- Mycolic Acids Constitute a Scaffold for Mycobacterial Lipid Antigens Stimulating CD1-Restricted T Cells
-
CD1-restricted lipid-specific T lymphocytes are primed during infection with Mycobacterium tuberculosis, the causative agent of tuberculosis. Here we describe the antigenicity of glycerol monomycolate (GroMM), which stimulates CD1b-restricted CD4+/s
- Layre, Emilie,Collmann, Anthony,Bastian, Max,Mariotti, Sabrina,Czaplicki, Jerzy,Prandi, Jacques,Mori, Lucia,Stenger, Steffen,De Libero, Gennaro,Puzo, Germain,Gilleron, Martine
-
-
Read Online
- Gold(I)-catalyzed, one-pot, oxidative formation of 2,4-disubstituted thiazoles: Application to the synthesis of a pateamine-related macrodiolide
-
Thiazoles are important heterocyclic motifs in many target molecules. Extension of a reported gold(I)-catalyzed oxidative coupling of alkynes and thioamides to the synthesis of functionalized thiazole-containing products is presented, including the compatibility of this reaction with ester, protected hydroxyl, alkene and thioether groups. The utility of this one-pot process is demonstrated in the preparation of the thiazole-containing macrodiolide of a simplified analogue of pateamine A.
- Xu, Tao,Cuyamendous, Claire,Brown, Sarah L.,Andreassend, Sarah K.,Cumming, Hemi,Evans, Gary B.,Teesdale-Spittle, Paul H.,Harvey, Joanne E.
-
-
Read Online
- Design and Synthesis of Tetrazole- And Pyridine-Containing Itraconazole Analogs as Potent Angiogenesis Inhibitors
-
Itraconazole, a widely used antifungal drug, was found to possess antiangiogenic activity and is currently undergoing multiple clinical trials for the treatment of different types of cancer. However, it suffers from extremely low solubility and strong interactions with many drugs through inhibition of CYP3A4, limiting its potential as a new antiangiogenic and anticancer drug. To address these issues, a series of analogs in which the phenyl group is replaced with pyridine or fluorine-substituted benzene was synthesized. Among them the pyridine- and tetrazole-containing compound 24 has significantly improved solubility and reduced CYP3A4 inhibition compared to itraconazole. Similar to itraconazole, compound 24 inhibited the AMPK/mTOR signaling axis and the glycosylation of VEGFR2. It also induced cholesterol accumulation in the endolysosome and demonstrated binding to the sterol-sensing domain of NPC1 in a simulation study. These results suggested that compound 24 may serve as an attractive candidate for the development of a new generation of antiangiogenic drug.
- Cheng, Zhiqiang,Head, Sarah A.,Li, Ruo-Jing,Li, Yingjun,Liu, Jun O.,Liu, Wukun,Pasunooti, Kalyan Kumar,Peng, Hanjing,Shi, Wei Q.
-
supporting information
p. 1111 - 1117
(2020/07/04)
-
- Discovery of novel potent HCV NS5B polymerase non-nucleoside inhibitors bearing a fused benzofuran scaffold
-
This letter describes the discovery of a fused benzofuran scaffold viable for preparing a series of novel potent HCV NS5B polymerase non-nucleoside inhibitors. Designed on the basis of the functionalized benzofuran derivative nesbuvir (HCV-796), these com
- Zhong, Min,Peng, Eric,Huang, Ningwu,Huang, Qi,Huq, Anja,Lau, Meiyen,Colonno, Richard,Li, Leping
-
supporting information
p. 963 - 968
(2018/02/09)
-
- SMALL MOLECULE INHIBITORS OF FIBROSIS
-
Described herein are compounds and compositions for the treatment of a fibrotic disease.
- -
-
Paragraph 00471
(2016/06/28)
-
- Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic
-
Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.
- Pace, Jennifer R.,Deberardinis, Albert M.,Sail, Vibhavari,Tacheva-Grigorova, Silvia K.,Chan, Kelly A.,Tran, Raymond,Raccuia, Daniel S.,Wechsler-Reya, Robert J.,Hadden, M. Kyle
-
supporting information
p. 3635 - 3649
(2016/05/24)
-
- PROCESS FOR PREPARATION OF PROSTAGLANDIN F2 ALPHA ANALOGUES
-
A convergent synthesis of the prostaglandin F2α analogues, travoprost and bimatoprost, was developed employing Julia-Lythgoe olefination of the structurally advanced phenylsulfone with an enantiomerically pure aldehyde ω-chain synthon. The novel convergent strategy allows the synthesis of a whole series of prostaglandin analogues of high purity from a common and structurally advanced prostaglandin intermediate.
- -
-
Paragraph 0221; 0222; 0223
(2015/02/19)
-
- PROCESS FOR PREPARATION OF PROSTAGLANDIN F2α ANALOGUES
-
A convergent synthesis of the prostaglandin F2α analogues, travoprost and bimatoprost, was developed employing Julia-Lythgoe olefination of the structurally advanced phenylsulfone with an enantiomerically pure aldehyde ω-chain synthon. The novel convergent strategy allows the synthesis of a whole series of prostaglandin analogues of high purity from a common and structurally advanced prostaglandin intermediate.
- -
-
Page/Page column 34
(2013/09/26)
-
- A novel convergent synthesis of the potent antiglaucoma agent travoprost
-
The 16-(3-trifluoromethyl)phenoxy PGF2α analogue travoprost (8a) has potent topical ocular activity. A novel convergent synthesis of 13,14-en-15-ol PGF2α analogues was developed employing Julia-Lythgoe olefination of the structurally advanced prostaglandin phenylsulfone (5Z)-(+)-15 with a new enantiomerically pure aldehyde ω-chain synthon (S)-(-)-16a. Subsequent hydrolysis of protecting groups and final esterification of fluprostenol (7a) yielded travoprost (8a). The main advantages are the preparation of high purity travoprost (8a) and the application of comparatively cheap reagents. The novel convergent strategy allows the synthesis of a whole series of 13,14-en-15-ol PGF2α analogues from a common and structurally advanced prostaglandin intermediate 15. The preparation and identification of two synthetic impurities, 15-epi isomer (8b) of travoprost and a new prostaglandin related ester (5Z)-(+)-18, are also described.
- Dams, Iwona,Chodyński, Micha?,Krupa, Ma?gorzata,Pietraszek, Anita,Zezula, Marta,Cmoch, Piotr,Kosińska, Monika,Kutner, Andrzej
-
p. 1634 - 1648
(2013/02/26)
-
- Asymmetric synthesis and effect of absolute stereochemistry of YCZ-2013, a brassinosteroid biosynthesis inhibitor
-
The four stereoisomers of 2RS,4RS-1-[[2-(2,4-dichlorophenyl)-4-(2-(2- propenyloxy)phenoxymethyl)-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole (YCZ-2013), a novel brassinosteroid biosynthesis inhibitor, were prepared. The diastereomers of 2RS,4R-5 and 2RS,4S-5 were prepared by using the corresponding optically pure R and S toluene-4-sulfonic acid 2,3-dihydroxypropyl ester (R-4,S-4). The enatiomerically and diastereomerically pure acetonide (5) was obtained by a method involving diastereoselective crystallisation of the tosylate salt, followed by re-equilibration with the mother liquor and chromatography. The optical purity of four target compounds (YCZ-2013) was confirmed by chiral high-performance liquid chromatography (HPLC) and NMR. The effects of these stereoisomers on Arabidopsis stem elongation indicated that the cis isomers of 2S,4R-YCZ-2013 and 2R,4S-YCZ-2013 exhibited potent inhibitory activity with IC50 values of approximately 24 ± 3 and 24 ± 2 nM, respectively. The IC50 values of the trans isomers of 2S,4S-YCZ-2013 and 2R,4R-YCZ-2013 are approximately 1510 ± 50 and 3900 ± 332 nM, respectively. Co-application of brassinolide (10 nM), the most potent BR, and GA3 (1 μM) to Arabidopsis seedlings grown in the dark with 2R,4S-YCZ-2013 and 2S,4R-YCZ-2013 revealed that brassinolide recovered the induced dwarfism of Arabidopsis seedlings, whereas GA3 showed no effect.
- Oh, Keimei,Yamada, Kazuhiro,Yoshizawa, Yuko
-
p. 6915 - 6919
(2014/01/06)
-
- AMINOGLYCOSIDE DERIVATIVES
-
The present invention relates to antimicrobial and antibiotic aminoglycoside derivatives. The compounds of the present application have the following chemical structures. The invention also relates to compositions, methods of preparation and methods of treatment of bacterial infections using the above aminoglycoside derivative.
- -
-
Page/Page column 50
(2011/12/02)
-
- Structure-activity relationships in toll-like receptor-2 agonistic diacylthioglycerol lipopeptides
-
The N-termini of bacterial lipoproteins are acylated with a (S)-(2,3-bisacyloxypropyl)cysteinyl residue. Lipopeptides derived from lipoproteins activate innate immune responses by engaging Toll-like receptor 2 (TLR2) and are highly immunostimulatory and yet without apparent toxicity in animal models. The lipopeptides may therefore be useful as potential immunotherapeutic agents. Previous structure-activity relationships in such lipopeptides have largely been obtained using murine cells, and it is now clear that significant species-specific differences exist between human and murine TLR responses. We have examined in detail the role of the highly conserved Cys residue as well as the geometry and stereochemistry of the Cys-Ser dipeptide unit. (R)-Diacylthioglycerol analogues are maximally active in reporter gene assays using human TLR2. The Cys-Ser dipeptide unit represents the minimal part-structure, but its stereochemistry was found not to be a critical determinant of activity. The thioether bridge between the diacyl and dipeptide units is crucial, and replacement by an oxoether bridge results in a dramatic decrease in activity.
- Wu, Wenyan,Li, Rongti,Malladi, Subbalakshmi S.,Warshakoon, Hemamali J.,Kimbrell, Matthew R.,Amolins, Michael W.,Ukani, Rehman,Datta, Apurba,David, Sunil A.
-
experimental part
p. 3198 - 3213
(2010/10/02)
-
- An expedient route to new spiroheterocycles: Synthesis and structural studies
-
We have developed a short, efficient and enantioselective synthesis of 1,4,7,10-tetraoxa- and 1,7-dioxa-4,10-dithiaspiro[5.5]undecanes. The method involved the reaction of solketal 5 or thiol derivative 6 with 1,3-dichloropropanone O-benzyloxime (4) which
- Goubert, Marlene,Canet, Isabelle,Sinibaldi, Marie-Eve
-
p. 4805 - 4812
(2007/10/03)
-
- Alkylation of 2-pyridinones: Synthesis of novel acyclonucleosides
-
This paper presents the synthesis of some novel acyclonucleosides containing 2-pyridinones and 2-hydroxyethoxymethyl, 2,3-dihydroxy-propyl side chain. The tosylate of these nucleosides analogues could be modified to azido derivatives. Also, acyclonucleosides with 1-ethoxymethyl, 1-benzyloxymethyl, 1-methylthiomethyl and 2-hydroxyethyl side chains have been investigated. The O-alkylated pyridine derivatives were obtained during most reactions.
- El-Essawy, Farag A.,Khattab, Ahmed F.
-
p. 311 - 316
(2007/10/03)
-
- Naphthyloxy acetic acid derivatives and a pharmaceutical composition comprising them as an active ingredient
-
The naphthyloxyacetic acid derivatives of the formula (I) wherein A is H, -(alkylene)COOR1, -(alkylene)CONR2R3, -(alkylene)OH, -(alkylene)tetrazole, -(alkylene)CN; E is single bond or alkylene; G is —S—, —SO—, —SO2—, —O— or —NR4—; L is alkylene, —(CH2)m—CH═CH—(CH2)n— or —(CH2)x—CH(OH)—(CH2)y—; M is phenyl, phenyl(thio, oxy, amino), diphenylmethyl, diphenylmethyl(thio, oxy, amino), and pharmaceutical composition comprising them as an active ingradient. The compounds of the formula (I) can combine PGE2receptor and exhibit the activity to antagonize or agonize for PGE2receptor. Therefore, they are useful as anti-hyperlipemia, for the prevention of abortion, for analgesics, as antidiarrheals, sleep inducer, diuretic, anti-diabetes, abortient, cathartics, antiulcer, anti-gastritis or antihypertensive etc.
- -
-
Referential example 6(1)
(2010/11/29)
-
- Scavenger assisted combinatorial process for preparing libraries of tertiary amine compounds
-
This invention relates to a novel solution phase process for the preparation of tertiary amine combinatorial libraries. These libraries have utility for drug discovery and are used to form wellplate components of novel assay kits.
- -
-
-
- Assignment of the stereochemistry of spiroxamine by two-dimensional NMR spectroscopy and stereoselective chemical synthesis
-
Spiroxamine is a new powdery mildew fungicide in cereals consisting of four biologically active isomers (two diastereomers, four enantiomers). The four isomers were separated by preparative high-performance liquid chromatography (HPLC) on a chiral stationary phase. At this stage it was not possible to assign their stereochemistry. Using stereoselective synthesis starting with the corresponding chirally pure glycerol derivates, the configuration at the asymmetric center, could be fixed. The resulting diastereomers were separated by preparative HPLC. Using COSY, HSQC and NOESY NMR spectroscopy it was possible to assign the configuration of the amino residue relative to the cyclohexyl ring. The 600 MHz 1H NMR spectra permitted a complete assignment of all proton signals. The stereochemical assignment is based on NOEs observed in the NOESY spectrum.
- Etzel,Gau,Kraemer,Stelzer,Weissmueller
-
-
- Efficient Pathways to (R)- and (S)-5-Hydroxymethyl-2-oxazolidinone and some Derivatives
-
2-Oxazolidinones are a very interesting class of compounds due to their various pharmacological effects.Two new syntheses of enantiomerically pure (R)- and (S)-5-hydroxymethyl-2-oxazolidinone have been developed starting with D-mannitol, L-ascorbic acid and (R)- or (S)-malic acid. (R)- and (S)-5-hydroxymethyl-2-oxazolidinone have been used to synthesize some new homochiral 2-oxazolidinone derivatives.
- Danielmeier, Karsten,Steckhan, Eberhard
-
p. 1181 - 1190
(2007/10/02)
-
- Studies on agents with vasodilator and β-blocking activities. III synthesis and activity of optical isomers of TZC-1370
-
Optical isomers of TZC-1370 (1) were prepared from (R)- and (S)-1-(2- chlorophenoxy)-2,3-epoxypropane. When given intravenously to anesthetized rats, the (S)-isomer was about 40 times more potent in terms of β-blocking activity than the (R)-isomer, while
- Seki,Takezaki,Ohuchi,Saitoh,Ishimori,Yasuda
-
p. 1719 - 1723
(2007/10/03)
-
- Naphthyloxazolidone derivatives
-
A naphthyloxazolidone derivative of the formula: STR1 wherein R1 is hydrogen atom, hydroxy group, nitro group, amino group, sulfo group, aminosulfoyul group, a lower alkenyloxy group, a lower alkynyloxy group, a mono or di(lower alkyl)aminocarb
- -
-
-
- SYNTHESIS OF N-(3-FLUORO-2-PHOSPHONOMETHOXYPROPYL) (FPMP) DERIVATIVES OF HETEROCYCLIC BASES
-
A new groupnof compounds has been prepared: N-(3-fluoro-2-phosphonomethoxypropyl) (FPMP) derivatives of purine and pyrimidine bases which exhibit a significant selective activity against a broad spectrum of retroviruses.Racemic N-(3-fluoro-2-phosphonomethoxypropyl) derivatives of adenine (V), guanine (IX), cytosine (XIII), 2,6-diaminopurine (XXI), 3-deazaadenine (XVII), xanthine (X) and hypoxanthine (VI) were prepared from the corresponding n-(3-fluoro-2-hydroxypropyl) derivatives after protection of amino group at the heterocyclic ring by selective benzoylation, reaction with diisopropyl p-toluenesulfonyloxymethylphosphonate (II), and subsequent removal of the protecting groups.Chiral FPMP derivatives were prepared by reaction of heterocyclic base with corresponding chiral synthon (XXX; XXXVII) followed by deprotection.The required chiral synthons were obtained from enantiomeric 3-fluoro-1,2-propanediols by two methods.In the first, the primary hydroxyl group was tritylated, the obtained derivative was reacted with compound II, the trityl group was removed and the product was mesylated to give synthon XXXVII.The second pathway considered tosylation of the primary hydroxyl group and conversion of the secondary hydroxyl into the acetoxymethyl ether via the methoxymethyl ether; treatment of the acetoxy compound with bromotrimethylsilane and triisopropyl phosphite afforded the desired synthon XXX.
- Jindrich, Jindrich,Holy, Antonin,Dvorakova, Hana
-
p. 1645 - 1667
(2007/10/02)
-
- Synthesis and antimuscarinic properties of some N-substituted 5- (aminomethyl)-3,3-diphenyl-2(3H)-furanones
-
In a study aimed toward developing new, selective antimuscarinic drugs with potential utility in the treatment of urinary incontinence associated with bladder muscle instability, a series of N-substituted 5-(aminomethyl)- 3,3-diphenyl-2(3H)-furanones, conformationally-constrained lactone relatives of benactyzine, was prepared. The compounds were examined in several paradigms that measure muscarinic (M1, M2, and M3) receptor antagonist activity. Selected members of the series that displayed potency and/or selectivity in these tests were studied for their effects on urinary bladder contraction, mydriasis, and salivation in guinea pigs. These studies revealed that incorporation of the amino functionality into an imidazole or pyrazole ring resulted in some novel, potent, and selective antimuscarinic agents. Appropriate alkyl substitution of position 2 of the imidazole strikingly affected muscarinic, particularly M3, receptor activity and may reflect a complementary site of interaction. Some of the compounds selectively reduced bladder pressure in a cystometrogram (CMG) model without producing concomitant mydriatic and salivary effects. The separate and distinct action of several compounds of this series in these in vivo protocols suggests the possibility of subtypes of muscarinic receptors that may correspond to previously characterized molecular cloned subpopulations. In this article, structure-activity relationships for the series of substituted lactones are discussed. These studies led to the identification of (R)-[(2-isopropyl-1H- imidazol-1-yl)methyl]-4,5-dihydro-3,3-diphenyl-2(3H)-furanone (23) as a clinical candidate for treating urinary bladder dysfunction.
- Kaiser,Spagnuolo,Adams Jr.,Audia,Dupont,Hatoum,Lowe,Prosser,Sturm,Noronha-Blob
-
p. 4415 - 4424
(2007/10/02)
-
- Enzymatic Resolution of 1,2-Diols: Comparison between Hydrolysis and Transesterification Reactions
-
A new practical procedure for the enzymatic resolution of 1,2-diols 1a-e has been developed by lipase-catalysed regio- and enantio-selective esterification using anhydrides as acylating agents in organic solvents.
- Bosetti, Aldo,Bianchi, Daniele,Cesti, Pietro,Golini, Paolo,Spezia, Sandro
-
p. 2395 - 2398
(2007/10/02)
-
- Levo and dextro dropropizine having antitussive activity
-
The optical isomers of 3-(4-phenyl-1-piperazinyl)-1,2-propanediol, a process for the stereo-selective preparation and pharmaceutical composition containing the same as active principles are described.
- -
-
-
- Total Synthesis of the Potent Mutagen (S)-3-(Dodeca-1,3,5,7,9-pentaenyloxy)propane-1,2-diol
-
A total synthesis of the mutagenic (S)-3-(dodeca-1,3,5,7,9-pentaenyloxy)propane-1,2-diol (1) from (R)-glycerol acetonide (2), potassium glutaconate (6), and the diphenylphosphine oxide (11) is reported.
- Nicolaou, K. C.,Zipkin, Robert,Tanner, David
-
p. 349 - 350
(2007/10/02)
-
- Total Synthesis of (R)-Glycerol Acetonide and the Antiepileptic and Hypotensive Drug (-)-γ-Amino-β-hydroxybutyric Acid (GABOB): Use of Vitamin C as a Chiral Starting Material
-
Ascorbic acid (Vitamin C) (9) is shown to be a useful, inexpensive chiral starting material for natural products synthesis.It is converted in high yield via two synthetic operations into (R)-glycerol acetonide (7), the more inaccessible enantiomer of glycerol acetonide.Since D-(R)-glyceraldehyde acetonide (4) and the corresponding alcohol 1 have been used in many total syntheses of a wide variety of compounds, the ready availability of the opposite enantiomers L-(S)-glyceraldehyde acetonide (6) and glycerol (7) should be of greate value.As one indication of this potential synthetic utility, the hypotensive, antiepileptic compound (R)-(-)-γ-amino-β-hydroxybutyric acid (GABOB) (8) has been synthesized from ascorbic acid (9) via nine steps in 10percent overall yield.As further evidence of the importance of these synthesis, several useful intermediates for the preparation of the highly active hypotensive agents, the aryloxypropanolamines (5), were prepared from Vitamin C.
- Jung, Michael E.,Shaw, Teresa J.
-
p. 6304 - 6311
(2007/10/02)
-
