- SUBSTITUTED 2,3-BENZODIAZEPINES DERIVATIVES
-
Derivatives of 2,3- benzodiazepines as inhibitors of Bromodomain and extra C-terminal domain (BET) proteins, in particular the BRD4 family member, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceuti
- -
-
Page/Page column 52
(2021/08/06)
-
- Discovery of a crystalline sulforaphane analog with good solid-state stability and engagement of the Nrf2 pathway in vitro and in vivo
-
The antioxidant natural product sulforaphane (SFN) is an oil with poor aqueous and thermal stability. Recent work with SFN has sought to optimize methods of formulation for oral and topical administration. Herein we report the design of new analogs of SFN with the goal of improving stability and drug-like properties. Lead compounds were selected based on potency in a cellular screen and physicochemical properties. Among these, 12 had good aqueous solubility, permeability and long-term solid-state stability at 23 °C. Compound 12 also displayed comparable or better efficacy in cellular assays relative to SFN and had in vivo activity in a mouse cigarette smoke challenge model of acute oxidative stress.
- Boehm, Jeffrey,Davis, Roderick,Murar, Claudia E.,Li, Tindy,McCleland, Brent,Dong, Shuping,Yan, Hongxing,Kerns, Jeffrey,Moody, Christopher J.,Wilson, Anthony J.,Graves, Alan P.,Mentzer, Mary,Qi, Hongwei,Yonchuk, John,Kou, Jen-Pyng,Foley, Joseph,Sanchez, Yolanda,Podolin, Patricia L.,Bolognese, Brian,Booth-Genthe, Catherine,Galop, Marc,Wolfe, Lawrence,Carr, Robin,Callahan, James F.
-
supporting information
p. 579 - 588
(2019/01/08)
-
- NOVEL TETRAHYDROPYRIDOPYRIMIDINES FOR THE TREATMENT AND PROPHYLAXIS OF HBV INFECTION
-
The present invention provides novel compounds having general formula (I), wherein R1 to R4, A, W, Q and Y are as described herein, compositions including the compounds and methods of using the compounds.
- -
-
Page/Page column 159; 160
(2018/09/25)
-
- Combined inhibition of the EGFR/AKT pathways by a novel conjugate of quinazoline with isothiocyanate
-
Epidermal growth factor receptor inhibitors (EGFR-TKIs) represent a class of compounds widely used in anticancer therapy. An increasing number of studies reports on combination therapies in which the block of the EGFR-TK activity is associated with inhibition of its downstream pathways, as PI3K-Akt. Sulforaphane targets the PI3K-Akt pathway whose dysregulation is implicated in many functions of cancer cells. According to these considerations, a series of multitarget molecules have been designed by combining key structural features derived from an EGFR-TKI, PD168393, and the isothiocyanate sulforaphane. Among the obtained molecules 1-6, compound 6 emerges as a promising lead compound able to exert antiproliferative and proapoptotic effects in A431 epithelial cancer cell line by covalently binding to EGFR-TK, and reducing the phosphorylation of Akt without affecting the total Akt levels.
- Tarozzi, Andrea,Marchetti, Chiara,Nicolini, Benedetta,D'Amico, Massimo,Ticchi, Nicole,Pruccoli, Letizia,Tumiatti, Vincenzo,Simoni, Elena,Lodola, Alessio,Mor, Marco,Milelli, Andrea,Minarini, Anna
-
p. 283 - 291
(2016/05/10)
-
- Inhibitors interacting with the magnesium binding site of reverse transcriptase: Synthesis and biological activity studies of 3′-(Ω- amino-acyl) amino-3′-deoxy-thymidine
-
Active site of reverse transcriptase contains carboxylate groups involved in the magnesium binding. We prepared some nucleoside analogs which could bind to these carboxylates preventing the binding of nucleotides. To the 3′-amino-3′-deoxy-thymidine, different N-protected ω-amino-acids were bound, the protection removed to give the 3′-(ω-amino-acyl-) amino-3′-deoxy-thymidines in good yield. Some showed moderate to low activity in HIV 1 replication test. Copyright Taylor & Francis Group, LLC.
- Goud, Thirumani Venkateshwar,Aubertin, Anne-Marie,Biellmann, Jean-Francois
-
p. 495 - 505
(2008/09/21)
-
- Synthesis and self-association properties of flexible guanidiniocarbonylpyrrole-carboxylate zwitterions in DMSO: Intra- versus intermolecular ion pairing
-
(Chemical Equation Presented) We have synthesized a new class of flexible zwitterions 6a-e, in which a carboxylate is linked via an alkyl chain with variable length (one to five methylene groups) to a guanidiniocarbonylpyrrole cation. The self-association properties of these zwitterions were determined by NMR dilution studies in DMSO and by ESI-MS experiments. The stability and hence also the size of the aggregates formed via self-assembly is critically dependent on the length and therefore flexibility of the spacer. Whereas the smallest zwitterion 6a forms large aggregates already at low concentrations, the more flexible zwitterions only form small oligomers (6b) or dimers (6c-e) at much larger concentrations. The differences between the five zwitterions can be explained based on the different extent of intramolecular ion pairing within the monomers. Any intramolecular ion pairing, which becomes possible with increasing linker length, stabilizes the monomer and therefore destabilizes any oligomer.
- Schmuck, Carsten,Rehm, Thomas,Geiger, Lars,Schaefer, Mathias
-
p. 6162 - 6170
(2008/02/10)
-
- Phospholipid prodrugs of anti-proliferative drugs
-
The invention discloses prodrugs comprising anti-proliferative drugs covalently linked, via bridging group, to a phospholipid moiety such that the active species is preferentially released, preferably by enzymatic cleavage, at the required site of action. The invention further discloses pharmaceutical compositions said prodrugs and the uses thereof for the treatment of diseases and disorders related to inflammatory, to degenerative or atrophic conditions, and to uncontrolled cell growth. FIG.1depicts a graph of animal survival during the course of an experiment wherein mice were i.p. transplanted with 11210 mouse leukemia cells and then treated with vehicle only (squares), MTX (triangles) or molar equivalent dose of DP-MTX071 (circles) according to the regiment described example in Example 11.
- -
-
Page/Page column 11
(2010/02/08)
-
- PHOSPHOLIPID DERIVATIVES OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
-
Disclosed are compounds having non-steroidal anti-inflammatory drugs (NSAIDS) covalently linked to a phospholipid moiety via a bridging group. Also disclosed are a process for the synthesis of the compounds, pharmaceutical compositions comprising the compounds and the use thereof for the treatment of diseases and disorders related to inflammatory conditions.
- -
-
-
- Reagents and methods for specific binding assays
-
The present invention relates to compounds that are bis-biotins. These compounds comprise two biotinyl radicals connected by a chain of atoms, usually at least 16 atoms in length. The bis-biotin is conjugated to a member of a specific binding pair ("sbp m
- -
-
-
- The Preference Profile in Ruthenium Tetroxide Oxidations
-
The preference profile of RuVIII-generated in a catalytic cycle, maintained by periodate in carbon tetrachloride : acetonitrile : water -has been examined from a practical vantage using tyrosine, phenylalanine and lysine as primary substrates. Other factors such as pH, acetonitrile versatility, transport of oxidized ruthenium species across the layers and hydrophobic alignment, influence the course of the reaction. Aryl oxidation, which takes place at the organic interface, is strongly influenced by ring perturbation (pOH-C6H4CH2CH,++; PhCH2CH,+, PhCH2O,+; PhCH2OCONH(Z),-; PhCH2OCO,-; pOH-C6H4CH2CO,+; PhCH2CO,-; PhCO,-). In the case of tyrosine, the preference profile switches from ring oxidation at pH 3 to α-amino group oxidation at pH 6 and 9, whilst with phenylalanine, the amino group is exclusively oxidized even at pH 3. With lysine, the reasonable differences in pKa between the α-amino group (8.95) and the ω-amino unit (10.53), elicit sharp preferences. At pH 3 as well as at 6, the α-amino group is selectively oxidized leading to glutaric acid mono-amide, a finding supported by studies with Nα and Nω protected lysines. Lysine and arginine side-chains are found largely unaffected by the reagent at pH 3 and 6. The findings have been rationalized on the basis of an integrated mechanism. The work has endeavoured to reconcile seemingly conflicting reports in the literature and to project the reagent for selective modifications in synthesis.
- Ranganathan,Muraleedharan,Bhattacharyya,Kundu
-
p. 583 - 589
(2007/10/03)
-
- Use of conformationally restricted benzamidines as arginine surrogates in the design of platelet GPIIb-IIIa receptor antagonists
-
The use of 5,6-bicyclic amidines as arginine surrogates in the design of a novel class of potent platelet glycoprotein IIb-IIIa receptor (GPIIb-IIIa) antagonists is described. The additional conformational restriction offered by the bicyclic nucleus results in 20-400-fold increases in potency compared to the freely flexible, acyclic benzamidine counterpart. The design, synthesis, structure-activity relationships (SAR), and in vitro activity of this novel class of GPIIb-IIIa antagonists are presented.
- Sall, Daniel J.,Arfsten, Ann E.,Bastian, Jolie A.,Denney, Michael L.,Harms, Cathy S.,McCowan, Jefferson R.,Morin Jr., John M.,Rose, Jack W.,Scarborough, Robert M.,Smyth, Mark S.,Um, Suzane L.,Utterback, Barbara G.,Vasileff, Robert T.,Wikel, James H.,Wyss, Virginia L.,Jakubowski, Joseph A.
-
p. 2843 - 2857
(2007/10/03)
-
- Asymmetric catalysis of intramolecular N-H insertion reactions of α-diazocarbonyls
-
Intramolecular N-H insertion reactions of α-diazocarbonyl substrates are catalysed by rhodium(II) carboxylates with catalyst-dependent competition with C-H insertion and β-elimination; asymmetric N-H insertion leading to a pipecolic acid derivative with ee up to 45% is achieved using chiral catalysts.
- Garcia, Concepcion Fernandez,McKervey, M. Anthony,Ye, Tao
-
p. 1465 - 1466
(2007/10/03)
-
- Phenylalanine derivative and proteinase inhibitor
-
A phenylalanine derivative having the formula (I): X represents hydrogen, (b) hydroxy, (c) nitro, or (d) C?-C? alkyloxy which may be substituted with phenyl; Y represents wherein R1 and R2 are, independently, (a) hydrogen, provided that both R1 and R2 are not hydrogen at the same time; (b) phenyl, which may be substituted with (i) phenylcarbonyl, (ii) C?-C? alkylcarbonyl, (iii) C?-C? alkyl, which may be further substituted with C?-C? alkoxycarbonyl or hydroxycarbonyl, (iv) C?-C? alkenyl, which may further be substituted with C?-C? alkoxy-carbonyl, (v) trifluoromethyl; (c) pyridyl, which may be substituted with C?-C? alkoxy; (d) C?-C? alkyl, which may be substituted with (i) hydroxy, (ii) C?-C? alkoxycarbonyl, (iii) pyridyl, or (iv) phenyl, which may be further substituted with C?-C? alkylaminocarbonyl; (e) C?-C? cycloalkyl, which may be substituted with C?-C? alkyl; or (f) R1 and R2 may form, with the nitrogen atom attached thereto, (i) piperidino, which may be substituted with phenylcarbonyl or (ii) pyrrolidyl, which may be substituted with C?-C? alkoxycarbonyl; or a pharmaceutically acceptable salt thereof. This phenylalanine derivative is effective as a proteinase inhibitor.
- -
-
-
- Composition containing a penem or carbapenem antibiotic and the use of the same
-
Administration of an N-acylated amino acid in association with a penem or carbapenem antibiotic relieves or eliminates the renal problems associated with administration of the antibiotic alone. The amino acid derivative and antibiotic may be formulated together as a composition or administered separately, either simultaneously or sequentially.
- -
-
-
- THE ENZYMATIC RING EXPANSION OF PENICILLINS TO CEPHALOSPORINS: SIDE CHAIN SPECIFICITY
-
Structural variants of the acylamino side chain of penicillins have been tested as substrates for Deacetoxy/Deacetyl Cephalosporin C Synthetase from C. acremonium CO 728.A six carbon chain terminating in a carboxyl group was found to permit efficient ring expansion to cephems, with the exception of δ-(L-α-aminoadipoyl).
- Baldwin, Jack E.,Adlington, Robert M.,Crabbe, M. James,Knight, Graham,Nomoto, Takashi,et al.
-
p. 3009 - 3014
(2007/10/02)
-
- STUDIES ON LACTAMS IX. A CONVENIENT SYNTHESIS OF LACTAM RINGS
-
The auto-cyclization reaction has been employed for the synthesis of lactam rings by means of reduction from ω-carbobenzoxyamino acid active esters in high dilution method.
- Ogura, Haruo,Takeda, Kazuyoshi
-
p. 467 - 468
(2007/10/02)
-
