- Aminopropylindenes derived from Grundmann's ketone as a novel chemotype of oxidosqualene cyclase inhibitors
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A series of aminopropylindenes, designed as mimics of a cationic high energy intermediate in the oxidosqualene cyclase1 (OSC)-mediated cyclization of 2,3-oxidosqualen to lanosterol was prepared from Grundmann's ketone. Screening on OSCs from five different organisms revealed interesting activities and selectivities of some of the compounds. A N,N-dimethylaminopropyl derivative showed promising inhibition of Trypanosoma cruzi OSC in combination with low cytotoxicity, and showed significant reduction of cholesterol biosynthesis in a human cell line.
- Lange, Stefanie,Keller, Marco,Müller, Christoph,Oliaro-Bosso, Simonetta,Balliano, Gianni,Bracher, Franz
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- Indene Compounds Synthetically Derived from Vitamin D Have Selective Antibacterial Action on Helicobacter pylori
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Helicobacter pylori infects the human stomach and is closely linked with the development of gastric cancer. When detected, this pathogen can be eradicated from the human stomach using wide-spectrum antibiotics. However, year by year, H. pylori strains resistant to the antibacterial action of antibiotics have been increasing. The development of new antibacterial substances effective against drug-resistant H. pylori is urgently required. Our group has recently identified extremely selective bactericidal effects against H. pylori in (1R,3aR,7aR)-1-[(1R)-1,5-dimethylhexyl]octahydro-7a-methyl-4H-inden-4-one (VDP1) (otherwise known as Grundmann's ketone), an indene compound derived from the decomposition of vitamin D3 and proposed the antibacterial mechanism whereby VDP1 induces the bacteriolysis by interacting at least with PtdEtn (dimyristoyl-phosphatidylethanolamine [di-14:0 PtdEtn]) retaining two 14:0 fatty acids of the membrane lipid constituents. In this study, we synthesized new indene compounds ((1R,3aR,7aR)-1-((2R,E)-5,6-dimethylhept-3-en-2-yl)-7a-methyloctahydro-4H-inden-4-one [VD2-1], (1R,3aR,7aR)-1-((S)-1-hydroxypropan-2-yl)-7a-methyloctahydro-1H-inden-4-ol [VD2-2], and (1R,3aR,7aR)-7a-methyl-1-((R)-6-methylheptan-2-yl)octahydro-1H-inden-4-ol [VD3-1]) using either vitamin D2 or vitamin D3 as materials. VD2-1 and VD3-1 selectively disrupted the di-14:0 PtdEtn vesicles without destructing the vesicles of PtdEtn (dipalmitoyl-phosphatidylethanolamine) retaining two 16:0 fatty acids. In contrast, VD2-2, an indene compound lacking an alkyl group, had no influence on the structural stability of both PtdEtn vesicles. In addition, VD2-1 and VD3-1 exerted extremely selective bactericidal action against H. pylori without affecting the viability of commonplace bacteria. Meanwhile, VD2-2 almost forfeited the bactericidal effects on H. pylori. These results suggest that the alkyl group of the indene compounds has a crucial conformation to interact with di-14:0 PtdEtn of H. pylori membrane lipid constituents whereby the bacteriolysis is ultimately induced.
- Wanibuchi, Kiyofumi,Hosoda, Kouichi,Ihara, Masato,Tajiri, Kentaro,Sakai, Yuki,Masui, Hisashi,Takahashi, Takashi,Hirai, Yoshikazu,Shimomura, Hirofumi
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- Large-Scale Synthesis of Eldecalcitol
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Industrial-scale synthesis of eldecalcitol is described. AA highly diastereoselective epoxidation of p-methoxybenzyl (PMB) protected dienol at room temperature provides the key epoxide intermediate with a secondary hydroxyl group, which is alkylated with a triflate to set up all of the subunits at the C-1, C-2, and C-3 positions of the A-ring fragment. Selective protecting group manipulation followed by palladium-catalyzed cyclization then provides the A-ring synthon. The C/D-ring fragment is obtained by (1) direct C-H hydroxylation of Grundman's ketone using in situ prepared trifluoropropanone dioxirane and (2) protection. Finally, the coupling of the A-ring with the C/D-ring fragment, global deprotection, and recrystallization provide the highly crystalline eldecalcitol.
- Moon, Hyung Wook,Lee, Seung Jong,Park, Seong Hu,Jung, Se Gyo,Jung, In A.,Seol, Chang Hun,Kim, Seung Woo,Lee, Seon Mi,Gangganna, Bogonda,Park, Seokhwi,Lee, Kee-Young,Oh, Chang-Young,Song, Juyoung,Jung, Jaehun,Heo, Ji Soo,Lee, Kang Hee,Kim, Hae Sol,Lee, Won Taek,Baek, Areum,Shin, Hyunik
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- Total synthesis of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (ED-71)
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A convergent method for the synthesis of ED-71 has been developed. Starting from the reported epoxide 5 which could be easily prepared from D-mannitol, ED-71 was synthesized in 11 linear steps with 17% overall yield.
- Deng, Wutong,Gong, Yimou,Pu, Qingyin,Sun, Jian,Wang, Chao,Zhou, Li
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supporting information
(2020/03/13)
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- Structure–Activity Relationship Studies of Vitamin D3 Analogues Containing an Ether or Thioether Linker as Hedgehog Pathway Inhibitors
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The Hedgehog (Hh) signaling pathway is critical for embryonic patterning and postembryonic tissue regeneration. Constitutive pathway activation has also been linked to human malignancies such as basal cell carcinoma (BCC) and medulloblastoma; therefore, multiple small-molecule scaffolds that inhibit Hh signaling are in development. Previously, Grundmann's alcohol, also known as the “northern region” of vitamin D3 (VD3), has been identified as a moderate Hh pathway inhibitor. In this study, isomers of Grundmann's alcohol with different orientations of the C4 hydroxy group and C3α proton were investigated to determine the optimal configuration for this hexahydroindane scaffold with respect to Hh inhibition. A series of analogues containing Grundmann's alcohol linked to a substituted phenyl or benzyl ring through an ether or thioether linker were synthesized and evaluated for their anti-Hh activity. Of these, analogue 17 ((1R,3aR,4R,7aR)-1-[(R)-1,5-dimethylhexyl]-4-(4-aminophenoxy)-7a-methyloctahydro-1H-indene) demonstrated potent anti-Hh activity in Hh-dependent BCC cells and did not activate canonical vitamin D receptor signaling, demonstrating its selective nature for the Hh signaling pathway.
- Wen, Jiachen,Hadden, M. Kyle
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supporting information
p. 748 - 753
(2018/03/05)
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- A route to the 9,10-secosteroid astrogorgiadiol featuring a key sp 2-sp3 Suzuki type cross-coupling
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The described semi-synthetic route differs from the previously published approaches by an original C-7-C-8 disconnection. The kinetic enol triflate of Grundmann ketone was chosen as the CD-ring platform on which to couple an A-ring synthon via a challengi
- Médard, Guillaume
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p. 186 - 196
(2014/01/06)
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- Synthesis and preliminary biological evaluation of new antiproliferative aromatic analogues of 1α,25-dihydroxyvitamin D3
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In an effort to develop novel vitamin D3 analogues, a series of aromatic compounds was synthetized, using efficient Negishi cross coupling between alkenylzinc reagents of the C,D-ring moiety of vitamin D3, and various substituted aromatic halides as A-ring mimics. The study aimed at exploring the influence of the replacement of the original vitamin D3 diene by a styrene unit on the biological activities. Potency in the induction of the differentiation of HL-60 cells for the lead compound 36 was 12 fold less important than calcitriol correlating with a weaker binding affinity for VDR.
- Thomas, Emmanuel,Brion, Jean-Daniel,Peyrat, Jean-Fran?ois
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p. 381 - 393
(2014/11/07)
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- Probing the structural requirements for vitamin D3 inhibition of the hedgehog signaling pathway
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A structure-activity relationship study to elucidate the structural basis for hedgehog (Hh) signaling inhibition by vitamin D3 (VD3) was performed. Functional and non-functional regions of VD3 and VD2 were obtained through straightforward synthetic means
- Deberardinis, Albert M.,Banerjee, Upasana,Miller, Michele,Lemieux, Steven,Hadden
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scheme or table
p. 4859 - 4863
(2012/08/13)
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- Cytotoxic ring A-modified steroid analogues derived from Grundmann's ketone
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A series of steroid and azasteroid analogues containing a six-membered ring A with various functionalities were synthesized. Furthermore, the syntheses of tetracyclic analogues bearing a five-membered A-ring and the syntheses of a number of bicyclic secosteroid analogues were carried out. All compounds were tested for their antibacterial, antifungal and cytotoxic activities. Among all tested compounds 7 and 9 showed outstanding cytotoxic activities but were devoid of antimicrobial activities. The cytotoxic activities of compounds 7, 9 and 10 were initially verified by the National Cancer Institute (NCI) in a one-dose 60 cell assay. In accordance with our results 7 and 9 satisfied pre-determined threshold inhibition criteria for progression to the 5-dose NCI screening, which revealed a selective activity profile for both candidates.
- Mayer, Christoph D.,Bracher, Franz
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supporting information; experimental part
p. 3227 - 3236
(2011/08/03)
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- Synthesis and NMR studies of 13C-labeled vitamin D metabolites
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Isotope-labeled drug molecules may be useful for probing by NMR spectroscopy the conformation of ligand associated with biological hosts such as membranes and proteins. Triple-labeled [7,9,19-13C3]-vitamin D3 (56), its 25-hydroxylated and 1α,25-dihydroxylated metabolites (58 and 68, respectively), and other labeled materials have been synthesized via coupling of [9-13C]-Grundmann's ketone 39 or its protected 25-hydroxy derivative 43 with labeled A ring enyne fragments 25 or 26. The labeled CD-ring fragment 39 was prepared by a sequence involving Grignard addition of [13C]-methylmagnesium iodide to Grundmann's enone 28, oxidative cleavage, functional group modifications leading to seco-iodide 38, and finally a kinetic enolate SN2 cycloalkylation. The C-7,19 double labeling of the A-ring enyne was achieved by the Corey-Fuchs/Wittig processes on keto aldehyde 11. By employing these labeled fragments in the Wilson-Mazur route, the C-7,9,19 triple-13C-labeled metabolites 56, 58, and 68 as well as other 13C-labeled metabolites have been prepared. In an initial NMR investigation of one of the labeled metabolites prepared in this study, namely [7,9,19-13C3]-25-hydroxyvitamin D3 (58), the three 13C-labeled carbons of the otherwise water insoluble steroid could be clearly detected by 13C NMR analysis at 0.1 mM in a mixture of CD3OD/D2O (60/40) or in aqueous dimethylcyclodextrin solution and at 2 mM in 20 mM sodium dodecyl sulfate (SDS) aqueous micellar solution. In the SDS micellar solution, a double half-filter NOESY experiment revealed that the distance between the H19Z and H7 protons is significantly shorter than that of the corresponding distance calculated from the solid state (X-ray) structure of the free ligand. The NMR data in micelles reveals that 58 exists essentially completely in the α-conformer with the 3β-hydroxyl equatorially oriented, just as in the solid state. The shortened distance (H19Z-H7) in micellar solutions as compared to that in the solid state is most easily rationalized on the basis that the 5(10)-torsion angle in 58 is decreased in micellar solutions as compared to that in the solid state.
- Okamura, William H.,Zhu, Gui-Dong,Hill, David K.,Thomas, Richard J.,Ringe, Kerstin,Borchardt, Daniel B.,Norman, Anthony W.,Mueller, Leonard J.
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p. 1637 - 1650
(2007/10/03)
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- Synthesis and pharmacokinetics of 1α-hydroxyvitamin D3 tritiated at 22 and 23 positions showing high specific radioactivity
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A novel synthesis of a radioactive compound of 1α-hydroxyvitamin D3 (1αOHD3) (1) and its pharmacokinetics are described. Radioactive 1αOHD3 tritiated at 22 and 23 positions ([22,23-3H4]1αOHD3) (5) was prepared via key reactions of the reduction of acetylenic side chain in the ketone (12) with tritium gas in the presence of palladium-charcoal and the subsequent Wittig reaction with the A-ring synthon (16). [22,23-3H4]1αOHD3 (5) showed high specific radioactivity (111.5 Ci/mmol) and was used successfully in pharmacokinetics studies with rats. In the pharmacokinetics studies, the plasma concentration level of the active form of vitamin D3, 1α,25- dihydroxyvitamin D3 [1α,25(OH)2D3], after oral or intravenous administration of [22,23-3H4]1αOHD3 (5), showed longer half-life, lower maximum concentration, and lower area under the curve than those after treatment of 1α,25(OH)2D3 tritiated at 26 and 27 positions (4). These results might suggest a beneficial therapeutic utility of 1αOHD1 (1) over the treatment of 1α,25(OH)2D3 (2).
- Kawase, Akira,Ichikawa, Fumihiko,Koike, Nobuo,Kamachi, Shinichi,Stumpf, Walter E.,Nishii, Yasuho,Kubodera, Noboru
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p. 215 - 219
(2007/10/03)
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- Synthesis of a novel class of cdc25A inhibitors from Vitamin D3
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We have developed a novel class of cdc25A inhibitors by drastic modification of hydrophobic and hydrophillic substructures of dysidiolide. The unsaturated derivative 3b strongly inhibited cdc25A (IC50=7.7 μM) and caused G1 arrest of HL60 cells. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Dodo, Kosuke,Takahashi, Masato,Yamada, Yuji,Sugimoto, Yoshikazu,Hashimoto, Yuichi,Shirai, Ryuichi
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p. 615 - 617
(2007/10/03)
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- Synthesis and cytotoxic activity of steroid-anthraquinone hybrids
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Synthesis of cytotoxic steroidal derivatives containing a quinone moiety is described. The synthetic strategy is based on an unusual A + CD → ABCD Diels-Alder approach which generates 9β-H cholestane analogs. The adducts formed are efficiently aromatized
- De Riccardis, Francesco,Izzo, Irene,Di Filippo, Marcello,Sodano, Guido,D'Acquisto, Fulvio,Carnuccio, Rosa
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p. 10871 - 10882
(2007/10/03)
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- Synthesis and biological activity of 1α,25-dihydroxy-18-norvitamin D3 and 1α,25-dihydroxy-18,19-dinorvitamin D3
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1α,25-Dihydroxy-18-norvitamin D3 and 1α,25-dihydroxy-18,19- dinorvitamin D3 were prepared via Wittig-Horner coupling of 25-hydroxy-18- nor Grundmann type ketone with the corresponding A-ring phosphine oxides. Configuration at C-13 in
- Sicinski, Rafal R.,Perlman, Kato L.,Prahl, Jean,Smith, Connie,DeLuca, Hector F.
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p. 4497 - 4506
(2007/10/03)
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- Photochemical synthesis of C/D-ring synthons of vitamin D
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Beginning with a steroid-5-ene, C/D-ring synthons of vitamin D are readily prepared via ozonization followed by a Norrish II photoelimination reaction.
- Dauben, William G.,Ollmann Jr., Richard R.,Wu, Shung C.
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p. 2149 - 2152
(2007/10/02)
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- New strategies for the synthesis of vitamin D metabolites via Pd-catalyzed reactions
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The invention of new palladium-catalyzed reactions offers new insights into synthetic strategies directed toward the vitamin D system. The palladium-catalyzed cycloisomerization of 1,6- and 1,7-enynes to dialkylidenecycloalkanes permits a lynchpin approach to the A ring of vitamin Ds. Using the thioacetal of formaldehyde, the proper subunits containing the olefin and the acetylene were attached. Pd(2+) effected cycloisomerization to an A ring subunit. A more effective strategy evolved from the evolution of a Pd-catalyzed alkylative cyclization of enynes. Whereas prior work established the feasibility of this process for 1,6-enynes, model studies reported herein demonstrate the feasibility of its extension to 1,7-enynes. This reaction permits the creation of a new concept for vitamin D synthesis wherein A ring formation is concomitant with its attachment to an appropriate CD fragment. An asymmetric synthesis of the requistite 1,7-enyne required six steps. Bromomethylenation of Grundmann's ketone and its side chain hydroxylated derivative proceeded with excellent geometrical selectivity (>30:1) using the Wittig reaction. A Pd catalyst generated from (dba)3Pd2·CHCl3 and triphenylphosphine stitched together these two units in a single step resulting in syntheses of alphacalcidiol and calcitriol.
- Trost, Barry M.,Dumas, Jacques,Villa, Marco
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p. 9836 - 9845
(2007/10/02)
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- Chemical conversion of vitamin D3 to its 1,25-dihydroxy metabolite
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Vitamin D3 (6) has been converted to the 1,25-dihydroxy vitamin D3 metabolite (1) and the 1α-fluoro derivative 2 via a new process. The strategy involved the cleavage of the ring A portion from the CD portion in vitamin D3
- Kiegiel,Wovkulich,Uskokovic
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p. 6057 - 6060
(2007/10/02)
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- Thermal -Sigmatropic Hydrogen Shifts: Stereochemistry, Kinetics, Isotope Effects, and ?-Facial Selectivity
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The antarafacial stereochemistry of the thermal -sigmatropic hydrogen shift has been demonstrated.The substrates studied include the epimeric cis-isotachysterol analogues 1 and 4 and their stereospecifically 15α-deuterium-labelled derivatives 7 and 1
- Hoeger, Carl A.,Johnston, Allen D.,Okamura, William H.
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p. 4690 - 4698
(2007/10/02)
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- Total Synthesis of Dihydrovitamin DHV3 and Dihydrotachysterol DHT3. Application of the Low-Valent Titanium-Induced Reductive Elimination
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Optically active ring A synthons 6, 11, 13, and 14, precursors of DHV3 and DHT3, were synthetized from (-)- and (+)-carvone.Application of the low-valent titanium-induced reductive elimination gave a new synthetic approach to vitamin D3 analogues, as show
- Solladie, Guy,Hutt, Jean
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p. 3560 - 3566
(2007/10/02)
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- A Novel Approach to the Stereocontrolled Synthesis of Steroid Side Chains Including the CD-Ring System: The First Total Synthesis of (+)-8α-(Phenylsulfonyl)des-AB-cholestane and Its Efficient Conversion into Grundmann's Ketone and Vitamin D3
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A new stereocontrolled approach to steroid CD-ring system including side chain starting from an optically active indenedione 6 is described.The application of this finding allows for the asymmetric synthesis of des-AB-cholestane 3 and 8α-(phenylsulfonyl)des-AB-cholestane 37; from the latter Grundmann's ketone 25 and vitamin D3 (27) were synthesized efficiently.
- Nemoto, Hideo,Kurobe, Hiroshi,Fukumoto, Keiichiro,Kametani, Tetsuji
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p. 5311 - 5320
(2007/10/02)
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- Studies on Vitamin D (Calciferol) and Its Analogues. 18. The Vinylallene Approach to the 1-Hydroxyvitamin D System. New Sigmatropic Reactions in the Vitamin D Series
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The thermally induced -sigmatropic hydrogen shift of the diastereomeric vitamin D type vinylallenols 6a (1R,6R), 6b (1R,6S), 7a (1S,6S) and vinylallenols 5a (6R) and 5b (6S) were studied.The 1S,6S (7b) and 1R,6R(6a) alcohols afforded ca. 60percent yi
- Condran, Patrick,Hammond, Milton L.,Mourino, Antonio,Okamura, William H.
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p. 6259 - 6267
(2007/10/02)
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