- Supramolecular complexes obtained from porphyrin-crown ether conjugates and a fullerene derivative bearing an ammonium unit
-
A methanofullerene derivative with an ammonium subunit (1) has been prepared and its ability to form a supramolecular complex with a porphyrin-crown ether conjugate evidenced by NMR, UV-vis, electrospray mass spectrometry (ES-MS) and luminescence experime
- Solladié, Nathalie,Walther, Mathieu E.,Herschbach, Haiko,Leize, Emmanuelle,Dorsselaer, Alain Van,Duarte, Teresa M. Figueira,Nierengarten, Jean-Fran?ois
-
-
Read Online
- A benzylic linker promotes methyltransferase catalyzed norbornene transfer for rapid bioorthogonal tetrazine ligation
-
Site-specific alkylation of complex biomolecules is critical for late-stage product diversification as well as post-synthetic labeling and manipulation of proteins and nucleic acids. Promiscuous methyltransferases in combination with analogs of S-adenosyl-l-methionine (AdoMet) can functionalize all major classes of biomolecules. We show that benzylic moieties are transferred by Ecm1 with higher catalytic efficiency than the natural AdoMet. A relative specificity of up to 80% is achieved when a norbornene moiety is placed in para-position, enabling for the first time enzymatic norbornene transfer to specific positions in DNA and RNA - even in cell lysate. Subsequent tetrazine ligation of the stable norbornene moiety is fast, efficient, biocompatible and-in combination with an appropriate tetrazine-fluorogenic.
- Muttach,Muthmann,Reichert,Anh?user,Rentmeister
-
-
Read Online
- Polymer-bound self-folding cavitands
-
The attachment of self-folding cavitands to polymeric supports has been succesfully demonstrated. Crosslinked polystyrene and PEGA were used. The synthesis of cavitands properly functionalized for this purpose is reported. The uptake of quest molecules by the resulting materials and the formation of inclusion complexes on the supports was demonstrated.
- Rafai Far, Adel,Lag Cho, Young,Rang, Alexander,Rudkevich, Dmitry M,Rebek Jr., Julius
-
-
Read Online
- Discovery of Tetrahydroisoquinoline-Containing CXCR4 Antagonists with Improved in Vitro ADMET Properties
-
CXCR4 is a seven-transmembrane receptor expressed by hematopoietic stem cells and progeny, as well as by ≥48 different cancers types. CXCL12, the only chemokine ligand of CXCR4, is secreted within the tumor microenvironment, providing sanctuary for CXCR4+ tumor cells from immune surveillance and chemotherapeutic elimination by (1) stimulating prosurvival signaling and (2) recruiting CXCR4+ immunosuppressive leukocytes. Additionally, distant CXCL12-rich niches attract and support CXCR4+ metastatic growths. Accordingly, CXCR4 antagonists can potentially obstruct CXCR4-mediated prosurvival signaling, recondition the CXCR4+ leukocyte infiltrate from immunosuppressive to immunoreactive, and inhibit CXCR4+ cancer cell metastasis. Current small molecule CXCR4 antagonists suffer from poor oral bioavailability and off-target liabilities. Herein, we report a series of novel tetrahydroisoquinoline-containing CXCR4 antagonists designed to improve intestinal absorption and off-target profiles. Structure-activity relationships regarding CXCR4 potency, intestinal permeability, metabolic stability, and cytochrome P450 inhibition are presented.
- Miller, Eric J.,Jecs, Edgars,Truax, Valarie M.,Katzman, Brooke M.,Tahirovic, Yesim A.,Wilson, Robert J.,Kuo, Katie M.,Kim, Michelle B.,Nguyen, Huy H.,Saindane, Manohar T.,Zhao, Huanyu,Wang, Tao,Sum, Chi S.,Cvijic, Mary E.,Schroeder, Gretchen M.,Wilson, Lawrence J.,Liotta, Dennis C.
-
p. 946 - 979
(2018/02/17)
-
- CHEMOKINE CXCR4 RECEPTOR MODULATORS AND USES RELATED THERETO
-
The disclosure relates to chemokine CXCR4 receptor modulators and uses related thereto. The receptor modulators can be formulated to form pharmaceutical compositions comprising the disclosed compounds or pharmaceutically acceptable salts or prodrugs thereof. The compositions may be used for managing CXCR4 related conditions, typically prevention or treatment of viral infections abnormal cellular proliferation, retinal degeneration, inflammatory diseases, or as an immunostimulant or immunosuppressant or for managing cancer and may be administered with another active ingredient such as an antiviral agent or chemotherapeutic agent.
- -
-
Page/Page column 173; 174; 175
(2018/09/19)
-
- SUBSTITUTED PYRIDINES AS INHIBITORS OF DNMT1
-
The invention is directed to substituted pyridine derivatives. Specifically, the invention is directed to compounds according to Formula (Iar): (Iar) wherein Yar, X1ar, X2ar, R1ar, R2ar, R3ar, R4ar and R5ar are as defined herein; or a pharmaceutically acceptable salt or prodrug thereof. The compounds of the invention are selective inhibitors of DNMT1 and can be useful in the treatment of cancer, pre-cancerous syndromes, beta hemoglobinopathy disorders, sickle cell disease, sickle cell anemia, and beta thalassemia, and diseases associated with DNMT1 inhibition. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting DNMT1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
- -
-
Page/Page column 621
(2018/01/20)
-
- HETEROCYCLIC SULFONAMIDE DERIVATIVE AND MEDICINE COMPRISING SAME
-
The present invention provides a compound represented by the formula (I): wherein each symbol is as defined in the DESCRIPTION, or a pharmaceutically acceptable salt thereof. The compound has a superior TRPA1 antagonist activity, and can provide a medicament useful for the prophylaxis or treatment of diseases involving TRPA1 antagonist and TRPA1.
- -
-
Paragraph 0411; 0426; 0427
(2016/12/01)
-
- Nucleotides and aptamers containing boronic acid groups having biased binding to glycosylated proteins, and uses thereof
-
The present disclosure encompasses oligonucleotide aptamers selectively binding a target glycosylated polypeptide or protein, and having biased affinity for the glycan through a boronic acid linked to a nucleosidic base of a nucleotide(s). The disclosure further encompasses methods for isolating an aptamer(s) selectively binding a target glycosylated polypeptide, where, from a population of randomized oligonucleotides that have at least one nucleotide having a boronic acid label linked to a base, is selected a first subpopulation of aptamers binding to the target glycosylated polypeptide or protein. This subpopulation is then amplified without using boronic acid-modified TTP, and amplification products not binding to a target glycosylated polypeptide or protein are selected. The second subpopulation of aptamers is then amplified using boronic acid-modified TTP to provide a population of boronic acid-modified aptamers capable of selectively binding to a glycosylation site of a target polypeptide or protein. Other aspects of the disclosure encompass methods for the use of the modified aptamers to detect glycosylated species of a polypeptide or protein.
- -
-
-
- HETEROCYCLIC AMIDE DERIVATIVE AND MEDICINE CONTAINING SAME
-
Compound represented by formula (I): wherein each symbol is as defined herein, exhibit TRPA1 antagonist activity, and are useful for the prophylaxis or treatment of diseases involving TRPA1 antagonist and TRPA1.
- -
-
Paragraph 0323; 0334; 0335
(2015/10/28)
-
- Quantitative analysis of histone demethylase probes using fluorescence polarization
-
We previously reported methylstat as a selective inhibitor of jumonji C domain-containing histone demethylases (JHDMs). Herein, we describe the synthesis of a fluorescent analogue of methylstat and its application as a tracer in fluorescence polarization assays. Using this format, we have evaluated the binding affinities of several known JHDM probes, as well as the native cofactor and substrate of JHDM1A. This fluorophore allowed a highly robust and miniaturized competition assay sufficient for high-throughput screening.
- Xu, Wenqing,Podoll, Jessica D.,Dong, Xuan,Tumber, Anthony,Oppermann, Udo,Wang, Xiang
-
supporting information
p. 5198 - 5202
(2013/07/26)
-
- HISTONE DEACETYLASE INHIBITORS
-
The disclosure provides compounds of formula I and methods for preparation thereof. The compounds act as inhibitor of histone deacetylase.
- -
-
Page/Page column 18; 19
(2012/05/04)
-
- A traceless vascular-targeting antibody-drug conjugate for cancer therapy
-
Right on target: A chemically defined vascular-targeting antibody-drug conjugate (ADC) that offers comprehensive tumor coverage has been developed. When injected intravenously, this ADC potently inhibited tumor growth in a syngeneic immunocompetent model of murine cancer which cannot be cured by conventional cytotoxic agents. Copyright
- Bernardes, Go?alo J. L.,Casi, Giulio,Trüssel, Sabrina,Hartmann, Isabelle,Schwager, Kathrin,Scheuermann, J?rg,Neri, Dario
-
supporting information; experimental part
p. 941 - 944
(2012/03/26)
-
- GLUCOSE SENSOR MOLECULE
-
The present invention provides a glucose sensor having a glucose receptor containing a binding site of formula (I): wherein X, n, m and R1 are defined herein. Also provided is a glucose sensor molecule for use in such a glucose sensor, the glucose sensor molecule containing the binding site of formula (I). The binding site has been found to have particularly good selectivity for glucose.
- -
-
Page/Page column 18
(2012/07/28)
-
- HISTONE DEACETYLASE INHIBITORS
-
The disclosure provides compounds of formula I and methods for preparation thereof. The compounds act as inhibitor of histone deacetylase.
- -
-
Page/Page column 49; 50
(2011/04/13)
-
- Boronic acid-modified DNA that changes fluorescent properties upon carbohydrate binding
-
A long wavelength boronic acid-modified TTP (NB-TTP) has been synthesized and enzymatically incorporated into DNA. Such DNA shows intrinsic fluorescent changes upon carbohydrate addition.
- Yang, Xiaochuan,Dai, Chaofeng,Dayan Calderon Molina, Angie,Wang, Binghe
-
supporting information; experimental part
p. 1073 - 1075
(2010/06/19)
-
- NEW BRADYKININ B1 ANTAGONISTS
-
The invention relates to compounds of formula (I) where in R1, R1a, R1b, R2, R3 and X, X1, X2, X3 have the meaning as cited in the description and the claims. Said compounds are useful as Bradykinin B1 antagonists. The invention also relates to pharmaceutical compositions, the preparation of such compounds as well as the production and use as medicament.
- -
-
Page/Page column 71
(2010/04/03)
-
- IMIDAZOLE CARBOXAMIDES
-
The present invention provides certain imidazole carboxamide derivatives, pharmaceutical compositions thereof, methods of using the same and processes for preparing the same.
- -
-
Page/Page column 12
(2010/02/17)
-
- Antagonists of the human A2A adenosine receptor. 4. Design, synthesis, and preclinical evaluation of 7-aryltriazolo[4,5-d]pyrimidines
-
Antagonism of the human A2A receptor has been implicated as a point of therapeutic intervention in the alleviation of the symptoms associated with Parkinson's disease. This is thought to occur, at least in part, by increasing the sensitivity of the dopaminergic neurons to the residual, depleted levels of striatal dopamine. We herein describe a novel series of functionalized triazolo[4,5-d]pyrimidine derivatives that display functional antagonism of the A2A receptor. Optimization of these compounds has resulted in improvements in potency, selectivity, and the pharmacokinetic properties of key derivatives. These efforts have led to the discovery of 60 (V2006/BIIB014), which demonstrates strong oral activity in commonly used models of Parkinson's disease. Furthermore, this derivative has shown excellent preclinical pharmacokinetics and has successfully completed phase I clinical studies. This compound is presently undergoing further clinical evaluation in collaboration with Biogen Idec.
- Gillespie, Roger J.,Bamford, Samantha J.,Botting, Ruth,Comer, Mike,Denny, Sarah,Gaur, Suneel,Griffin, Michael,Jordan, Allan M.,Knight, Anthony R.,Lerpiniere, Joanne,Leonardi, Stefania,Lightowler, Sean,McAteer, Steven,Merrett, Angela,Misra, Anil,Padfield, Antony,Reece, Mark,Saadi, Mona,Selwood, Daniel L.,Stratton, Gemma C.,Surry, Dominic,Todd, Richard,Tong, Xin,Ruston, Vicki,Upton, Rebecca,Weiss, Scott M.
-
experimental part
p. 33 - 47
(2011/04/19)
-
- HYDROXAMATES AS INHIBITORS OF HISTONE DEACETYLASE
-
Compounds of formula (I), and salts, N-oxides, hydrates and solvates thereof are histone deacetylase inhibitors and are useful in the treatment of cell proliferative diseases, including cancers: wherein Q, V and W independently represent -N= or -C=; B is
- -
-
Page/Page column 58; 60
(2008/12/05)
-
- HDAC INHIBITORS
-
Compounds of formula (I) inhibit HDAC activity, wherein A, B and D independently represent =C- or =N-; W is a divalent radical -CH=CH- or CH2CH2-; R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group; R2 is the side chain of a natural or non-natural alpha amino acid; z is 0 or 1; and Y, L1, and X1 are as defined in the claims.
- -
-
Page/Page column 58-59
(2008/06/13)
-
- An unexpected triethylsilane-triggered rearrangement of thioaurones to thioflavonols under SPPS conditions
-
Thioaurones are converted to a mixture of thiaindenes and thioflavonols when exposed to reaction conditions employed in SPPS, that is, treatment with trifluoroacetic acid in the presence of triethylsilane.
- Varedian, Miranda,Langer, Vratislav,Bergquist, Jonas,Gogoll, Adolf
-
supporting information; experimental part
p. 6033 - 6035
(2009/04/11)
-
- Chemistry and folding of photomodulable peptides - Stilbene and thioaurone-type candidates for conformational switches
-
Optimized synthetic strategies for the preparation of photoswitchable molecular scaffolds based on stilbene or on thioaurone chromophores and their conformationally directing properties, as studied by computations and by NMR spectroscopy, are addressed. For the stilbene peptidomimetics 1, 2 and 3, the length of connecting linkers between the chromophore and the peptide strands was varied, resulting in photochromic dipeptidomimetics with various flexibility. Building blocks of higher rigidity, based on para-substituted thioaurone (4 and 6) and meta-substituted thioaurone chromophores (5 and 7) are shown to have a stronger conformationally directing effect. Design, synthesis, theoretical and experimental conformational analyses are presented.
- Erdelyi, Mate,Varedian, Miranda,Skoeld, Christian,Niklasson, Ida B.,Nurbo, Johanna,Persson, Asa,Bergquist, Jonas,Gogoll, Adolf
-
experimental part
p. 4356 - 4373
(2009/02/07)
-
- HYDRAZONE DERIVATIVE
-
A compound represented by the following formula (I): wherein R1 represents hydrogen, aryl which may have a substituent, a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent, etc.; R2 represents hydrogen, aryl which may have a substituent, a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent, etc.; R3 represents hydrogen, etc.; Ar represents a divalent group derived from aromatic hydrocarbon, etc.; X represents a single bond, linear or branched alkylene having from 1 to 3 carbon atoms which may have a substituent, etc.; and G represents halogen, a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent, a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent, etc., a salt thereof or a solvate thereof; and an agent for inhibiting aggregation and/or deposition of an amyloid protein or an amyloid-like protein, which comprises the compound, a salt thereof or a solvate thereof
- -
-
Page/Page column 41
(2010/11/08)
-
- BASIC AMINE COMPOUND AND USE THEREOF
-
Novel amine compounds which are represented by the following formula (1) and efficacious against diseases such as a viral infectious disease with HIV, rheumatism, and cancer metastasis; typically, A 1 and A 2 represent a hydrogen atom or a substitutable monocyclic or polycyclic heteroaromatic ring and W represents a substitutable benzene ring or any group represented by the following formula (10) or (11): where X represents O, CH 2 , C(=O), NR 11 , or CHR 35 and D represents a group represented by the following formula (6): where Q represents a single bond, NR 12 , or a group represented by the formula (13): and Y represents a group represented by the following formula (7) : where z represents a substitutable monocyclic or polycyclic aromatic ring; and B represents -NR 25 R 26 ; and R 1 to R 26 in the above formulae represent a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group.
- -
-
Page/Page column 48
(2010/11/24)
-
- ENZYME INHIBITORS
-
Compounds of formula (I) are inhibitors of histone deacetylase activity, and are useful in the treatment of, for example, cancers, wherein R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group; R2is the side chain of a natural or non-natural alpha amino acid; Y is a bond, -C(=O)-, -S(=O)2-, -C(=O)O-, -C(O)NR3-, -C(=S)-NR3 , -C(=NH)NR3 or -S(=O)2NR3- wherein R3 is hydrogen or optionally substituted C1-C6 alkyl; L1 is a divalent radical of formula -(Alk1)m(Q)n(Alk2)p- wherein m, n and p are independently 0 or 1 , Q is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5 - 13 ring members, or (ii), in the case where both m and p are 0, a divalent radical of formula -X2-Q1- or -Q1-X2- wherein X2 is -O-, S- or NRA- wherein RA is hydrogen or optionally substituted C1-C3 alkyl, and Q1 is an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5 - 13 ring members, AIk1 and AIk2 independently represent optionally substituted divalent C3-C7 cycloalkyl radicals, or optionally substituted straight or branched, C1-C6 alkylene, C2-C6 alkenylene ,or C2-C6 alkynylene radicals which may optionally contain or terminate in an ether (-O-), thioether (-S-) or amino (-NRA-) link wherein RA is hydrogen or optionally substituted C1-C3 alkyl; X1 represents a bond; -C(=O); or -S(=O)2-; -NR4C(=O)-, -C(=O)NR4-, -NR4C(=O)NR5- , -NR4S(=O)2-, or -S(=O)2NR4-wherein R4 and R5 are independently hydrogen or optionally substituted C1-C6 alkyl; z is 0 or 1 ; A represents an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system wherein the radicals R1R2NH-Y-L1-X1-[CH2]Z- and HONHCO-[LINKER]- are attached different ring atoms; and -[Linker]- represents a divalent linker radical linking a ring atom in A with the hydroxamic acid group CONHOH, the length of the linker radical, from the terminal atom linked to the ring atom of A to the terminal atom linked to the hydroxamic acid group, is equivalent to that of an unbranched saturated hydrocarbon chain of from 3-10 carbon atoms.
- -
-
Page/Page column 147
(2008/06/13)
-
- QUATERNARY SALT CCR2 ANTAGONISTS
-
Quaternary salt compounds of Formula (I) or pharmaceutically acceptable forms thereof, which are CCR2 antagonists and are useful in preventing, treating or ameliorating CCR2 mediated inflammatory syndromes, disorders or diseases in a subject in need thereof.
- -
-
Page/Page column 49-51
(2008/06/13)
-
- Quaternary salt CCR2 antagonists
-
Quaternary salt compounds of Formula (I) or pharmaceutically acceptable forms thereof, which are CCR2 antagonists and are useful in preventing, treating or ameliorating CCR2 mediated inflammatory syndromes, disorders or diseases in a subject in need thereof.
- -
-
Page/Page column 63
(2008/06/13)
-
- ALKYNYL ARYL CARBOXAMIDES
-
The present invention is related to alkynyl aryl carboxamides of Formula (I’) and use thereof for the treatment and/or prevention of an inflammatory disorder, obesity and/or metabolic disorders mediated by insulin resistance or hyperglycemia, comprising diabetes type I and/or II, inadequate glucose tolerance. insulin resistance, hyperlipidemia, hypertriglyceridemia- hypercholesterolemia, polycystic ovary syndrome (PCOS). In particular, the present invention is related to the use of alkynyl aryl carboxamides of Formula (I’) to modulate, notably to inhibit the activity of PTPs. (I’) A is a C2-C15 alkynyl, C2-C6-alkynyl aryl, C2-C6-alkynyl heteroaryl. Cy is an aryl, heteroaryl, cycloalkyl or heterocycle group; n is either 0 or 1. Cy' is an aryl., which may optionally be fused by a 3-8 membered cycloalkyl. R1and R2 are independently from each other is selected from the group consisting of hydrogen or (CI-C6)alkyl. R4and R5 are each independently from each other selected from the group consisting of H, hydroxy. C1 -C6 alkyl, carboxy, C1-C6 alkoxy, C1 -C3 alkyl carboxy, C2-C3 alkenyl carboxy, C2-C3 alkynyl carboxy, amino or R4 and R5 may form an unsaturated or saturated heterocyclic ring, whereby at least one of R4 or R5 is not a hydrogen or C1-C6 alkyl.
- -
-
Page/Page column 52
(2008/06/13)
-
- Cryptophycin compounds
-
The present invention provides cryptophycin compounds of Formula I that are useful in the treatment of neoplasms.
- -
-
Page/Page column 151
(2010/02/05)
-
- Development of Irreversible Diphenyl Phosphonate Inhibitors for Urokinase Plasminogen Activator
-
In this letter we report the synthesis and biochemical evaluation of selective, irreversible diphenyl phosphonate inhibitors for urokinase plasminogen activator (uPA). A diphenyl phosphonate group was introduced on the substratelike peptide Z-D-Ser-Ala-Arg, and modification of the guanidine side chain was investigated. A guanylated benzyl group appeared the most promising side chain modification. A kapp value in the 103 M -1 s-1 range for uPA was obtained, together with a selectivity index higher than 240 toward other trypsin-like proteases such as tPA, thrombin, plasmin, and FXa.
- Joossens,Van Der Veken,Lambeir,Augustyns,Haemers
-
p. 2411 - 2413
(2007/10/03)
-
- A supramolecular oligophenylenevinylene-C60 conjugate
-
A new methanofullerene derivative with an ammonium subunit has been prepared and its ability to form a supramolecular complex with an oligophenylenevinylene (OPV)-crown ether conjugate evidenced by NMR, electrospray mass spectrometry and luminescence expe
- Gutiérrez-Nava, Manuel,Nierengarten, Hélène,Masson, Patrick,Van Dorsselaer, Alain,Nierengarten, Jean-Fran?ois
-
p. 3043 - 3046
(2007/10/03)
-
- Bicyclic fibrinogen antagonists
-
This invention relates to compounds of the formulae: wherein A1is O, S, N—R1or CHR1; A4is N—R4or CHR4; R2is a sidechain containing an acid or ester group; R1, R4and R5are substituents such as H, alkyl and aryl alkyl, and R6is a sidechain containing a nitrogen group; and pharmaceutically acceptable salts thereof, which are effective for inhibiting platelet aggregation, pharmaceutical compositions for effecting such activity, and a method for inhibiting platelet aggregation.
- -
-
-
- Design, synthesis, and proposed active site binding analysis of monocyclic 2-azetidinone inhibitors of prostate specific antigen
-
A homology derived molecular model of prostate specific antigen (PSA) was created and refined. The active site region was investigated for specific interacting functionality and a binding model postulated for the novel 2-azetidinone acyl enzyme inhibitor 1 (IC50 = 8.98 ± 0.90 μM) which was used as a lead compound in this study. A single low energy conformation structure II (Figure 2) was adopted as most likely to represent binding after minimization and dynamics calculations. Systematic analysis of the binding importance of all three side chains appended to the 2-azetidinone was conducted by the synthesis of several analogues. A proposed salt bridge to Lys-145 with 4 (IC50 = 5.84 ± 0.92 μM) gave improved inhibition, but generally the binding of the N-1 side chain in a specific secondary aromatic binding site did not tolerate much structural alteration. A hydrophobic interaction of the C-4 side chain afforded inhibitor 6 (IC50 = 1.43 ± 0.19 μM), and polar functionality could also be added in a proposed interaction with Gln-166 in 5 (IC50 = 1.34 ± 0.05 μM). Reversal of the C-4 ester connectivity furnished inhibitors 7 (IC50 = 1.59 ± 0.15 μM), 11 IC50 = 3.08 ± 0.41 μM) and 13 (IC50 = 2.19 ± 0.36 Mμ) which were perceived to bind to PSA by a rotation of 180° relative to the C-4 ester of normal connectivity. Incorporation of hydroxyl functionality into the C-3 side chain provided 16 IC50 = 348 ± 50 nM) with the greatest increase in PSA inhibition by a single modification. Multiple copy simultaneous search (MCSS) analysis of the PSA active site further supported our model and suggested that 18 would bind strongly. Asymmetric synthesis yielded 18 (IC50 = 226 ± 10 nM) as the most potent inhibitor of PSA reported to date. It is concluded that our design approach has been successful in developing PSA inhibitors and could also be applied to the inhibition of other enzymes, especially in the absence of crystallographic information.
- Adlington,Baldwin,Becker,Chen,Cheng,Cooper,Hermann,Howe,McCoull,McNulty,Neubauer,Pritchard
-
p. 1491 - 1508
(2007/10/03)
-
- Fused imidazopyridine derivatives as antihyperlipidemic agents
-
A novel compound of the formula: wherein ring Q is an optionally substituted pyridine ring; One of R0, R1and R2is —Y0—Z0, and the other tow groups are a hydrogen, a halogen, an optionally substituted hydroxy group, a hydrocarbon group that may be an optionally substituted hydrocarbon group or an acyl group; Y0is a bond or an optionally substituted bivalent hydrocarbon group; Z0is a basic group which may be bonded via oxygen, nitrogen, —CO—, —CS—, —SO2N(R3)— (where R3is hydrogen or an optionally substituted hydrocarbon group), or S(O)n(wherein n is to 0, 1 or 2); .........is a single bond or a double bond, or a salt thereof, which has an excellent LDL receptor up-regulating, blood-lipids lowering, blood-sugar lowering and diabetic complication-ameliorating activity.
- -
-
-
- Dendronized polyacrylates with glucose units in the periphery
-
The synthesis of dendritic building blocks (dendrons) of the first (G-1) and second generation (G-2) with peripheral acetyl-protected glucose moieties is reported. The dendrons can be selectively deprotected at the focal point and the resulting carboxylic
- Zistler, Andrea,Koch, Sabine,Schlueter, A. Dieter
-
p. 501 - 508
(2007/10/03)
-
- Synthesis and study of peptides with semirigid i and i+7 side-chain bridges designed for α-helix stabilization
-
A search for conformational constraints on the peptide α-helical conformation indicated that para-substituted amino acid derivatives of a benzene ring might be suitable for linking pairs of side chains that are separated by two turns of the helix. A 14-residue synthetic, amphiphilic α-helical peptide model system has been used to study the helix stabilizing effects of a series of four such bridges having constitutionally isomeric structures. These bridges were used to link positions 3 and 10 of the model peptides. The peptides were synthesized in good yield by standard solid-phase methods, including cyclization on the solid support. They were then studied for their solution conformations and melting behavior by circular dichroism (CD) spectropolarimetry, and for their elution behavior on reversed-phase HPLC columns. In aqueous solution and in 50% (v/v) trifluoroethanol, the most effective bridge for helix stabilization consisted of a 4-(aminomethyl)phenylacetic acid residue (AMPA) linked by amide bonds to the side chain functional groups of a (S)-2,3-diaminopropionic acid residue (Dap) in position 3 of the model peptide and an aspartic acid residue in position 10. This Dap3(AMPA), Asp10 bridge was about as effective as two Lys(i), Asp(i+4) lactam bridges incorporated linking residues 3 and 7, and 10 and 14, in the same model peptide sequence. This suggests that it is worth about 1kcal/mol of helix stabilization energy. Copyright (C) 1999 Elsevier Science Ltd.
- Yu, Chongxi,Taylor, John W.
-
p. 161 - 175
(2007/10/03)
-