- Design and synthesis of analogues of the sphingosine-1-phosphate receptor 1 agonist IMMH001 with improved phosphorylation rate in human blood
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IMMH001, which is a prodrug for sphingosine-1-phosphate receptor 1 (S1P1) agonist, is converted to the active form, its monophosphate ester (S)-IMMH001-P, by sphingosine kinase 1 (SphK1) and sphingosine kinase 2 (SphK2) in vivo. In this study, we designed head-piece-modified analogues of IMMH001 based on structural information and prepared them with an efficient modular synthetic strategy. The analogues showed higher phosphorylation rates in human blood than the parent compound. These results indicated that the pro-R hydroxymethyl in the head-piece-moiety of IMMH001 prevents the pro-S hydroxymethyl from being phosphorylated by the kinase and ATP. The analogues may have better therapeutic potential.
- Xiao, Qiong,Hu, Minwan,Chen, Si,Shi, Zeyu,Hu, Jinping,Xie, Ping,Yin, Dali
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- 2,6-Disubstituted and 2,2,6-trisubstituted piperidines from serine: Asymmetric synthesis and further elaboration
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(Figure presented) 4-Hydroxy-3,4-dihydro-2H-pyridine-1-carboxylic acid benzyl esters, which are readily prepared from serine and terminal acetylenes, undergo Claisen rearrangement to piperidine derivatives when heated with butyl vinyl ether in the presence of Hg(OAc)2 and Et3N. This route to optically pure piperidines having substituents α to nitrogen is general, and the rearrangement products are versatile intermediates for making a broad range of amines containing a substituted piperidine subunit.
- Acharya, Hukum P.,Clive, Derrick L. J.
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scheme or table
p. 5223 - 5233
(2010/09/05)
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- SPHINGOLIPID DERIVATIVES AND THE COMPOSITION FOR ANTI-CANCER CONTAINING THE SAME
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Disclosed are a novel sphingolipid derivative having a sphingosine kinase suppressing activity and a composition containing the same. When the newly synthesized sphingolipid derivative of the invention is used, it is possible to maintain concentrations of ceramide and sphingosine to be high by preventing ceramide and sphingosine from being phosphorylated due to sphingosine kinase since an activity of sphingosine kinase is suppressed. In addition, since the apoptosis is induced in a cancer cell by ceramide and sphingosine, it is possible to treat or prevent a cancer or disease related to the cancer. Further, it is possible to treat or prevent a hyper- proliferative disease such as cancer or proliferation-promoting activity of sphingosine kinase. Accordingly, the composition containing the same can be used as a composition for suppressing sphingosine kinase and a composition for treating or preventing a cancer or hyper-proliferative disease.
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Page/Page column 14; 21
(2010/02/15)
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- Synthesis and evaluation of sphingoid analogs as inhibitors of sphingosine kinases
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Sphingosine 1-phosphate (S1P), a product of sphingosine kinases (SphK), mediates diverse biological processes such as cell differentiation, proliferation, motility, and apoptosis. In an effort to search and identify specific inhibitors of human SphK, the inhibitory effects of synthetic sphingoid analogs on kinase activity were examined. Among the analogs tested, we found two, SG12 and SG14, that have specific inhibitory effects on hSphK2. N,N-Dimethylsphingosine (DMS), a well-known SphK inhibitor, displayed inhibitory effects for both SphK1 and SphK2, as well as protein kinase C. In contrast, SG12 and SG14 exhibited selective inhibitory effects on hSphK2. Furthermore, SG14 did not affect PKC. In isolated platelets, SG14 blocked the conversion of sphingosine into sphingosine 1-phosphate significantly. This is the first report on the identification of a hSphK2-specific inhibitor, which may provide a useful tool for studying the biological functions of hSphK2.
- Kim, Jin-Wook,Kim, Yong-Woo,Inagaki, Yuichi,Hwang, You-A,Mitsutake, Susumu,Ryu, Yeon-Woo,Lee, Won Koo,Ha, Hyun-Joon,Park, Chang-Seo,Igarashi, Yasuyuki
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p. 3475 - 3485
(2007/10/03)
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- Investigations of a nucleophilic alaninol synthon derived from serine
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A nucleophilic synthon, (S)-(+)-4-(2-oxazolidonyl)-methyltriphenylphosphinyl iodide 6, available from L-serine in five steps (overall yield of 52%), reacts with aldehydes to produce alkenes in good to excellent yields (74-89%) and, in some cases, provides
- Sibi, Mukund P.,Rutherford, Drew,Renhowe, Paul A.,Li, Biqin
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p. 7509 - 7516
(2007/10/03)
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- Preparation and reactivity of chiral β-amino-alkylzinc iodides and related configurationally stable zinc organometallics
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Several zinc organometallics bearing at the β-position a carbamate or an amido function with an acidic N-H group were prepared using the direct insertion of zinc dust into the corresponding alkyl iodides in THF or THF:DMSO mixtures. Most of the starting iodides were obtained from natural α-amino acids and the resulting zinc species afforded after transmetalation with CuCN.2LiCl and reaction with a selection of relatively reactive electrophiles a variety of polyfunctional 1,2-amino alcohol derivatives and carbamates in optically pure form. Several secondary β-amido alkyl iodides were converted to the corresponding chiral zinc reagents and trapped with electrophiles. The configurational stability of chiral secondary organozinc compounds and the stereochemical course of their reactions were examined.
- Duddu,Eckhardt,Furlong,Knoess,Berger,Knochel
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p. 2415 - 2432
(2007/10/02)
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- A NEW NUCLEOPHILIC ALANINOL SYNTHON FROM SERINE
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A new nucleophilic alaninol synthon derived from serine is reported.The utility of this reagent in the stereoselective synthesis of β,γ-unsaturated amino alcohols is described.
- Sibi, Mukund P.,Renhowe, Paul A.
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p. 7407 - 7410
(2007/10/02)
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