- Design, Synthesis, and Antimicrobial Evaluation of a Novel Bone-Targeting Bisphosphonate-Ciprofloxacin Conjugate for the Treatment of Osteomyelitis Biofilms
-
Osteomyelitis is a major problem worldwide and is devastating due to the potential for limb-threatening sequelae and mortality. Osteomyelitis pathogens are bone-attached biofilms, making antibiotic delivery challenging. Here we describe a novel osteoadsorptive bisphosphonate-ciprofloxacin conjugate (BV600022), utilizing a “target and release” chemical strategy, which demonstrated a significantly enhanced therapeutic index versus ciprofloxacin for the treatment of osteomyelitis in vivo. In vitro antimicrobial susceptibility testing of the conjugate against common osteomyelitis pathogens revealed an effective bactericidal profile and sustained release of the parent antibiotic over time. Efficacy and safety were demonstrated in an animal model of periprosthetic osteomyelitis, where a single dose of 10 mg/kg (15.6 μmol/kg) conjugate reduced the bacterial load by 99% and demonstrated nearly an order of magnitude greater activity than the parent antibiotic ciprofloxacin (30 mg/kg, 90.6 μmol/kg) given in multiple doses. Conjugates incorporating a bisphosphonate and an antibiotic for bone-targeted delivery to treat osteomyelitis biofilm pathogens constitute a promising approach to providing high bone-antimicrobial potency while minimizing systemic exposure.
- Sedghizadeh, Parish P.,Sun, Shuting,Junka, Adam F.,Richard, Eric,Sadrerafi, Keivan,Mahabady, Susan,Bakhshalian, Neema,Tjokro, Natalia,Bartoszewicz, Marzenna,Oleksy, Monika,Szymczyk, Patrycja,Lundy, Mark W.,Neighbors, Jeffrey D.,Russell, R. Graham G.,McKenna, Charles E.,Ebetino, Frank H.
-
-
Read Online
- Synthesis and pharmacological characterisation of arctigenin analogues as antagonists of AMPA and kainate receptors
-
(-)-Arctigenin and a series of new analogues have been synthesised and then tested for their potential as AMPA and kainate receptor antagonists of human homomeric GluA1 and GluK2 receptors expressed in HEK293 cells using a Ca2+ influx assay. In general, these compounds showed antagonist activity at both receptors with greater activity evident at AMPARs. Schild analysis indicates that a spirocyclic analogue 6c acts as a non-competitive antagonist. Molecular docking studies in which 6c was docked into the X-ray crystal structure of the GluA2 tetramer suggest that (-)-arctigenin and its analogues bind in the transmembrane domain in a similar manner to the known AMPA receptor non-competitive antagonists GYKI53655 and the antiepileptic drug perampanel. The arctigenin derivatives described herein may serve as novel leads for the development of drugs for the treatment of epilepsy. This journal is
- Butts, Craig P.,Collingridge, Graham L.,Jane, David E.,Mallah, Shahida,Molnár, Elek,Re?nik, Lisa-Maria,Thatcher, Robert J.,Willis, Christine L.
-
supporting information
p. 9154 - 9162
(2021/11/16)
-
- Application of gastrodia elata bl derived derivative to preparation of medicine for treating acute or chronic pain
-
The invention discloses application of gastrodia elata bl derived derivatives to preparation of a medicine for treating the acute or chronic pain, in particular to compounds as shown in general formulas (I), (II) and (III) and application of pharmaceutically acceptable salt thereof to preparation of the medicine for preventing and/or treating the acute or chronic pain, discloses a preparation method of the compounds, and belongs to the technical field of medicine.
- -
-
Paragraph 0087; 0089; 0094; 0096; 0102; 0104
(2021/01/20)
-
- Application of gastrodia elata bl derived derivatives to preparation of medicine for treating Inflammatory Bowel disease (IBD)
-
The invention discloses compounds as shown in general formulas (I) and (II) and application of pharmaceutically acceptable salt thereof to preparation of a medicine for treating the Inflammatory Boweldisease (IBD), and discloses a preparation method of the compounds.
- -
-
Paragraph 0058; 0060
(2021/01/20)
-
- New 3-(1H-benzo[d]imidazol-2-yl)quinolin-2(1H)-one-based triazole derivatives: Design, synthesis, and biological evaluation as antiproliferative and apoptosis-inducing agents
-
A series of 1,2,3-triazole derivatives based on the quinoline–benzimidazole hybrid scaffold was designed, synthesized, and screened against a panel of NCI-60 humanoid cancer cell lines for in vitro cytotoxicity evaluation, which revealed that compound Q6 was the most potent cytotoxic agent with excellent GI50, TGI, and LC50 values on multiple cancer cell lines. Q6 was tested further on the BT-474 breast cancer line to evaluate the mechanism of action. Preliminary screening studies based on the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay revealed that compound Q6 had an excellent antiproliferative effect against human breast cancer cells, BT-474, with IC50 values of 0.59 ± 0.01 μM. The detailed study based on the acridine orange/ethidium bromide staining (AO/EB) and the 4′,6-diamidino-2-phenylindole (DAPI) assay suggested that the antiproliferative activity shown was due to the induction of apoptosis on exposure to Q6. Further, DCFDA staining showed the generation of reactive oxygen species, altering the mitochondrial potential and leading to the initiation of apoptosis. This was further supported by JC-1 staining, indicating that this scaffold can contribute to the development of more potent derivatives.
- Gaikwad, Nikhil B.,Bansode, Sapana,Biradar, Shankar,Ban, Mayuri,Srinivas, Nanduri,Godugu, Chandraiah,Yaddanapudi, Venkata M.
-
-
- Homologation of Electron-Rich Benzyl Bromide Derivatives via Diazo C-C Bond Insertion
-
The ability to manipulate C-C bonds for selective chemical transformations is challenging and represents a growing area of research. Here, we report a formal insertion of diazo compounds into the "unactivated"C-C bond of benzyl bromide derivatives catalyzed by a simple Lewis acid. The homologation reaction proceeds via the intermediacy of a phenonium ion, and the products contain benzylic quaternary centers and an alkyl bromide amenable to further derivatization. Computational analysis provides critical insight into the reaction mechanism, in particular the key selectivity-determining step.
- Alegre-Requena, Juan V.,De Lescure, Louis,Modak, Atanu,Paton, Robert S.,Race, Nicholas J.,Rynders, Kathryn J.
-
supporting information
(2021/12/27)
-
- BONE TARGETED ANTIMICROBIAL OXAZOLIDINONE RELATED COMPOUNDS, FORMULATIONS THEREOF, AND USES THEREOF
-
Described herein are bisphosphonate oxazolidinone compounds, and conjugates and pharmaceutical formulations thereof, that can include a bisphosphonate and an oxazolidinone (or an oxazolidinone antimicrobial or antibiotic agent, substituent or derivative thereof), where the oxazolidinone can be releasably coupled to the bisphosphonate. Also provided herein are methods of making and methods of using the bisphosphonate oxazolidinone compounds, conjugates and pharmaceutical formulations thereof. Also provided herein are methods of use of the compounds, conjugates and formulations for treating a bone disease or for use in preparing a formulation for the treatment a bone disease.
- -
-
Page/Page column 55
(2020/01/24)
-
- Electrochemical Dimerization of Phenylpropenoids and the Surprising Antioxidant Activity of the Resultant Quinone Methide Dimers
-
A simple method for the dimerization of phenylpropenoid derivatives is reported. It leverages electrochemical oxidation of p-unsaturated phenols to access the dimeric materials in a biomimetic fashion. The mild nature of the transformation provides excellent functional group tolerance, resulting in a unified approach for the synthesis of a range of natural products and related analogues with excellent regiocontrol. The operational simplicity of the method allows for greater efficiency in the synthesis of complex natural products. Interestingly, the quinone methide dimer intermediates are potent radical-trapping antioxidants; more so than the phenols from which they are derived—or transformed to—despite the fact that they do not possess a labile H-atom for transfer to the peroxyl radicals that propagate autoxidation.
- Romero, Kevin J.,Galliher, Matthew S.,Raycroft, Mark A. R.,Chauvin, Jean-Philippe R.,Bosque, Irene,Pratt, Derek A.,Stephenson, Corey R. J.
-
supporting information
p. 17125 - 17129
(2018/12/04)
-
- BISPHOSPHONATE QUINOLONE CONJUGATES AND USES THEREOF
-
Described herein are bisphosphonate quinolone conjugates and pharmaceutical formulations thereof that can include a bisphosphonate and a quinolone, where the quinolone can be releasably coupled to the bisphosphonate. Also provided herein are methods of making and methods of using the bisphosphonate quinolone conjugates and pharmaceutical formualtions thereof.
- -
-
Page/Page column 48; 84
(2018/01/17)
-
- Complete synthesis method of natural product Nostosin B
-
The invention discloses a complete synthesis method of a natural product Nostosin B, and belongs to the technical field of organic synthesis. According to the synthesis method, complete synthesis of the natural product Nostosin B is completed by natural amino acid L-isoleucine, arginine and a non-natural compound 2 which are cheap and easy to obtain through peptide coupling and using of various of functional group protecting groups. The natural product Nostosin B is prepared through the complete synthesis method for the first time. The synthesis method has the advantages of being simple, convenient, feasible, easy to operate and high in yield.
- -
-
-
- New synthesis method of two enantiomers of 4-(4-(benzyloxy)phenyl)-2-hydroxybutyric acid
-
The invention discloses a new synthesis method of two enantiomers of 4-(4-(benzyloxy)phenyl)-2-hydroxybutyric acid. The invention adopts cheap and easily available p-hydroxy benzaldehyde and (R)-(+)-2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde as initial raw materials to conduct total synthesis study on brand new compounds (R)-4-(4-(benzyloxy)phenyl)-2-hydroxybutyric acid and (S)-4-(4-(benzyloxy)phenyl)-2-benzyl hydroxybutyric acid. The invention uses an asymmetric synthesis method to synthesize two molecules by one route, fills the blank, and provides convenience for future scientific research.
- -
-
-
- Discovery and structural optimization of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-ones as RORc inverse agonists
-
Aim: Retinoic acid receptor-related orphan nuclear receptors (RORs) are orphan nuclear receptors that show constitutive activity in the absence of ligands. Among 3 subtypes of RORs, RORc is a promising therapeutic target for the treatment of Th17-mediated autoimmune diseases. Here, we report novel RORc inverse agonists discovered through structure-based drug design. Methods: Based on the structure of compound 8, a previously described agonist of RORa, a series of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives were designed and synthesized. The interaction between the compounds and RORc was detected at molecular level using AlphaScreen assay. The compounds were further examined in 293T cells transfected with RORc and luciferase reporter gene. Thermal stability shift assay was used to evaluate the effects of the compounds on protein stability. Results: A total of 27 derivatives were designed and synthesized. Among them, the compound 22b was identified as the most potent RORc inverse agonist. Its IC50 values were 2.39 μmol/L in AlphaScreen assay, and 0.82 μmol/L in inhibition of the cell-based luciferase reporter activity. Furthermore, the compound 22b displayed a 120-fold selectivity for RORc over other nuclear receptors. Moreover, a molecular docking study showed that the structure-activity relationship was consistent with the binding mode of compound 22b in RORc. Conclusion: 4-(4-(Benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives are promising candidates for the treatment of Th17-mediated autoimmune diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis.
- Wu, Xi-Shan,Wang, Rui,Xing, Yan-Li,Xue, Xiao-Qian,Zhang, Yan,Lu, Yong-Zhi,Song, Yu,Luo, Xiao-Yu,Wu, Chun,Zhou, Yu-Lai,Jiang, Jian-Qin,Xu, Yong
-
p. 1516 - 1524
(2016/11/11)
-
- Synthesis, antiproliferative and pro-apoptotic activity of 2-phenylindoles
-
Breast cancer is the second most common cancer worldwide after lung cancer with the vast majority of early stage breast cancers being hormone-dependent. One of the major therapeutic advances in the clinical treatment of breast cancer has been the introduction of selective estrogen receptor modulators (SERMs). We describe the design and synthesis of novel SERM type ligands based on the 2-arylindole scaffold to selectively target the estrogen receptor in hormone dependent breast cancers. Some of these novel compounds are designed as bisindole type structures, while others are conjugated to a cytotoxic agent based on combretastatin A4 (CA4) which is a potent inhibitor of tubulin polymerisation. The indole compounds synthesised within this project such as 31 and 86 demonstrate estrogen receptor (ER) binding and strong antiproliferative activity in the ER positive MCF-7 breast cancer cell line with IC50values of 2.71?μM and 1.86?μM respectively. These active compounds induce apoptotic activity in MCF-7 cells with minimal effects on normal peripheral blood cells. Their strong anti-cancer effect is likely mediated by the presence of two ER binding ligands for 31 and an ER binding ligand combined with a cytotoxic agent for 86.
- Kelly, Patrick M.,Bright, Sandra A.,Fayne, Darren,Pollock, Jade K.,Zisterer, Daniela M.,Williams, D. Clive,Meegan, Mary J.
-
p. 4075 - 4099
(2016/08/23)
-
- Chiral N-benzyl-N-methyl-1-(naphthalen-1-yl)ethanamines and their in vitro antifungal activity against Cryptococcus neoformans, Trichophytonmentagrophytes and Trichophyton rubrum
-
In the search for new antifungal compounds and to explore structure activity relationships, a series of 24 chiral benzyl amine type antifungals was synthesised and characterised. In vitro testing against the human pathogen Cryptococcus neoformans revealed that several derivatives had MIC50 values similar to that of the commercial drug Butenafine. All of these contained a bulky group in the para position of the benzyl fragment. Eighteen compounds were also tested for activity against the dermatophytes Trichophyton mentagrophytes and Trichophyton rubrum. Of these (R)-N-(4-tert-butylbenzyl)-N- methyl-1-(naphthalen-1-yl)ethanamine (MIC50: 0.06 μg/mL) and a para-benzyloxy substituted derivative (MIC50: 0.125 μg/mL) possessed high activity. Testing of derivatives with a stereocentre at the benzylic carbon, revealed that (S)-stereochemistry was required for potency: a MIC50 value of 1 μg/mL was obtained for (S)-1-(4-tert-butylphenyl) -N-methyl-N-(naphthalen-1-ylmethyl)ethanamine. Preparation of the corresponding fluoromethyl compound was achieved employing lipase B from Candida antarctica as catalyst in the key step. A low antifungal activity was observed for the fluorinated derivative indicating the importance of the amine basicity for the antifungal potency of these compounds.
- Krane Thvedt, Thor H.,Kaasa, Kristin,Sundby, Eirik,Charnock, Colin,Hoff, B?rd Helge
-
p. 482 - 496
(2013/10/08)
-
- APOPTOSIS-INDUCING AGENTS FOR THE TREATMENT OF CANCER AND IMMUNE AND AUTOIMMUNE DISEASES
-
Disclosed are compounds which inhibit the activity of anti-apoptotic Bc1-xL proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bc1-xL protein.
- -
-
Paragraph 1232
(2013/04/24)
-
- FAMILY OF ARYL, HETEROARYL, O-ARYL AND O-HETEROARYL CARBASUGARS
-
The present invention relates to a compound of the following formula (I): as well as its process of preparation, pharmaceutical and cosmetics composition comprising it and use thereof, notably as an inhibitor of the sodium-dependent glucose co-transporter, such as SGLTl, SGLT2 and SGLT3, in particular in the treatment or prevention of diabetes, and more particularly type-II diabetes, diabetes-related complications, such as arthritis of the lower extremities, cardiac infarction, renal insufficiency, neuropathy or blindness, hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, X syndrome and arteriosclerosis, as well as for its use as an anticancer, anti-infective, anti-viral, anti-thrombotic or anti- inflammatory drug, or for lightening, bleaching, depigmenting the skin, removing blemishes from the skin, particularly age spots and freckles, or preventing pigmentation of the skin.
- -
-
-
- Polyvinylpyrrolidone-bromine complex: An efficient polymeric reagent for selective preparation of benzyl bromides in the presence of hexamethyldisilane
-
Benzylic bromides were conveniently obtained in high yields via the reaction of the corresponding alcohols with crosslinked polyvinylpyrrolidone- bromine complex (PVPP-Br2)/hexamethyldisilane in chloroform at reflux condition. Selective conversion of benzyl alcohol to benzyl bromide in the presence of primary aliphatic alcohols, e.g. 2-phenylethanol was also achieved.
- Mokhtary, Masoud,Lakouraj, Moslem M.
-
p. 305 - 309
(2012/10/29)
-
- One-pot synthesis of 1-iodoalkynes and trisubstituted alkenes from benzylic and allylic bromides
-
1-Iodoalkynes are formed in moderate to high yields from readily accessible benzylic and allylic alkyl bromides by a one-pot homologation/double elimination procedure with iodoform (CHI3). The developed conditions include facile purification and avoid the use of an excess of triphenylphosphine (PPh3), as described in classical Corey-Fuchs iodoalkynylation conditions. Replacing CHI3 with CHI2Cl allows the isolation of the corresponding gem-(Z)-chloro-(E)-iodoalkene in good yield and stereoselectivity. Moreover, the use of benzhydryl bromides as nucleophiles enables the synthesis of trisubstituted alkenes under similar reaction conditions.
- Pelletier, Guillaume,Lie, Sharon,Mousseau, James J.,Charette, Andre B.
-
supporting information
p. 5464 - 5467,4
(2020/10/15)
-
- Synthesis and biological activity of pyridopyridazin-6-one p38α MAP kinase inhibitors. Part 2
-
This manuscript concludes the Structure Activity Relationship (SAR) on the pyridazinone scaffold and identifies a compound with subnanomolar p38α activity and 24 h coverage in the rat arthritis efficacy model.
- Tynebor, Robert M.,Chen, Meng-Hsin,Natarajan, Swaminathan R.,O'Neill, Edward A.,Thompson, James E.,Fitzgerald, Catherine E.,O'Keefe, Stephen J.,Doherty, James B.
-
p. 5971 - 5975
(2012/11/07)
-
- Total synthesis of naturally occurring furan compounds 5-{[(4- hydroxybenzyl)oxy]methyl}-2-furaldehyde and pichiafuran C
-
The synthesis of the natural furan derivatives 5-{[(4-hydroxybenzyl)oxy] methyl}-2-furaldehyde and pichiafuran C is described. Diverse alternative synthetic approaches were developed for the preparation of these natural products. They were prepared through an etherification reaction of the key furan precursor 5-(hydroxymethyl)-2-furaldehyde (HMF), which can be readily obtained from d-fructose, d-glucose, or sucrose, with the corresponding alcohols. 5-{[(4-Hydroxybenzyl)oxy]methyl}-2-furaldehyde was not only obtained in a two-step methodology but also by a biomimetic single-step synthesis. Similarly, pichiafuran C was prepared by three different syntheses, each one by a two-step procedure, also including a biomimetic approach. Georg Thieme Verlag Stuttgart.
- Quiroz-Florentino, Hector,Hernandez-Benitez, R. Israel,Avina, Judit A.,Burgueno-Tapia, Eleuterio,Tamariz, Joaquin
-
p. 1106 - 1112
(2011/06/20)
-
- PHOSPHORUS-CONTAINING THYROID HORMONE RECEPTOR AGONISTS AND METHODS OF USE
-
The present invention relates to sulfonic acid containing compounds that bind to thyroid receptors in the liver. Activation of these receptors results in modulation of gene expression of genes regulated by thyroid hormones. The compounds can be used to treat diseases and disorders including metabolic diseases such as NASH, hypercholesterolemia and hyperlipidemia, as well as associated conditions such as atherosclerosis, coronary heart disease, impaired glucose tolerance, and metabolic syndrome X.
- -
-
Page/Page column 93
(2011/04/24)
-
- GPR120 RECEPTOR AGONISTS AND USES THEREOF
-
GPR120 agonists are provided. These compounds are useful for the treatment of metabolic diseases, including Type II diabetes and diseases associated with poor glycemic control.
- -
-
Page/Page column 146
(2012/01/06)
-
- H3PW12O40-[bmim][FeCl4]: A novel and green catalyst-medium system for microwave-promoted selective interconversion of alkoxymethyl ethers into their corresponding nitriles, bromides and iodides
-
In the present work, the catalytic activity of 12-tungstophosphoric acid immobilized on [bmim][FeCl4] ionic liquid as a highly efficient and eco-friendly catalytic system for rapid and chemoselective direct conversion of MOM- or EOM-ethers into their corresponding nitriles, bromides and iodides under microwave irradiation is reported. In these reactions, the products are obtained in high yields. The catalyst exhibited remarkable reactivity and was reused several times.
- Mohammadpoor-Baltork, Iraj,Moghadam, Majid,Tangestaninejad, Shahram,Mirkhani, Valiolah,Mirjafari, Arsalan
-
experimental part
p. 1468 - 1473
(2011/10/09)
-
- Microwave-promoted, one-pot conversion of alkoxymethylated protected alcohols into their corresponding nitriles, bromides, and iodides using [bmim][InCl4] as a green catalyst
-
The Lewis acid room temperature ionic liquid, [bmim][InCl4], was found to be an efficient and green catalyst for the highly chemoselective and one-pot conversion of MOM- or EOM-ethers into their corresponding nitriles, bromides, and iodides under microwave irradiation. The procedures are simple, rapid, and high yielding. The catalyst exhibited a remarkable reactivity and is reusable.
- Mirjafari, Arsalan,Mohammadpoor-Baltork, Iraj,Moghadam, Majid,Tangestaninejad, Shahram,Mirkhani, Valiollah,Khosropour, Ahmad Reza
-
supporting information; experimental part
p. 3274 - 3276
(2010/07/18)
-
- Phenolic bis-styrylbenzenes as β-amyloid binding ligands and free radical scavengers
-
Starting from bisphenolic bis-styrylbenzene DF-9 (4), β-amyloid (Aβ) binding affinity and specificity for phenolic bis-styrylbenzenes, monostyrylbenzenes, and alkyne controls were determined by fluorescence titration with β-amyloid peptide Aβ1-40 and a fluorescence assay using APP/PS1 transgenic mouse brain sections. Bis-styrylbenzene SAR is derived largely from work on symmetrical compounds. This study is the first to describe Aβ binding data for bis-styrylbenzenes unsymmetrical in the outer rings. With one exception, binding affinity and specificity were decreased by adding and/or changing the substitution pattern of phenol functional groups, changing the orientation about the central phenyl ring, replacing the alkene with alkyne bonds, or eliminating the central phenyl ring. The only compound with an Aβ binding affinity and specificity comparable to 4 was its 3-hydroxy regioisomer 8. Like 4, 8 crossed the blood-brain barrier and bound to Aβ plaques in vivo. By use of a DPPH assay, phenol functional groups with para orientations seem to be a necessary, but insufficient, criterion for good free radical scavenging properties in these compounds.
- Flaherty, Daniel P.,Kiyota, Tomomi,Dong, Yuxiang,Ikezu, Tsuneya,Vennerstrom, Jonathan L.
-
supporting information; experimental part
p. 7992 - 7999
(2011/03/19)
-
- ALKANOIC ACID DERIVATIVES AND THEIR THERAPEUTIC USE AS HDAC INHIBITORS
-
The invention related to alkanoic acid derivatives of Formula (IIa) and (IIb). These compounds of the invention were found to have activity as HDAC inhibitors.
- -
-
Page/Page column 100
(2010/08/05)
-
- GPR120 RECEPTOR AGONISTS AND USES THEREOF
-
GPR120 agonists are provided. These compounds are useful for the treatment of metabolic diseases, including Type II diabetes and diseases associated with poor glycemic control.
- -
-
Page/Page column 120
(2010/08/04)
-
- New PPARγ ligands based on 2-hydroxy-1,4-naphthoquinone: Computer-aided design, synthesis, and receptor-binding studies
-
FlexX-based molecular docking study was employed to identify 2-hydroxy-1,4-naphthoquinone as a new 'acidic head group' for the design of a novel series of PPARγ ligands. To provide the proof of concept, designed molecules were synthesized and evaluated in a standard radioligand-binding assay. Out of eight molecules, four were found to bind to the murine PPARγ with IC50 ranging from 0.2 to 56.2 μM as compared to standard pioglitazone, with IC50 of 0.7 μM.
- Sundriyal, Sandeep,Viswanad, Bhoomi,Bharathy, Elumalai,Ramarao, Poduri,Chakraborti, Asit K.,Bharatam, Prasad V.
-
scheme or table
p. 3192 - 3195
(2009/04/06)
-
- Soluble and polymer-supported 2- and 3-benzylated furans for the preparation of α,β-ethylenic carbonyl compounds
-
Soluble and polymer-supported 2- and 3-benzylated furans were subjected to a sequence involving a Diels-Alder reaction with α,β-acetylenic carbonyl compounds, a Michael addition, and a subsequent retro-Diels-Alder reaction to yield olefinic compounds. On solid support, this traceless strategy is advantageous since pure compounds were released in the thermal cycloreversion step. The fur-2-ylated resin allowed a highly diastereoselective synthesis.
- Albert, Sébastien,Soret, Adrien,Blanco, Luis,Deloisy, Sandrine
-
p. 2888 - 2900
(2007/10/03)
-
- SYNTHESIS OF 13C-LABELLED ESTROGEN ANALOGUES
-
There is provided a method of producing novel 13C-labelled estrogen analogues. The method preferably proceeds via an intermediate A or B or which is a mixture of (A) or (B): wherein a13C atom is located at one or more of positions 1, 2, 3 or 4 and wherein R is an optionally substituted alkane, alkene, alkyne or aryl group. Preferably R is -CH2Ph. An alternative preferred intermediate compound is 13C-resorcinol.
- -
-
-
- Substituted γ-phenyl-Δ-lactams and uses related thereto
-
γ-Phenyl-substituted Δ-lactams are disclosed. They may be formulated into pharmaceutical compositions, and/or used in the treatment or prevention of inflammation or other conditions or disease states.
- -
-
-
- Antidiabetic agents
-
The present invention provides compounds of Formula (I): wherein A, X, Q, Y, B, D, Z, and E have any of the values defined in the specification, and pharmaceutically acceptable salt thereof, that are useful as antidiabetic agents. Also disclosed are pharmaceutical compositions comprising one or more compounds of Formula I, processes for preparing compounds of Formula I, and intermediates useful for preparing compounds of Formula I.
- -
-
-
- Substituted gamma-phenyl-delta-lactams and uses related thereto
-
gamma-Phenyl-substituted Delta-lactams are disclosed. They may be formulated into pharmaceutical compositions, and/or used in the treatment or prevention of inflammation or other conditions or disease states.
- -
-
-
- Reductive cyclizations of hydroxysulfinyl ketones: Enantioselective access to tetrahydropyran and tetrahydrofuran derivatives
-
The stereocontrolled formation of cis-2,5-disubstituted tetrahydrofurans and cis-2,6-disubstituted tetrahydropyrans is achieved from enantiopure ketosulfinyl esters by reduction, Weinreb's amide, and ketone formation, followed by the reductive cyclization (Et3SiH/TMSOTf) of the resulting hydroxysulfinyl ketones. The sulfoxide-bearing heterocycles were transformed into two natural products, (-)-centrolobine (1) and both enantiomers of cis-(6-methyltetrahydropyran-2-yl)acetic acid (2).
- Carreno, M. Carmen,Des Mazery, Renaud,Urbano, Antonio,Colobert, Francoise,Solladie, Guy
-
p. 7779 - 7787
(2007/10/03)
-
- Triphenyl compounds as interleukin-4 antagonists
-
Triphenyl compounds of the formulae I, II, and VI: methods of making them, pharmaceutical compositions containing them, and methods for their use. The compounds are compounds are interleukin-4 antagonists; and are useful for the treatment of asthma and al
- -
-
-
- New optically active 2H-azirin-3-amines as synthons for enantiomerically pure 2,2-disubstituted glycines: Synthesis of synthons for Tyr(2Me) and Dopa(2Me), and their incorporation into dipeptides
-
The synthesis of novel unsymmetrically 2,2-disubstituted 2H-azirin-3-amines with chiral auxiliary amino groups is described. Chromatographic separation of the mixture of diastereoisomers yielded (1′R,2S)-2a,b and (1′R.2R)-2a,b (c.f. Scheme 1 and Table 1), which are synthons for (S)- and (R)-2-methyltyrosine and 2-methyl-3′,4′-dihydroxyphenylalanine. Another new synthon 2c, i.e., a synthon for 2-(azidomethyl)alanine, was prepared but could not be separated into its pure diastereoisomers. The reaction of 2 with thiobenzoic acid, benzoic acid, and the amino acid Fmoc-Val-OH yielded the monothiodiamides 11, the diamides 12 (cf. Scheme 3 and Table 3), and the dipeptides 13 (cf. Scheme 4 and Table 4), respectively. From 13, each protecting group was removed selectively under standard conditions (cf. Schemes 5-7 and Tables 5-6). The configuration at C(2) of the amino acid derivatives (1R,1′R)-11a, (1R,1′R)-11b, (1S,1′R)-12b, and (1R,1′R)-12b was determined by X-ray crystallography relative to the known configuration of the chiral auxiliary group.
- Brun, Kathrin A.,Linden, Anthony,Heimgartner, Heinz
-
p. 3422 - 3443
(2007/10/03)
-
- First enantioselective total synthesis of (-)-Centrolobine.
-
[structure: see text] The first enantioselective total synthesis of (-)-Centrolobine is described. The key reaction is the synthesis of the cis-disubstituted tetrahydropyran framework by intramolecular cyclization of the enantiopure hydroxyketone 3 with E
- Colobert, Francoise,Mazery, Renaud Des,Solladie, Guy,Carreno, M Carmen
-
p. 1723 - 1725
(2007/10/03)
-
- Substituted γ-phenyl-Δ-lactones and analogs thereof and uses related thereto
-
γ-Phenyl-substituted Δ-lactones and analogs thereof, including lactams, are disclosed. They may be formulated into pharmaceutical compositions, and/or used in the treatment or prevention of inflammation or other conditions or disease states.
- -
-
-
- Poly(ethylene glycol)-supported bisoxazolines as ligands for catalytic enantioselective synthesis
-
Two chiral bisoxazolines (box) supported on a modified poly(ethylene glycol) (PEG) have been prepared by a reaction sequence that involved formation of the properly functionalized box and their attachment to the polymer matrix by means of a spacer and a linker. The solubility properties of PEG allowed use of the supported box as ligands in some catalytic asymmetric transformations carried out under homogeneous conditions and to recover the ligands as if bound to an insoluble support. When the supported box were employed in combination with Cu(II) salts in the Diels-Alder cycloaddition between cyclopentadiene and N-acryloyloxazolidinone, low levels of enantioselectivity were observed (up to 45% ee). Much better results were obtained in the cyclopropanation of styrenes carried out in the presence of CuOTf (up to 93% ee) and in the ene-reaction between α-methylstyrene or methylenecyclohexane and ethylglyoxalate (up to 95% ee). One of the ligands, readily recovered by precipitation and filtration, was recycled two times in the ene-reaction with marginal loss in the catalytic activity and very limited erosion of the enantioselectivity.
- Annunziata,Benaglia,Cinquini,Cozzi,Pitillo
-
p. 3160 - 3166
(2007/10/03)
-
- Solid phase Diels-Alder/retro Diels-Alder reactions. A new method for traceless linker strategy
-
A resin-bound furan has been efficiently synthesized from Merrifield resin. This new polymer reacts with an acetylenic dienophile to afford a thermally stable Diels-Alder adduct. Transformation of the adduct by Michael reaction with thiophenol has allowed an easy retro Diels-Alder reaction. This 'safety-catch' procedure leads to the formation of a chemically and stereochemically pure alkene and to the regeneration of the polymer-bound furan. (C) 2000 Elsevier Science Ltd.
- Blanco,Bloch,Bugnet,Deloisy
-
p. 7875 - 7878
(2007/10/03)
-
- Synthesis of [4-13C]-isoflavonoid phytoestrogens
-
Efficient syntheses are described for 13C-labelled derivatives of the isoflavonoid phytoestrogens, genistein, biochanin A, daidzein and formononetin, for use in metabolic studies. The synthetic procedure employs 13C-labelled cyanide as the source of the label to produce the isoflavones with a single 13C atom at the C-4 position. (C) 2000 Elsevier Science Ltd.
- Whalley, Jacqueline L.,Oldfield, Mark F.,Botting, Nigel P.
-
p. 455 - 460
(2007/10/03)
-
- THROMBIN INHIBITORS
-
A compound which inhibits human thrombin and which has the general structure STR1
- -
-
-
- Synthesis of 13C labelled daidzein and formononetin.
-
Efficient methods are described for the synthesis of daidzein and formononetin labelled with a single 13C atom at the 4-position, to prepare material for metabolic studies.
- Whalley,Bond,Botting
-
p. 2569 - 2572
(2007/10/03)
-
- Dendritic bis(oxazoline)copper(II) catalysts. 2. Synthesis, reactivity, and substrate selectivity
-
A series of dendritic bis(oxazoline) ligands 1-4 were synthesized to evaluate the effects of the degree of branching of a dendritic sector on both the reactivity and selectivity of their corresponding copper(II) complex- catalyzed Diels-Alder reaction between cyclopentadiene and a crotonyl imide. Kinetic studies unveiled a two-step mechanism of the Diels-Alder reaction, in which a reversible binding of the dienophile to the copper complex was followed by a rate-determining reaction between the resulting dienophile- catalyst complex with the diene. Furthermore, two interesting features emerged: first, the formation constant of the dienophile-catalyst complex decreased gradually on going from the lower to higher generations, and secondly, while the Diels-Alder reaction rate constant remained essentially the same from the zeroth to second generation catalysts, it dropped abruptly for the third generation one. These observations were rationalized as a consequence of a folding-back of the dendritic sectors toward the catalytic unit at the third generation, so that increase in steric size impeded both the reactivity and binding profiles of the catalytic system. This behavior was reminiscent of related phenomena observed by others from solvatomatic, photophysical, and viscosity studies. In line with this reasoning, a slight but noticeable substrate selectivity was observed for the third generation catalyst, which was absence for the lower ones, in competitive kinetic studies involving two dienophiles of different steric sizes.
- Chow,Mak
-
p. 5116 - 5127
(2007/10/03)
-
- Synthesis and anti-HIV activity of dibenzylbutyrolactone lignans
-
Five optically active dibenzylbutyrolactone lignans were synthesized through a lipase-catalyzed transesterification route and evaluated for their inhibitory activity against HIV-1 replication in acutely infected H9 cells. Compounds 1 and 2 demonstrated anti-HIV replication activity with an EC50 values of 2.2 and 0.16 μg/ml and a therapeutic index values of 9.1 and 5, respectively. Structure-antiviral activity relationships are discussed.
- Yang, Li-Ming,Lin, Shwu-Jiuan,Yang, Tsang-Hsiung,Lee, Kuo-Hsiung
-
p. 941 - 944
(2007/10/03)
-
- (-)-Arctigenin as a lead structure for inhibitors of human immunodeficiency virus type-1 integrase
-
The natural dibenzylbutyrolactone type lignanelide (-)-arctigenin (2), an inhibitor of human irnmunodeficiency virus type-1 (HIV-1) replication in infected human cell systems, was found to suppress the integration of proviral DNA into the cellular DNA genome. In the present study 2 was tested with purified HIV-1 integrase and found to be inactive in the cleavage (3'- processing) and integration (strand transfer) assays. However, the semisynthetic 3-O-demethylated congener 9 characterized by a catechol substructure exhibited remarkable activities in both assays. Structure- activity relationship studies with 30 natural (1-6), semisynthetic (7-21), and synthetic (37-43, 45, 46) lignans revealed that (1) the lactone moiety is crucial since compounds with a butane-1,4-diol or tetrahydrofuran substructure and also lignanamide analogues lacked activity and (2) the number and arrangement of phenolic hydroxyl groups is important for the activity of lignanolides. The congener with two catechol substructures (7) was found to be the most active compound in this study. 7 was also a potent inhibitor of the 'disintegration' reaction which models the reversal of the strand transfer reaction. The inhibitory activity of 7 with the core enzyme fragment consisting of amino acids 50-212 suggests that the binding site of 7 resides in the catalytic domain.
- Eich, Eckart,Pertz, Heinz,Kaloga, Macki,Schulz, Jutta,Fesen, Mark R.,Mazumder, Abhijit,Pommier, Yves
-
-
- Squalene synthase inhibitors: Isosteric replacements of the farnesyl chain of benzyl farnesyl amine
-
Squalene synthase catalyzes the committed step of cholesterol biosynthesis. We report here the synthesis and in vivo activity of a series of squalene synthase inhibitors that contain isosteric replacements for the farnesyl chain of the known inhibitor ben
- Brinkman, John A.,Damon, Robert E.,Fell, Jay B.,Perez, Lawerence B.,Scallen, Terence J.,Vedananda
-
p. 2491 - 2494
(2007/10/03)
-
- MULTICYCLIC TERTIARY AMINE POLYAROMATIC SQUALENE SYNTHASE INHIBITORS
-
This invention relates to polycyclic compounds containing two mono- and/or bicyclic rings and a basic tertiary amino group capable of forming an ammonium ion at biological pH and which reduces levels of serum cholesterol in the body without significantly reducing mevalonic metabolite synthesis. This invention relates also to pharmacological compositions and method of treatment for lowering serum cholesterol levels using the compounds of this invention. The compounds of this invention are described by the formula where Ar I is phenylene or naphthylene, Ar II is phenyl or naphthyl and A is 1-azabicyclo[2.2.2]octan-3-yl
- -
-
-
- Synthesis and Protein-Tyrosine Kinase Inhibitory Activity of Polyhydroxylated Stilbene Analogues of Piceatannol
-
A series of hydroxylated trans-stilbene related to the antileukemic natural product trans-3,3',4,5'-tetrahydroxy stilbene (piceatannol) (1) has been prepared and tested for inhibition of the lymphoid cell lineage-specific protein-tyrosine kinase p56lck, which plays an important role in lymphocyte proliferation and immune function.A number of the analogues displayed enhanced enzyme inhibitory activity relative to the natural product.Reduction of the double bond bridging the two aromatic rings and benzylation of the phenolic hydroxyl groups was found to decrease activity significantly.The most potent compounds in the series proved to be trans-3,3',5,5'-tetrahydroxystilbene, trans-3,3',5-trihydroxystilbene, and trans-3,4,4'-trihydroxystilbene.
- Thakkar, Kshitij,Geahlen, Robert L.,Cushman, Mark
-
p. 2950 - 2955
(2007/10/02)
-
- Synthesis of 1,2,3,4-Tetrahydroisoquinolines
-
Several aspects of 1,2,3,4-tetrahydroisoquinoline synthesis have been examined.An improved synthesis of 2-(m-methoxyphenyl)ethylamine (4) is reported. m-Anisaldehyde (5) was treated with potassium cyanide and ethyl chloroformate to yield O-(ethoxycarbonyl)-3-methoxymandelonitrile (7).Hydrogenation afforded 2-(m-methoxyphenyl)ethylamine (4) in 87percent yield overall.Some observations have been made regarding the reduction of 3,4-dihydroisoquinolines derived from the Bischler-Napieralski reaction.Amides 3a and 3c were cyclized with phosphorus oxychloride, followed by reduction to the corresponding tetrahydroisoquinolines 1a and 1c.It was shown that 1a and 1c were contaminated with 4percent of 2a and 3percent of 2c, respectively.Both 2a and 2c were independently synthesized by routes with general applicability to 8-alkoxy-1,2,3,4-tetrahydroisoquinolines.
- Kashdan, David S.,Schwartz, John A.,Rapoport, Henry
-
p. 2638 - 2643
(2007/10/02)
-