

K Barry Sharpless