- Revisiting Bromohexitols as a Novel Class of Microenvironment-Activated Prodrugs for Cancer Therapy
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Bromohexitols represent a potent class of DNA-alkylating carbohydrate chemotherapeutics that has been largely ignored over the last decades due to safety concerns. The limited structure?activity relationship data available reveals significant changes in cytotoxicity with even subtle changes in stereochemistry. However, no attempts have been made to improve the therapeutic window by rational drug design or by using a prodrug approach to exploit differences between tumour physiology and healthy tissue, such as acidic extracellular pH and hypoxia. Herein, we report the photochemical synthesis of highly substituted endoperoxides as key precursors for dibromohexitol derivatives and investigate their use as microenvironment-activated prodrugs for targeting cancer cells. One endoperoxide was identified to have a marked increased activity under hypoxic and low pH conditions, indicating that endoperoxides may serve as microenvironment-activated prodrugs.
- Johansson, Henrik,Hussain, Omar,Allison, Simon J.,Robinson, Tony V.,Phillips, Roger M.,Sejer Pedersen, Daniel
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supporting information
p. 228 - 235
(2019/12/11)
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- A process for preparing dibromo mannitol method
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The invention discloses a method for preparing dibromo mannitol method, added in SO42 - /ZrO2 @ GO solid super strong acid catalyst, hydrogen bromide at a relatively low concentration can still be smooth reaction, join the bromide ion in the reaction of the material, can improve the reaction selectivity, catalytic reaction rate, effectively contribute to the reaction, the yield of the lifting dibromo mannitol. The method of the invention low cost, simple operation, safety and environmental protection, easy industrialized application.
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Paragraph 0032-0035; 0038; 0041
(2019/02/13)
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- A two-bromine mannitol preparation method (by machine translation)
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The invention discloses a method of preparing a two-bromine mannitol, added in SO4 2 - /TiO2 ? GO solid super strong acid catalyst, hydrogen bromide at a relatively low concentration can still be smooth reaction, join the bromide ion in the reaction of the material, can improve the reaction selectivity, catalytic reaction rate, effectively contribute to the reaction, the yield of the lifting dibromo mannitol. The method of the invention low cost, simple operation, safety and environmental protection, easy industrialized application. (by machine translation)
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Paragraph 0030-0040
(2019/01/14)
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- Application of cation exchange resin to improvement of yield in bromination reaction of hexanehexol
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The invention relates to an application of cation exchange resin to a bromination reaction of hexanehexol. Yield of dibromohexanehexol is substantially increased in the preparation processes of dibromohexanehexol from hexanehexol by using the cation exchange resin, and the effects are obviously better than the effects in the prior art.
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Paragraph 0090 - 0095
(2017/07/08)
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- Stereoregular poly-O-methyl [m,n]-polyurethanes derived from D-mannitol
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Novel linear carbohydrate-derived [m,n]-polyurethanes are successfully prepared using D-mannitol as renewable and low cost starting material. The key comonomer, 1,6-di-O-phenylcarbonyl-2,3,4,5-tetra-O-methyl-D-mannitol is polymerized with a diamine synthesized from D-mannitol or with alkylenediamines. These polymerization reactions afford, respectively, a [6,6]-polyurethane entirely based on a carbohydrate derivative or [m,n]-polyurethanes constituted by a poly-O-methyl substituted unit alternating with a polymethylene chain. All these polymers are stereoregular, as result of the C2 axis of symmetry of mannitol. The optically active polyurethanes are characterized by standard methods (FTIR, RMN, GPC, TGA, and DSC). Thus, GPC analysis reveals weight-average molecular weights between 18,000 and 25,000 Da. Thermal studies (DSC) indicate that the polymers obtained are amorphous materials with T g values dependent on the structure and chain length of the diamine constituent.
- Fidalgo, Daniela M.,Kolender, Adriana A.,Varela, Oscar
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p. 463 - 470
(2013/02/23)
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- Short and efficient synthesis of polyhydroxylated tetrahydrothiophene, tetrahydrothiopyrane and thiepane from bielectrophilic erythro, threo, xylo, ribo, arabino, manno and gluco α,ω-dibromoalditol derivatives
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Polyhydroxylated tetrahydrothiophene, tetrahydrothiopyrane and thiepane rings have been readily obtained in excellent yields (78-95%) from thioheterocyclisation of the bielectrophilic peracetylated α,ω-dibrominated derivatives of tetritols (erythritol (1) and d,L-threitol (4)), pentitols (xylitol (7), ribitol (10) and D-arabinitol (14)) and hexitols (D-mannitol (17) and D-glucitol (20)), respectively. With 2,3,4,5-tetra-O-acetyl-1,6-dibromo-1,6-dideoxy-D-glucitol (21) as substrate, the unexpected 2,6-anhydro derivative 25 was obtained. This could be attributed to previous S= regioselective nucleophilic attack at C-1 position followed by 1,2-transesterification and 2,6-O-heterocyclisation. The preferential attack at C-1 of the D-glucitol derivative 21 subsequently allowed a facile direct synthesis in good yields of 2,3,4,5,6-penta-O-acetyl-1-bromo-1-deoxy-D-glucitol (26), 2,3,4,5-tetra-O-acetyl-6-bromo-6-deoxy-1-thiobutyl-1-deoxy-D-glucitol (28) and 2,3,4,5-tetra-O-acetyl-6-bromo-6-deoxy-1-thiooctyl-1-deoxy-D-glucitol (28).
- Halila, Sami,Benazza, Mohammed,Demailly, Gilles
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p. 3307 - 3310
(2007/10/03)
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- Total synthesis of 3-deoxy-D-manno-2-octulosonic acid (KDO) and 2-deoxy-β-KDO
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(equation presented) Total syntheses of KDO and 2-deoxy-β-KDO are reported. The C2-symmetric dienediol 4 was desymmetrized by conversion to its corresponding 1,4-dioxanone 5. Ireland-Claisen rearrangement of 5 provided the 6-vinyldihydropyran-2-carboxylate template 6. Double-Sharpless asymmetric dihydroxylation gave the tetraol 7a, which was converted to KDO and 2-deoxy-β-KDO using methods similar to those previously reported. This synthetic scheme provides a flexible route to KDO and KDO analogues.
- Burke, Steven D.,Sametz, Geoffrey M.
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- 2,5:3,4-DIANHYDRO-1,6-DIDEOXY-6-(TRIMETHYLAMINO)-D-ALLITOL AND -D-GALACTITOL
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A new, four-step synthesis of 2,5:3,6-dianhydro-1-deoxy-D-glucitol 16 was worked out, starting from 1,6-dibromo-1,6-dideoxy-D-mannitol.Compound 16 was converted into different 4-O-acyl derivatives, the 3,6-anhydro rings of which where opened with hydrogen bromide, yielding the corresponding 6-bromo compounds.These were converted, via the 6-azides, into the 6-(dimethylamino) derivatives, the sulfonic esters of which gave, on treatment with base, the 2,5:3,4-dianhydro-D-allitol and -D-galactitol derivatives.These were converted with methyl iodide into the corresponding quaternary salts.On biological testing, only the D-allitol derivative showed weak, muscarine-like activity.
- Kuszmann, Janos
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