- Design, synthesis, and biological evaluation of simplified side chain hybrids of the potent actin binding polyketides rhizopodin and bistramide
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The natural products rhizopodin and bistramide belong to an elite class of highly potent actin binding agents. They show powerful antiproliferative activities against a range of tumor cell lines, with IC50 values in the low-nanomolar range. At the molecular level they disrupt the actin cytoskeleton by binding specifically to a few critical sites of G-actin, resulting in actin filament stabilization. The important biological properties of rhizopodin and bistramide, coupled with their unique and intriguing molecular architectures, render them attractive compounds for further development. However, this is severely hampered by the structural complexity of these metabolites. We initiated an interdisciplinary approach at the interface between molecular modeling, organic synthesis, and chemical biology to support further biological applications. We also wanted to expand structure-activity relationship studies with the goal of accessing simplified analogues with potent biological properties. We report computational analyses of actin-inhibitor interactions involving molecular docking, validated on known actin binding ligands, that show a close match between the crystal and modeled structures. Based on these results, the ligand shape was simplified, and more readily accessible rhizopodin-bistramide mimetics were designed. A flexible and modular strategy was applied for the synthesis of these compounds, enabling diverse access to dramatically simplified rhizopodin-bistramide hybrids. This novel analogue class was analyzed for its antiproliferative and actin binding properties.
- Herkommer, Daniel,Dreisigacker, Sandra,Sergeev, Galina,Sasse, Florenz,Gohlke, Holger,Menche, Dirk
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p. 470 - 489
(2015/04/21)
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- Total synthesis of (+)-negamycin and its 5-epi-derivative
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(+)-Negamycin was prepared in 13 steps in an overall yield of 31% from commercially available ethyl (R)-(+)-4-chloro-3-hydroxybutanoate. The key step in the reaction sequence was a highly stereoselective asymmetric Michael addition of chiral amine (-)-21
- Nishiguchi, Shigenobu,Sydnes, Magne O.,Taguchi, Akihiro,Regnier, Thomas,Kajimoto, Tetsuya,Node, Manabu,Yamazaki, Yuri,Yakushiji, Fumika,Kiso, Yoshiaki,Hayashi, Yoshio
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experimental part
p. 314 - 320
(2010/03/01)
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- An efficient transformation of cyclic ene-carbamates into ω-(N-formylamino)carboxylic acids by ruthenium tetroxide oxidation
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The ruthenium tetroxide (RuO4) oxidation of cyclic ene-carbamates resulted in the endo-cyclic carbon-carbon double bond cleavage to afford the corresponding ω-(N-formylamino)carboxylic acids in good yields. Substituted cyclic ene-carbamates der
- Kaname, Mamoru,Yoshifuji, Shigeyuki,Sashida, Haruki
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experimental part
p. 1310 - 1313
(2009/11/30)
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- Asymmetric synthesis of (R)-(-)-carnitine
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A TiCl4-promoted Mukaiyama-type aldol reaction of the ketenesilyl acetal of ethyl acetate with the lactone carbonyl of (5R,6S)-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin- 2-one (1) proceeds with a high degree of diastereoselectivity. The TBDMS-protected hemiketal thus obtained was efficiently converted into highly enantiomerically enriched (R)-(-)-carnitine by following an elimination-reduction protocol. This approach further demonstrates the utility of commercially available glycine template 1 as a potential substrate for the asymmetric synthesis of both enantiomers of carnitine.
- Jain, Rajendra P.,Williams, Robert M.
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p. 4437 - 4440
(2007/10/03)
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- Stereospecific synthesis of functionalized ether phospholipids
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A new stereospecific synthesis of functionalized alkyl ether phospholipids is reported. The synthesis is based upon the following: (1) the use of (R)-glycidyl tosylate as a chiral glycerol precursor; (2) the opening of a boron trifluoride catalyzed epoxide ring to introduce the functionalized sn-1-alkyl substituents; (3) the role of tetrahydropyranyl in protecting the sn-2-glycerol position; and (4) the elaboration of the sn-3-carbinol function, via the base hydrolysis of the acetoxy intermediate, obtained from the displacement of the toluenesulfonyl group of the substrate in dipolar aprotic media. Phosphorylation, using two different methods, has led to the development of two major classes of alkyllysophospholipids. For preparation of 'modulator-phospholipid' analogues, the substituted glycerol is coupled with 2,2,2-trichloro-tert-butyl phosphodichloridite and an N-protected amino acid ester, while elaboration of the phosphocholine headgroup of the target platelet-activating factor (PAF) analogues is achieved via the 2-chloro-2- oxo-1,3,2-dioxaphospholane/trimethylamine sequence. The synthesis provides rapid and efficient access to both types of phospholipids: (1) construction of the functionalized/substituted glycerol skeleton is achieved in a straightforward four-step sequence in better than 50% overall yield, and (2) phosphitylation or phosphorylation of the respective glycerol intermediates relies on reagents that require minimal use of protecting groups. The phospholipid compounds prepared include (1) the first synthetic analogue exhibiting modulator activity in conjunction with the glucocorticoid-receptor complex and (2) an sn-1-(ωamino)alkyl derivative of PAF, suitable for introduction of chain-terminal spectroscopic labels for biological and physicochemical studies to elucidate the mechanism of action of this highly potent alkyl ether phospholipid. The synthetic methods described herein have a great deal of flexibility, thus providing convenient general routes to a wide range of alkyl ether phospholipids.
- Kazi, Abul B.,Shidmand, Sean,Hajdu, Joseph
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p. 9337 - 9347
(2007/10/03)
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- A Facile Synthesis of (R)-4-Amino-3-hydroxybutanoic Acid (GABOB) from 3-Hydroxypyridine
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(R)-4-Amino-3-hydroxybutanoic acid (GABOB) has been synthesized facilely from 3-hydroxypyridine via 1-carbobenzoxy-1,2,3,4-tetrahydro-3-hydroxypyridine employing lipase-mediated kinetic resolution.
- Sakagami, Hideki,Kamikubo, Takashi,Ogasawara, Kunio
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p. 221 - 222
(2007/10/03)
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- Short and Practical Syntheses of (R)-(-)-Carnitine and (R)-(-)-γ-Amino-β-hydroxybutyric Acid (GABOB)
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Short and practical syntheses of (R)-(-)-carnitine and (R)-(-)-γ-amino-β-hydroxybutyric acid have been developed, both commencing with the catalytic asymmetric dihydroxylation of allyl bromide.
- Kolb, Hartmuth C.,Bennani, Youssef L.,Sharpless, K. Barry
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p. 133 - 141
(2007/10/02)
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- Baker's yeast reduction of N-protected methyl 4-amino-3-oxobutanoates and 3-oxopentanoates
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Baker's yeast reduction of N-tert-butoxycarbonyl (Boc) or N-benzyloxycarbonyl (Cbz) protected methyl 4-amino-3-oxopentanoates 4b-e and 4-amino-3-oxobutanoates 7a,b stereoselectively afforded the erythro-hydroxy esters 5b-e and (R)-hydroxy esters 8a,b, res
- Hashiguchi,Kawada,Natsugari
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p. 403 - 408
(2007/10/02)
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- Oxaziridine-mediated ring expansions of substituted cyclobutanones: Synthesis of (-)-γ-amino-β-hydroxybutyric acid (GABOB)
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The synthesis and photochemical rearrangement chemistry of oxaziridines derived from 3-benzyloxy- and 3-phenylcyclobutanone were examined. The oxaziridines were prepared by condensation of the ketones with α-methylbenzylamine followed by oxidation. Photolysis at 254 nm afforded good yields of readily separable lactams; 4-benzyloxy-pyrrolidin-2-one obtained in this way was converted to 4-amino-3-hydroxybutanoic acid (GABOB) by catalytic hydrogenolysis followed by acid hydrolysis.
- Aube,Wang,Ghosh,Langhans
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p. 693 - 701
(2007/10/02)
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- A New Synthesis of (R)-GABOB and (R)-Oxiracetam
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The synthesis of both (R)-GABOB 1 and (R)-Oxiracetam 2 through the same diastereomer intermediate 8a is reported.
- Orena, Mario,Porzi, Gianni,Sandri, Sergio
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p. 2701 - 2711
(2007/10/02)
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- Enantiomerically pure β,γ-epoxyesters from β-hydroxylactones: Synthesis of β-hydroxyesters and (-)-GABOB
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The preparation of enantiomerically pure β,γ-epoxyesters was achieved by chemoselective opening of β-hydroxybutanolides with trimethylsilyliodide followed by cyclisation of the resulting iodohydrins with silver oxide. The reaction of these epoxyesters with lithio or magnesiocuprates afforded stereochemically pure α-substituted β-hydroxyesters. Alternatively, (-)-GABOB was synthesized in optically pure form from the iodohydrin 2′a.
- Larcheveque,Henrot
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p. 4277 - 4282
(2007/10/02)
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- Simple Three-Step Synthesis of (R)- and (S)-4-Amino-3-hydroxybutanoic Acid (GABOB) by Stereoselective Aldol Addition
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A simple synthesis of both (R)- and (S)-GABOB (5) is reported.In the key step, doubly deprotonated (R)- or (S)-2-Hydroxy-1,2,2-triphenylethyl acetate (HYTRA) (1) is added to Cbz-protected glycinal (2).
- Braun, Manfred,Waldmueller, Delia
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p. 856 - 858
(2007/10/02)
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- PRACTICAL SYNTHESIS OF (R)-γ-AMINO-β-HYDROXYBUTANOIC ACID (GABOB) FROM (R)-EPICHLOROHYDRIN
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(R)-Epichlorohydrin has efficiently been converted to the hypotensive and antiepileptic compound, (R)-γ-amino-β-hydroxybutanoic acid (GABOB), in six steps in 57percent overall yield.
- Takano, Seiichi,Yanase, Masashi,Sekiguchi, Yoshinori,Ogasawara, Kunio
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p. 1783 - 1784
(2007/10/02)
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- A Convenient Synthesis of (R)-γ-Amino-β-hydroxybutanoic Acid (GABOB) from Natural (2S,4R)-4-Hydroxyproline (Short Communication)
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The oxidative decarboxylation sequence (1a --> 2a --> 3a --> 4a --> 5a) affording γ-aminobutanoic acid (5a) is adapted to the synthesis of its hydroxy derivative 5b.A facile high yield conversion of (2S,4R)-4-hydroxyproline-methylester-hydrochloride (7) to (R)-GABOB (5b) on a preparative scale is reported with the hydroxypyrrolidone 8 as the intermediate. - Keywords: Oxidation of amino acid derivatives; γ-Amino-β-hydroxybutanoic acid (GABOB); 1-Pyrroline-2-carboxylic acid derivatives
- Haeusler, Johannes
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p. 865 - 870
(2007/10/02)
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- FURTHER INFORMATION ON THE STERIC COURSE OF THE BAKER'S YEAST REDUCTION OF 4-SUBSTITUTED-3-OXOBUTANOATES
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Yeast reduction of (6), (7), (8), (12) and (13) affords (3R)(9) and (3R)(10) of high optical purity, racemic (11), and (3S)(14) and (3S)(15).
- Fuganti, Claudio,Grasselli, Piero,Seneci, P. Fausto,Casati, Paolo
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p. 5275 - 5276
(2007/10/02)
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- ON THE STERIC COURSE OF BAKER' S YEAST MEDIATED REDUCTION OF ALKYL 4-AZIDO-AND 4-BROMO-3-OXOBUTYRATE. SYNTHESIS OF (R)- AND (S)-CARNITIN
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Baker's yeast reduction of ethyl 4-azido-and 4-bromo-3-oxobutyrate affords (3R) (8) and (3S) (2), respectively, in high optical purity.
- Fuganti, Claudio,Grasselli, Piero
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p. 101 - 104
(2007/10/02)
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- (-)-β-PINENE AS CHIRAL PROMOTER. STEREOSPECIFIC ACCESS TO (-)-γ-AMINO-β(R)-HYDROXYBUTYRIC ACID (GABOB) AND (R)-CARNITINE. 2
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The stereochemical correlation between the ene adducts 2 and 4a and their products of alkaline hydrolysis is reported.Starting from 2, by using a degradative sequence, a stereocontrolled approach to γ-amino-β(R)-hydroxybutyric acid (GABOB) 8f and (R)-carnitine hydrochloride 8g is described.
- Pellegata, R.,Dosi, I.,Villa, M.,Lesma, G.,Palmisano, G.
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p. 5607 - 5614
(2007/10/02)
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- 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
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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.
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p. 6304 - 6311
(2007/10/02)
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