- Combination of chemotherapy and oxidative stress to enhance cancer cell apoptosis
-
Cancer cells are vulnerable to reactive oxygen species (ROS) due to their abnormal redox environment. Accordingly, combination of chemotherapy and oxidative stress has gained increasing interest for the treatment of cancer. We report a novel seleno-prodrug of gemcitabine (Gem), Se-Gem, and evaluated its activation and biological effects in cancer cells. Se-Gem was prepared by introducing a 1,2-diselenolane (a five-membered cyclic diselenide) moiety into the parent drug Gemvia a carbamate linker. Se-Gem is preferably activated by glutathione (GSH) and displays a remarkably higher potency than Gem (up to a 6-fold increase) to a panel of cancer cell lines. The activation of Se-Gem by GSH releases Gem and a seleno-intermediate nearly quantitatively. Unlike the most ignored side products in prodrug activation, the seleno-intermediate further catalyzes a conversion of GSH and oxygen to GSSG (oxidized GSH) and ROS via redox cycling reactions. Thus Se-Gem may be considered as a suicide agent to deplete GSH and works by a combination of chemotherapy and oxidative stress. This is the first case that employs a cyclic diselenide in prodrug design, and the success of Se-Gem as well as its well-defined action mechanism demonstrates that the 1,2-diselenolane moiety may serve as a general scaffold to advance constructing novel therapeutic molecules with improved potency via a combination of chemotherapy and oxidative stress.
- Fang, Jianguo,Hou, Yanan,Li, Jin,Li, Xinming,Wang, Song,Zhao, Jintao
-
p. 3215 - 3222
(2020/04/08)
-
- Novel protection of 1,2-diol for trans-dihydroxycyclopentene ring construction by the C[sbnd]H insertion of alkylidene carbene: Formal total synthesis of (+)-trehazolin
-
The chiral vicinal diol was protected as 6-methylene-1,4-dioxepane to construct a cyclopentene ring by the C[sbnd]H insertion of alkylidene carbene. The removal of the protecting group was achieved in a few steps, affording the corresponding diol in a reasonable yield. Using these reactions, the known synthetic intermediate for (+)-trehazolin was synthesized from D-diethyl tartrate. In addition, a short route to the intermediate from a D-mannitol derivative was described.
- Ohira, Susumu,Kuboki, Atsuhito,Takimoto, Yoshimi,Matsuda, Kyosuke,Itasaki, Saori,Urushibata, Yuki,Takano, Yoshiyuki,Nakamura, Yuuki
-
-
- Supramolecular gels from sugar-linked triazole amphiphiles for drug entrapment and release for topical application
-
A simple molecular framework obtained by cross-linking a hydrophobic chain with S,S- and R,R-tetritol by the copper-catalysed azide-alkyne cycloaddition reaction is found to serve as an excellent bioisostere for self-assembly. The hexadecyl-linked triazolyl tetritol composite spontaneously self-assembles in n-hepane and methanol to form hierarchical organogels. Microscopic analyses and X-ray diffraction studies demonstrate eventual formation of nanotubes through lamellar assembly of the amphiphiles. A rheological investigation shows solvent-dictated mechanical properties that obey power law behavior similar to other low molecular weight gelators (LMOGs). The gel network was then utilized for the entrapment of drugs e.g. ibuprofen and 5-fluorouracil, with tunable mechanical behaviour under applied stress. The differential release profiles of the drugs over a period of a few hours as a result of the relative spatio-temporal location in the supramolecular network can be utilized for topical formulations.
- Sharma, Komal,Joseph, Jojo P.,Sahu, Adarsh,Yadav, Narender,Tyagi, Mohit,Singh, Ashmeet,Pal, Asish,Kartha, K.P. Ravindranathan
-
p. 19819 - 19827
(2019/07/05)
-
- Chiroptical properties of 2,2’-bioxirane
-
The two enantiomers of 2,2′-bioxirane were synthesized, and their chiroptical properties were thoroughly investigated in various solvents by polarimetry, vibrational circular dichroism (VCD), and Raman optical activity (ROA). Density functional theory (DFT) calculations at the B3LYP/aug-cc-pVTZ level revealed the presence of three conformers (G+, G?, and cis) with Gibbs populations of 51, 44, and 5% for the isolated molecule, respectively. The population ratios of the two main conformers were modified for solvents exhibiting higher dielectric constants (G? form decreases whereas G+ form increases). The behavior of the specific optical rotation values with the different solvents was correctly reproduced by time-dependent DFT calculations using the polarizable continuum model (PCM), except for the benzene for which explicit solvent model should be necessary. Finally, VCD and ROA spectra were perfectly reproduced by the DFT/PCM calculations for the Boltzmann-averaged G+ and G? conformers.
- Daugey,De Rycke,Brotin,Buffeteau
-
supporting information
p. 342 - 350
(2018/01/15)
-
- Stereocontrolled synthesis of four isomeric linoleate triols of relevance to skin barrier formation and function
-
Linoleate triol esters are intermediates along the pathway of formation of the mammalian skin permeability barrier. In connection with the study of their involvement in barrier formation we required access to isomerically pure and defined samples of four linoleate triol esters. A common synthetic strategy was developed starting from isomeric alkynols derived from D-tartaric acid and 2-deoxy-D-ribose.
- Davis, Robert W.,Allweil, Alexander,Tian, Jianhua,Brash, Alan R.,Sulikowski, Gary A.
-
supporting information
p. 4571 - 4573
(2018/11/23)
-
- CYCLIC COMPOUND
-
The present invention provides compounds having a Toll-like receptor 4 (TLR4) signaling inhibitory action useful as preventive and therapeutic drugs of autoimmune disease and/or inflammatory disease or diseases such as chemotherapy-induced peripheral neuropathy (CIPN), chemotherapy-induced neuropathic pain (CINP), liver injury, ischemia-reperfusion injury (IRI) and the like. The present invention relates to a compound represented by formula (I) and a salt thereof: (wherein, each symbol is explained in greater detail in the specification).
- -
-
Paragraph 0320
(2018/04/13)
-
- Stereoselective synthesis of the lichen metabolite, (+) montagnetol and its congeners as antimicrobial agents
-
In view of structural diversity, (+) montagnetol, the major metabolite of the fruticose lichen, Roccella montagnei was synthesized along with three of its congeners by employing highly efficient protocols. (+) Montagnetol (2 R, 3S; 11) and (-) montagnetol (2S, 3R; 5) were synthesized in 7 and 9 steps, respectively, from L-ascorbic acid. The two new congeners 3 (2 R, 3R) and 6 (2S, 3S), which differ in configuration at C-2 and C-3 positions of the (+) montagnetol, were synthesized from (?) diethyl D-tartrate and (+) diethyl L-tartrate, respectively. The synthesized compounds were evaluated in vitro for antimicrobial activity against two Gram-positive (S. aureus and E. coli) and two Gram-negative (S. typhi and P. aeruginosa) bacteria and one fungal strain Candida albicans. Interestingly, the congener 3 showed promising anti-bacterial activity (MIC: 0.062 μg/ml) against P. aeruginosa, whereas the congener 6 displayed potent anti-fungal activity (MIC: 0.062 μg/ml) against C. Albicans.
- Mallavadhani, Uppuluri Venkata,Boddu, Ramakrishna,Rathod, Balaji B.,Reddy Setty, Prakasam
-
supporting information
p. 2992 - 2999
(2018/10/15)
-
- Hydrogen Bonding-Assisted Enhancement of the Reaction Rate and Selectivity in the Kinetic Resolution of d,l-1,2-Diols with Chiral Nucleophilic Catalysts
-
An extremely efficient acylative kinetic resolution of d,l-1,2-diols in the presence of only 0.5 mol% of binaphthyl-based chiral N,N-4-dimethylaminopyridine was developed (selectivity factor of up to 180). Several key experiments revealed that hydrogen bonding between the tert-alcohol unit(s) of the catalyst and the 1,2-diol unit of the substrate is critical for accelerating the rate of monoacylation and achieving high enantioselectivity. This catalytic system can be applied to a wide range of substrates involving racemic acyclic and cyclic 1,2-diols with high selectivity factors. The kinetic resolution of d,l-hydrobenzoin and trans-1,2-cyclohexanediol on a multigram scale (10 g) also proceeded with high selectivity and under moderate reaction conditions: (i) very low catalyst loading (0.1 mol%); (ii) an easily achievable low reaction temperature (0 °C); (iii) high substrate concentration (1.0 M); and (iv) short reaction time (30 min). (Figure presented.).
- Fujii, Kazuki,Mitsudo, Koichi,Mandai, Hiroki,Suga, Seiji
-
supporting information
p. 2778 - 2788
(2017/08/23)
-
- Formal Total Synthesis of Amphidinolide e
-
A formal total synthesis of the cytotoxic macrolide amphidinolide E is reported. The strategic steps are three Julia-Kocienski reactions (J-K), for the formation of the C5-C6, C9-C10, and C17-C18 double bonds, a Suzuki-Molander C21-C22 bond formation reaction, and a Kita-Trost macrolactonization. The "instability" of the two dienic systems and of the stereocenter at C2 (allylic methine, α to the carboxy group) and the protecting groups at C17-OH and C18-OH have posed difficult challenges. Each Julia-Kocienski olefination has been systematically optimized to provide the highest possible E/Z ratios.
- Bosch, Lluís,Mola, Laura,Petit, Elena,Saladrigas, Mar,Esteban, Jorge,Costa, Anna M.,Vilarrasa, Jaume
-
p. 11021 - 11034
(2017/10/27)
-
- Stereoselective Synthesis of the C27-C35 Eribulin Fragment and Its Utilization in Building Structurally Diverse Macrocycles
-
A practical and scalable stereoselective synthesis of the western substituted tetrahydrofuran ring C27-C35 fragment of eribulin was developed by using (2S,3S)-tartaric acid as a cheap starting material that was converted into an intermediate through a stereoselective vinylation and cross-metathesis as the key steps. A regio-and stero-selective intramolecular oxy-Michael cyclization or an iodocyclization reaction finally provided the required western tetrahydrofuran ring fragment and its related isomeric analogues. These key fragments were further utilized in obtaining several types of macrocyclic derivatives for exploration of their biological properties. The simplicity of our present approach has the potential to be considered for large-scale syntheses of key fragments of eribulin and related analogues.
- Konda, Saidulu,Khatravath, Mahender,Mallurwar, Naveen Kumar,Rao, Pallavi,Sripelly, Shivashankar,Iqbal, Javed,Arya, Prabhat
-
p. 1663 - 1683
(2016/05/24)
-
- Convergent Synthesis of the Dihydropyran Core Containing the C1-C15 Subunit of Sorangicin A Employing Gold(I)-Catalyzed Cyclization of an Allenic Alcohol
-
A convergent route to the C1-C15 subunit of sorangicin A is disclosed. The key steps include carbon-carbon bond formation using an α-chloro sulfide, regioselective hydrozirconation of an internal alkyne for the preparation of a trisubstituted iodoalkene, allene formation using the Myers-Movassaghi protocol, stereoselective reduction of allylic and propargylic ketones using Noyori's catalyst, and gold(I)-catalyzed cyclization of a β-hydroxy allene to construct the dihydropyran ring.
- Raghavan, Sadagopan,Nyalata, Satyanarayana
-
supporting information
p. 10698 - 10706
(2016/11/29)
-
- CYCLIC COMPOUNDS
-
The present invention provides compounds having a Toll-like receptor 4 (TLR4) signaling inhibitory action useful as preventive and therapeutic drugs of inflammatory disease and/or central nervous system disease or diseases such as chemotherapy-induced peripheral neuropathy (CIPN), chemotherapy-induced neuropathic pain (CINP), liver injury, ischemia-reperfusion injury (IRI) and the like. The present invention relates to a compound represented by formula (I) and a salt thereof: (wherein, each symbol is explained in greater detail in the specification).
- -
-
Page/Page column 0666; 0667; 0668
(2016/11/24)
-
- Enantioselective Rhodium-Catalyzed Atom-Economical Macrolactonization
-
A highly attractive route toward macrolactones, which form the cyclic scaffold of a multitude of diverse natural compounds, is described. Although many chemical approaches to this structural motif have been explored, an asymmetric variant of the cyclization is unprecedented. Herein we present an enantioselective macrolactonization through an intramolecular atom-economical rhodium-catalyzed coupling of ω-allenyl-substituted carboxylic acids. The use of a modified diop ligand, chiral DTBM-diop, led to high enantioselectivity (up to 93 % ee). The reaction tolerated a large variety of functionalities, including α,β-unsaturated carboxylic acids and depsipeptides, and provided the desired macrocycles with very high enantio- and diastereoselectivity.
- Ganss, Stephanie,Breit, Bernhard
-
supporting information
p. 9738 - 9742
(2016/08/10)
-
- Optimization of an electrolyte system for the simultaneous separation of nelfinavir mesylate and two impurities by micellar electrokinetic chromatography
-
A methodology for the simultaneous determination of nelfinavir mesylate and the impurities 3-hydroxy-2-methylbenzoic acid and (2R,3R)-4-((3S,4aS,8aS)-3-(tert-butylcarbamoyl) octahydroisoquinolin-2(1H)-yl)-3-hydroxy-1-(phenylthio)butan-2-aminium benzoate by micellar electrokinetic chromatography, with an analysis time of 25 min, was proposed. An electrolyte composed of sodium tetraborate buffer (pH 9.24; 25 mmol L-1), sodium dodecyl sulphate (9 mmol L-1) and methanol (10percent, v/v) was optimized using a mixed-level factorial design, with direct detection at 200 nm. After evaluating some figures of merit, such as selectivity, linearity, precision, limit of detection, limit of quantification, accuracy and robustness (using Youden's test), the method was successfully applied to the analysis of nelfinavir mesylate and its impurities in a pharmaceutical formulation. The optimized methodology is demonstrated to be useful in the determination of these analytes in a synthesis monitoring process, in raw materials and in pharmaceutical formulations, while offering low solvent consumption, requiring a small sample and using non-specific columns as advantages.
- Bastos, Carina A.,Gomes, Cláudia R. B.,De Souza, Marcus V. N.,De Oliveira, Marcone A. L.
-
p. 887 - 898
(2015/05/20)
-
- Stereoselective total synthesis of crassalactone A, a natural cytotoxic styryl lactone
-
A stereoselective total synthesis of a naturally occurring cytotoxic styryl lactone, crassalactone A (1), has been accomplished. The synthesis involves (-)-diisopropyl D-tartrate as the starting material, and the stereoselective additions of Grignard reag
- Raghavendar Reddy, Parigi,Das, Biswanath
-
p. 509 - 514
(2015/04/27)
-
- Stereoselective synthesis of tetrahydropyran-tetrahydrofuran (THP-THF) core of (+)-muconin via Prins cyclization
-
A stereoselective synthesis of tetrahydropyran-tetrahydrofuran (THP-THF) core 2 of (+)-muconin (1) has been achieved using Prins cyclization as a key step to construct tetrahydropyran moiety. Other important transformations such as Wittig olefination, Sharpless epoxidation, regio-, and stereoselective exo-cyclization of the epoxy alcohol, titanocene induced regioselective deoxygenation of 2,3-epoxy alcohol, Grignard reaction, and Barton-McCombie reaction are successfully employed to accomplish the synthesis of THP-THF core 2.
- Yadav,Reddy, U.V. Subba,Reddy, B.V. Subba
-
p. 3860 - 3863
(2014/07/08)
-
- Versicolactones A and B: Total synthesis and structure revision
-
To further determine absolute configurations of versicolactones A and B, total synthesis of versicolactones A and B and their six stereoisomers were reported in this Letter. The 1H and 13C NMR spectra of the synthetic erythro-stereoisomers matched perfectly with those of the natural products. Combined with the comparison of the specific rotations, the absolute configuration of versicolactones A and B were revised as (4Z,6R,7S)- and (4E,6R,7S)- from the corresponding (4Z,6R,7R)- and (4E,6R,7R)-6,7-dihydroxyocta- 2,4-dien-4-lactone, respectively.
- Wang, Liping,Zhu, Weiming
-
supporting information
p. 6729 - 6731
(2013/11/19)
-
- A convergent approach for the total synthesis of the α-glucosidase inhibitor (-)-panaxjapyne-C
-
The stereoselective total synthesis of (-)-panaxjapyne-C was accomplished in a convergent fashion. The synthesis utilizes the readily available enantiomers l-(+)-diethyltartrate and d-(-)-diethyltartrate and involves a Cadiot-Chodkiewicz coupling reaction, and an Ohira-Bestmann reaction as the key steps.
- Sathish Reddy,Gangadhar,Srihari
-
p. 1524 - 1530
(2013/12/04)
-
- A C2-symmetric pool based synthesis of the furanoside of hygromycin A
-
The readily available and inexpensive D-tartaric acid serves as the chiral building block for synthesis of the furanoside of hygromycin A. Key to our successes in the asymmetric synthesis of the furanose segment was the melding of several key reactions, such as the successful application of the monosilylation of C2-symmetric diol, diastereocontrolled di(2-propenyl)zinc addition to the aldehyde, and TMSCl-MeOH promoted desilylation, acetal-cleavage, and intramolecular esterification in one-step.
- Lo, Hong-Jay,Chang, Yuan-Kang,Lin, Feng-Yi,Yan, Tu-Hsin
-
p. 687 - 695
(2013/08/15)
-
- Synthesis of exo-methylenedifluorocyclopentanes as precursors of fluorinated carbasugars by 5-exo-dig radical cyclization
-
The synthesis of polyhydroxylated 1,1-difluoro-5-methylenecyclopentanes is described. The sequence involves an addition of PhSeCF2TMS to a tartrate-derived aldehyde or its corresponding tert-butanesulfinylimines followed by a radical cyclization. The use of a benzyl protected substrate led to an unproductive 1,5-hydrogen transfer after cyclization but the desired compound was eventually obtained from the unprotected substrate. A hydroboration/oxidation sequence was investigated on these 1,1-difluoro-5- methylenecyclopentanes as it would provide fluorinated carbasugars, a new and promising class of glycomimetics. Unfortunately, this reaction was poorly efficient and its regioselectivity not the expected one.
- Fourrire, Ga?lle,Leclerc, Eric,Quirion, Jean-Charles,Pannecoucke, Xavier
-
scheme or table
p. 172 - 179
(2012/03/08)
-
- Total synthesis of the marine toxin phorboxazole A using palladium(ii)-mediated intramolecular alkoxycarbonylation for tetrahydropyran synthesis
-
The potent antitumor agent phorboxazole A was synthesized from six subunits comprising C1-C2 (115), C3-C8 (98), C9-C19 (74), C20-C32 (52), C33-C41 (84) and C42-C46 (85). Tetrahydropyrans B and C containing cis-2,6-disubstitution were fabricated via palladium(ii)-mediated intramolecular alkoxycarbonylation which, in the case of tetrahydropyran C, was carried out with catalytic palladium(ii) and p-benzoquinone as the stoichiometric re-oxidant. Tetrahydropyran D was obtained by a stereoselective tin(iv)-catalyzed coupling of a C9 aldehyde with an allylsilane, and the C19-C20 connection was made using a completely stereoselective Wittig-Schlosser (E) olefination. Coupling of the oxazole C32 methyl substituent with the intact C33-C46 δ-lactone 3 was accompanied by elimination of the vinyl bromide to a terminal alkyne, but the C32-C33 linkage was implemented successfully with 83 and C33-C41 lactone 84. The C42-C46 segment of the side chain was then appended via Julia-Kocienski olefination. The macrolide portion of phorboxazole A was completed by means of an Ando-Still-Gennari intramolecular (Z)-selective olefination at C2-C3 which required placement of a (dimethoxyphosphinyl)acetate moiety at C24. Final deprotection led to phorboxazole A via a route in which the longest linear sequence is 37 steps and the overall yield is 0.36%.
- Kuntiyong, Punlop,Lee, Tae Hee,Kranemann, Christian L.,White, James D.
-
supporting information
p. 7884 - 7899
(2013/07/05)
-
- Synthesis of an acyclic C1-C11 fragment of peloruside B
-
The synthesis of a C1 reduced form of the C1-C11 fragment of peloruside B has been achieved in 15 synthetic steps. The strategy involved the use of D-tartaric acid to set the absolute stereochemistry and a 1,5-anti Mukiayama aldol reaction. Analog synthesis of C8-C11 is also reported, which enables changes at the C10 position of peloruside B to be made. The synthesis of the fragment concludes with C1 in the protected alcohol state rather than the natural ester. The synthesis of a C1 reduced form of the C1-C11 fragment of peloruside B was achieved in 15 synthetic steps. D-Tartaric acid was used to set the absolute stereochemistry, and a 1,5-anti Mukiayama aldolreaction was a key step. The methodology allows the framework to be synthesized in a remarkably efficient manner and enables changes to be made at the C10 position.
- Zang, Qin,Gulab, Shivali,Stocker, Bridget L.,Baars, Sylvia,Hoberg, John O.
-
scheme or table
p. 4465 - 4471
(2011/10/02)
-
- Synthesis of glycocinnasperimicin D
-
The first total synthesis of amino sugar antibiotic glycocinnasperimicin D (1) has been achieved by a convergent, three-component coupling strategy. The key steps involve the Heck-Mizoroki reaction by using the iodophenyl glycoside 50 and acryl amide 32 to furnish the right core structure of 1, and the construction of the urea glycoside employing the reaction of glycosyl isocyanate 8 with amino sugar 9. Glycosyl isocyanate 8 was prepared by the oxidation of isonitrile 10, which displayed excellent reactivity in the coupling event. Synthetic roadblocks, encountered during this synthetic effort, have led to the development of the α-selective, Lewis acid catalyzed phenyl glycosylation process with 2-amino-hexopyranose and a procedure for acetonide deprotection without affecting the silyl ethers.
- Nishiyama, Taihei,Kusumoto, Yoshifumi,Okumura, Ken,Hara, Kanako,Kusaba, Shohei,Hirata, Keiko,Kamiya, Yukihiro,Isobe, Minoru,Nakano, Keiji,Kotsuki, Hiyoshizo,Ichikawa, Yoshiyasu
-
scheme or table
p. 600 - 610
(2010/05/02)
-
- Studies toward the total synthesis of cyclodidemniserinol trisulfate. Part II: 3,5,7-Trisubstituted 6,8-dioxabicyclo [3.2.1] octane core structure construction via I2-mediated deprotection and ring closure tandem reaction
-
The 3,5,7-trisubstituted 6,8-dioxabicyclo [3.2.1] octane core structure was synthesized by employing a chiral pool convergent synthesis strategy and the I2-mediated simultaneous deprotection and ring closure reaction as the key step, providing a practical and efficient synthetic approach applicable to the further total synthesis of the natural product cyclodidemniserinol trisulfate.
- Liu, Jian-Hua,Long, Ya-Qiu
-
supporting information; experimental part
p. 4592 - 4594
(2009/10/18)
-
- Total synthesis of (+)-Oocydin A: Application of the suzuki-miyaura cross-coupling of 1,1-Dichloro-1-alkenes with 9-alkyl 9-BBN
-
(Chemical Equation Presented) Two sensitive fragments were coupled in the mild title reaction to create the Zchlorovinyl functionality of the target macrolide oocydin A (1; see scheme). Another highlight in the total synthesis of 1 was an efficient stereoselective Pd0-catalyzed cyclization to form the highly substituted tetrahydrofuran ring. Bz = benzoyl, TBS = tert-butyldimethylsilyl, MPM = 4-methoxyphenylmethyl.
- Roulland, Emmanuel
-
p. 3762 - 3765
(2008/12/23)
-
- First total synthesis and absolute configuration of the styryl lactone gonioheptolide A
-
Efficient asymmetric syntheses of both naturally occurring and non-naturally occurring enantiomers of gonioheptolide A are reported. The absolute configuration of (+)-gonioheptolide A was established by NOESY, Mosher ester analysis, and comparison with the specific rotation of the isolated (+)-gonioheptolide A. Georg Thieme Verlag Stuttgart.
- Gupta, Shuchi,Rajagopalan, Murali,Alhamadsheh, Mamoun M.,Tillekeratne, L. M. Viranga,Hudson, Richard A.
-
p. 3512 - 3518
(2008/09/20)
-
- Bifunctional acyclic nucleoside phosphonates: synthesis of chiral 9-{3-hydroxy[1,4-bis(phosphonomethoxy)]butan-2-yl} derivatives of purines
-
We report herein a general method for the synthesis of new types of chiral acyclic nucleoside four-carbon bisphosphonates. The alkylation of 2-amino-6-chloropurine and adenine was performed with (2S,3S)- or (2R,3R)-1,4-[bis(diisopropoxyphosphoryl)methoxy]]-3-[(methylsulfonyl)oxy]butan-2-yl benzoate. Alkylations provided (2R,3R) or (2S,3S) N9-substituted nucleobases, which were further converted to other derivatives. These conversions included either a modification of the nucleobase or transformation of the bisphosphonate chain. Subsequent deprotection of the diisopropyl esters with bromotrimethylsilane provided the resulting (2R,3R)- or (2S,3S)-bisphosphonic acids.
- Vrbkova, Silvie,Dracinsky, Martin,Holy, Antonin
-
p. 2233 - 2247
(2008/02/11)
-
- NEUROLOGICALLY-ACTIVE COMPOUNDS
-
The invention provides a compound of the formula (I): wherein R is methyl, ethyl, propyl, isopropyl, butyl, pentyl, neo-pentyl or cyclohexyl, or a salt or solvate thereof. These compounds are selective GABAC receptor antagonists. The invention also provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. The invention also provides methods of enhancing the cognitive activity of an animal and methods of stimulating memory capacity in an animal, comprising the step of administering to the animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
- -
-
Page/Page column 11-13
(2008/06/13)
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- Total synthesis of phorboxazole A. 1. Preparation of four subunits
-
(Chemical Equation Presented) Four subunits of the potent antitumor agent phorboxazole A were constructed; fragments C20-C32 and C9-C19 containing tetrahydropyrans A and B, respectively, were assembled using palladium-catalyzed intramolecular alkoxycarbonylation.
- White, James D.,Kuntiyong, Punlop,Tae, Hee Lee
-
p. 6039 - 6042
(2007/10/03)
-
- Interstrand and intrastrand DNA-DNA cross-linking by 1,2,3,4-diepoxybutane: Role of stereochemistry
-
1,2,3,4-Diepoxybutane (DEB) is a bifunctional electrophile capable of forming DNA-DNA and DNA-protein cross-links. DNA alkylation by DEB produces N7-(2′-hydroxy-3′,4′-epoxybut-1′-yl)-guanine monoadducts, which can then form 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) lesions. All three optical isomers of DEB are produced metabolically from 1,3-butadiene, but S,S-DEB is the most cytotoxic and genotoxic. In the present work, interstrand and intrastrand DNA-DNA cross-linking by individual DEB stereoisomers was investigated by PAGE, mass spectrometry, and stable isotope labeling. S,S-, R,R-, and meso-diepoxides were synthesized from L-dimethyl-2,3-O-isopropylidene-tartrate, D-dimethyl-2,3-O-isopropylidene- tartrate, and meso-erythritol, respectively. Total numbers of bis-N7G-BD lesions (intrastrand and interstrand) in calf thymus DNA treated separately with S,S-, R,R-, or meso-DEB (0.01-0.5 mM) were similar as determined by capillary HPLC-ESI+-MS/MS of DNA hydrolysates. However, denaturing PAGE has revealed that S,S-DEB produced the highest number of interchain cross-links in 5′-GGC-3′/3′-CCG-5′ sequences. Intrastrand adduct formation by DEB was investigated by a novel methodology based on stable isotope labeling HPLC-ESI+-MS/MS. Meso DEB treatment of DNA duplexes containing 5′-[1,7, NH2-15N3,2- 13C-G]GC-3′/3′-CCG-5′ and 5′-GGC-3′/ 3′-CC[15N3,2-13C-G]-5′ trinucleotides gave rise to comparable numbers of 1,2-intrastrand and 1,3-interstrand bis-N7G-BD cross-links, while S,S DEB produced few intrastrand lesions. R,R-DEB treated DNA contained mostly 1,3-interstrand bis-N7G-BD, along with smaller amounts of 1,2-interstrand and 1,2-intrastrand adducts. The effects of DEB stereochemistry on its ability to form DNA-DNA cross-links may be rationalized by the spatial relationships between the epoxy alcohol side chains in stereoisomeric N7-(2′-hydroxy-3′,4′-epoxybut-1′-yl)- guanine adducts and their DNA environment. Different cross-linking specificities of DEB stereoisomers provide a likely structural basis for their distinct biological activities.
- Park, Soobong,Anderson, Christopher,Loeber, Rachel,Seetharaman, Mahadevan,Jones, Roger,Tretyakova, Natalia
-
p. 14355 - 14365
(2007/10/03)
-
- Total synthesis of (-)-microcarpalide, a novel microfilament disrupting metabolite
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The stereoselective total synthesis of (-)-microcarpalide, a recently discovered 10-membered lactone of fungal origin displaying a remarkable disrupting action on actin microfilaments, was accomplished by using ring-closing metathesis (RCM) as the key step for the formation of the medium-sized ring. The diene ester required for the macrocyclization reaction was assembled via DCC-mediated esterification of two suitable partners, each bearing a terminal alkene group. The alcohol fragment was synthesized from n-bromohexane through a seven-step sequence entailing two consecutive stereoselective homologations of chiral boronic esters as strategic transformations for the sequential insertion of the two stereocentres with the final S absolute configuration, using (+)-pinanediol as the chiral director; final elaboration to the desired C11 framework envisaged treatment with an allyl Grignard reagent and oxidative cleavage of the boronic scaffold. In contrast, the acidic fragment was prepared in ten steps from D-tartaric acid, whose C4 backbone was elongated to the required C7 skeleton by means of two distinct Swern-Wittig oxidation-homologation sequences.
- Davoli, Paolo,Spaggiari, Alberto,Castagnetti, Luca,Prati, Fabio
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- Stereoselective synthesis of (+)-boronolide and its 8-epimer
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The synthesis of (+)-boronolide and its 8-epimer utilizing diastereoselective propargylation of α-hydroxy aldehyde was analyzed. The synthesis process was started with D-tertaric acid converted to diethyl (2S, 3S)-2,3-O-isopropylidenetartrate. A method was established with DIBAL-H as the reducing agent at -78°C to reduce esters directly to aldehydes. Diastereoselective propargylation was shown to be used in the synthesis of structurally diverse compounds.
- Hu, Shou-Gang,Hu, Tai-Shan,Wu, Yu-Lin
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p. 2305 - 2310
(2007/10/03)
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- A synthesis of the HIV-protease inhibitor nelfinavir from D-tartaric acid
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This letter describes a new synthesis of the HIV-protease inhibitor nelfinavir. The synthesis features a selective opening of a D-tartaric acid-derived cyclic sulfate with nitrogen nucleophiles.
- Albizati, Kim F.,Babu, Srinivasan,Birchler, Angela,Busse, Juliette K.,Fugett, Michelle,Grubbs, Alan,Haddach, Aubrey,Pagan, Miguel,Potts, Barbara,Remarchuk, Travis,Rieger, Dale,Rodriguez, Rick,Shanley, Jim,Szendroi, Robert,Tibbetts, Tony,Whitten, Kathleen,Borer, Bennett C.
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p. 6481 - 6485
(2007/10/03)
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- Synthesis of a chiral aziridine derivative as a versatile intermediate for HIV protease inhibitors.
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[reaction: see text] Chiral aziridine derivative 1 was prepared from D-tartaric acid. This compound could be utilized as a common intermediate for the synthesis of hydroxyethylamine class HIV protease inhibitors such as saquinavir, amprenavir, or nelfinavir.
- Kim,Bae,So,Yoo,Chang,Lee,Kang
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p. 2349 - 2351
(2007/10/03)
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- Radical cyclization of β-alkoxyacrylates: A formal synthesis of (-)-kumausallene
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Radical cyclization reaction of a bis(β-alkoxyacrylate) intermediate prepared from (-)-diethyl D-tartrate proceeded stereoselectively to give a 2,6-dioxabicyclo[3.3.0]octane product, which was converted into a known intermediate in the synthesis of kumausallene.
- Lee, Eun,Yoo, Sang-Ku,Choo, Hyunah,Song, Ho Young
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p. 317 - 318
(2007/10/03)
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- Stereocontrol in cyclisation of dioxolanyl radicals
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Appropriate nitrate esters are cleaved under photolytic or thermal (tributyltin radical) conditions to yield dioxolanyl radicals which undergo stereoselective cyclisation to heterocyclic products.The X-ray crystallographic structures for compounds 30a and 35 are reported.
- Batsanov, Andrei S.,Begley, Michael J.,Fletcher, Rodney J.,Murphy, John A.,Sherburn, Michael S.
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p. 1281 - 1294
(2007/10/02)
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- Polymers and polymerisation catalyst components
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A novel form of polypropylene which is clear and low melting, is predominantly isotactic but has 2 to 20% of oppositely oriented propylene residues. It may be made using novel optically active catalyst components which are derivatives of tartaric acid.
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- Synthesis and the Absolute Configuration of Panaxacol
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Panaxacol, a polyacetylene isolated from the callus of Panax ginseng, was synthesized from D-(-)-diethyl tartrate.The absolute configuration of panaxacol was determined to be 9R,10R.
- Fujimoto, Yasuo,Satoh, Mitsuru,Takeuchi, Naoki,Kirisawa, Makoto
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p. 1619 - 1622
(2007/10/02)
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- Enanthioselective Phase-Transfer Catalysis by Optically Active Crown Ethers
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1,2-Bis(hydroxymethyl)-15-crown-5 (1a), its dibenzyl ether (1b), and a series of esters with substituted benzoic acid (3) were probed as enanthioselective phase-transfer catalysts.Optical yields were observed in epoxidations of unsaturated ketones by hypochlorite and in cyanide additions to such compounds.The maximum ee value was 45percent.Polar side groups of the optically active crown ethers proved to be vital for enanthiomeric excesses.
- Dehmlow, Eckehard V.,Sauerbier, Christiane
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p. 181 - 186
(2007/10/02)
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- Total synthesis of (+)-colletodiol from (S,S)-tartrate and (R)-3-hydroxybutanoate
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The macrodiolide antibiotic (+)-colletodiol (7, Scheme 1) was synthesised.The configuration was thus proven to be (6R,11R,12R,14R). - Key intermediates (Schemes 9 and 10) are the two hydroxy acids 43 and 64, which were prepared from dimethyl (S,S)-tartrate in 20percent overall yield (12 steps) and from (R)-3-hydroxybutanoate in 57percent overall yield (6 steps), respectively.The two hydroxy acids were cyclised to give, after deprotection, the title compound. - Our investigations led to the production of a large number of chiral building blocks, many of them in different stereoisomeric forms.
- Schnurrenberger, Peter,Hungerbuehler, Ernst,Seebach, Dieter
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p. 733 - 744
(2007/10/02)
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- STEREOSPECIFIC SYNTHESIS OF ISOMERIC 4-SUBSTITUTED 9-(2,3-DIHYDROXYBUTYL)ADENINES
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Reduction of ethyl 2,3-O-isopropylidene-D-tartrate with sodium borohydride afforded (4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-dimethanol (Va) which was benzoylated to give monobenzoyl derivative Vd and further transformed into p-toluenesulfonyl derivative Ve.Reaction of the compound Ve with sodium salt of adenine followed by methanolysis gave 2,3-O-isopropylidene derivative Vf which on acid hydrolysis afforded 9-(2S,3S)-(2,3,4-trihydroxybutyl)adenine (Ia).The enantiomer IIa was obtained from 3,4-O-isopropylidene-D-mannitol via (4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-dimethanol (VIa) using the same procedure.Reaction of compounds Vf and VIf with p-toluenesulfonyl chloride afforded 4-O-p-toluenesulfonyl derivatives Vg and VIg.These compounds were also obtained from Va and VIa via di-p-toluenesulfonyl derivatives Vc and VIc by reaction with sodium salt of adenine.Treatment of compounds Vg and VIg with sodium iodide gave 4-iodo derivatives Vh and VIh which on reaction with tri-n-butyltin hydride, followed by acid hydrolysis, afforded enantiomeric threo-2,3-dihydroxybutyl derivatives Ib and IIb.Compounds Vg and VIg on treatment with sodium azide, subsequent catalytic hydrogenation of the intermediates Vj and VIj and acid hydrolysis afforded enantiomeric threo-9-(4-amino-2,3-dihydroxybutyl)adenines (Ic, IIc).Reaction of methyl threo-3-phenylglycerate (VIIb) with acetone, followed by reduction with lithium aluminum hydride, gave 2,2-dimethyl-4-phenyl-1,3-dioxolane-5-methanol (VIIIb) which was converted by reaction with p-toluenesulfonyl chloride, condensation with sodium salt of adenine and acid hydrolysis into 9-(RS)-threo-(3-phenyl-2,3-dihydroxypropyl)adenine (I, IId).Methyl ester of D-eritadenine (IXb) was transformed into 2,3-O-isopropylidene derivative XIa which on reduction with sodium borohydride afforded the alcohol XIb.Its acid hydrolysis gave 9-(2R,3S)-erythro-(2,3,4-trihydroxybutyl)adenine (IIIa); tosylation of compound XIb, successive treatment with sodium iodide and tri-n-butyltin hydride and acid hydrolysis afforded 9-(2R,3S)-erythro-(2,3-dihydroxybutyl)adenine (IIIb).The enantiomers IVa and IVb were obtained analogously from L-eritadenine.The racemic derivative Ib + IIb was prepared from (RS)-threo-2,3-dihydroxybutyric acid via p-toluenesulfonyl derivative of racemic 2,2,4-trimethyl-1,3-dioxolane-5-methanol (IIIc) by reaction of sodium salt of adenine followed by acid hydrolysis.
- HOLY, Antonin
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p. 173 - 189
(2007/10/02)
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