- Development of novel PP2A activators for use in the treatment of acute myeloid leukaemia
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AAL(S), the chiral deoxy analog of the FDA approved drug FTY720, has been shown to inhibit proliferation and apoptosis in several cancer cell lines. It has been suggested that it does this by activating protein phosphatase 2A (PP2A). Here we report the synthesis of new cytotoxic analogs of AAL(S) and the evaluation of their cytotoxicity in two myeloid cell lines, one of which is sensitive to PP2A activation. We show that these analogs activate PP2A in these cells supporting the suggested mechanism for their cytotoxic properties. Our findings identify key structural motifs required for anti-cancer effects.
- Toop, Hamish D.,Dun, Matthew D.,Ross, Bryony K.,Flanagan, Hayley M.,Verrills, Nicole M.,Morris, Jonathan C.
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Read Online
- Preparation method of 4-octylphenethyl alcohol
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The invention relates to the technical field of preparation of 4-octylphenethyl alcohol, in particular to a preparation method of 4-octylphenethyl alcohol. The method comprises the following operationsteps of 1, synthesizing a Grignard reagent R1-Mg-X1, wherein R1 is octyl, X1 is halogen (Cl, Br or I), and R1-X1 and magnesium powder react in anhydrous ether or tetrahydrofuran (THF) to prepare theGrignard reagent R1-Mg-X1; and 2, carrying out an alkylation reaction on R2-CH2-X2 and the R1-Mg-X1 to obtain R2-CH2-R1 and X1-Mg-X2, wherein R2 is phenethyl alcohol, X2 is halogen (Cl, Br or I), andR2-CH2-R1 is the product 4-octylphenethyl alcohol. The specific technological process is as follows: R2-CH2-X2 + R1-Mg-X1-R2-CH2-R1 + X1-Mg-X2, wherein R1 is octyl, X1 is halogen (Cl, Br or I), R2 isphenethyl alcohol, and X2 is halogen (Cl, Br or I). The method has the advantages of few byproducts, high yield, low cost and relatively low synthesis reaction temperature, is beneficial to industrial production, has low environmental pollution, and implements green production.
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Paragraph 0073; 0076; 0080; 0046-0083; 0089-0090
(2020/12/08)
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- PROCESS FOR PREPARATION OF FINGOLIMOD
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The present invention provides a process for preparation of fingolimod, a compound of Formula I or a pharmaceutically acceptable salt thereof, free of regioisomeric impurity compound of Formula IA
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- SELECTIVE INHIBITORS AND ALLOSTERIC ACTIVATORS OF SPHINGOSINE KINASE
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Sphingosine 1-phosphate (S1P) is involved in hyper-proliferative diseases, such as cancer and vascular remodeling in pulmonary arterial hypertension. Inhibitors of sphingosine kinase 1 and 2 (SK1 and SK2), which catalyze the synthesis of S1P, may be useful anti- proliferative agents. We have synthesized a series of sphingosine-based inhibitors of SK and SK2. Also provided in this invention are compounds that activate SK1 which can be used in diseases such as fibrosis, where intracellular S1P is anti-fibrotic.
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Page/Page column 50
(2014/08/19)
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- PREPARATION OF FINGOLIMOD AND ITS SALTS
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The present application provide processes for the preparation of fingolimod and its pharmaceutically acceptable salts, process for the purification of fingolimod hydrochloride and process for the preparation of amorphous fingolimod hydrochloride.
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Paragraph 0253
(2014/09/03)
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- Synthesis of selective inhibitors of sphingosine kinase 1
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Sphingosine kinase isoform 1 (SK1) inhibitors may serve as therapeutic agents for proliferative diseases, including hypertension. We synthesized a series of sphingosine-based SK1-selective inhibitors, the most potent of which is RB-005 (IC50 = 3.6 μM), which also induced proteasomal degradation of SK1 in human pulmonary arterial smooth muscle cells.
- Baek, Dong Jae,MacRitchie, Neil,Pyne, Nigel J.,Pyne, Susan,Bittman, Robert
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supporting information
p. 2136 - 2138
(2013/03/28)
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- Iron-catalyzed cross-coupling reactions. A scalable synthesis of the immunosuppressive agent FTY720
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A chemo- and regioselective cross-coupling reaction of the functionalized aryl triflate 5 with octylmagnesium bromide catalyzed by cheap, nontoxic, and environmentally benign Fe(acac)3 sets the basis for a practical and scaleable synthesis of the octylbenzene derivative 6, which serves as a key building block for the preparation of FTY720 (1). This 2-amino-1,3-propanediol derivative shows highly promising immunosuppressive properties and is currently in human clinical phase III trials.
- Seidel, Guenter,Laurich, Daniel,Fuerstner, Alois
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p. 3950 - 3952
(2007/10/03)
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- Production of 2-amino-2-[2-(4-C2-20-alkyl-phenyl)ethyl]propane-1,3-diols
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Disclosed is a process for the production of 2-amino-2-[2-(4-C2-20-alkyl-phenyl)ethyl]propane-1,3-diols.
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- Synthesis and immunosuppressive activity of 2-substituted 2- aminopropane-1,3-diols and 2-aminoethanols
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A series of 2-substituted 2-aminopropane-1,3-diols was synthesized and evaluated for their lymphocyte-decreasing effect and immunosuppressive effect on rat skin allograft. A phenyl ring was introduced into the alkyl chain of the lead compound 3, which is an immunosuppressive agent structurally simplified from myriocin (1, ISP-I) via compound 2. The potency of the various compounds was dependent upon the position of the phenyl ring within the alkyl side chain. The most suitable length between the quaternary carbon atom and the phenyl ring was two carbon atoms. 2-Substituted 2-aminoethanols were successively synthesized and evaluated for their T-cell-decreasing effect and immunosuppressive effect using a popliteal lymph node gain assay in rats. The absolute configuration at the quaternary carbon affected the activity, and the (pro-S)-hydroxymethyl group of compound 6 was essential for potent immunosuppressive activity. Favorable substituents for the (pro-R)- hydroxymethyl group of 6 were hydroxyalkyl (hydroxyethyl and hydroxypropyl) or lower alkyl (methyl and ethyl) groups. 2-Amino-2-[2-(4- octylphenyl)ethyl]propane-1,3-diol hydrochloride (6, FTY720) was found to possess considerable activity and is expected to be useful as an immunosuppressive drug for organ transplantation.
- Kiuchi, Masatoshi,Adachi, Kunitomo,Kohara, Toshiyuki,Minoguchi, Masanori,Hanano, Tokushi,Aoki, Yoshiyuki,Mishina, Tadashi,Arita, Masafumi,Nakao, Noriyoshi,Ohtsuki, Makio,Hoshino, Yukio,Teshima, Koji,Chiba, Kenji,Sasaki, Shigeo,Fujita, Tetsuro
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p. 2946 - 2961
(2007/10/03)
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- 2-amino-1,3-propanediol compound and immunosuppressant
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2-Amino-1,3-propanediol compounds of the formula (I) STR1 wherein R is an optionally substituted straight- or branched carbon chain, an optionally substituted aryl, an optionally substituted cycloalkyl or the like, and R2, R3, R4 and R5 are the same or different and each is a hydrogen, an alkyl, an aralkyl, an acyl or an alkoxycarbonyl, pharmaceutically acceptable salts thereof and immunosuppressants comprising these compounds as active ingredients. The 2-amino-1,3-propanediol compounds of the present invention show immunosuppressive action and are useful for suppressing rejection in organ or bone marrow tranplantation, prevention and treatment of autoimmune diseases or as reagents for use in medicinal and pharmaceutical fields.
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