- New aldehyde and vinylsulfone proteasome inhibitors for targeted melanoma therapy
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The proteasome is a promising target in cancer therapy. However, it is ubiquitous and its inhibitors cause side effects. To target melanoma cells we synthesized new peptide aldehyde and vinylsulfone inhibitors of the proteasome conjugated to the melanin-targeting ligand (MTL) derived from radiotracer [ 123I]-N-(2-diethylaminoethyl)benzamide ([123I]BZA) or [125I]-N-(4-dipropylaminobutyl)-4-iodobenzamide ([ 125I]BZ18). Influence on the cytotoxicity of the benzamide alkyl side chain length and the composition of the amino acid sequence was assessed. Among the conjugates evaluated, compound 16 and 22 presented the highest cytotoxicity (IC50, 0.71 and 0.64 μM respectively), which persisted in the presence of an MTL derived from N-(dialkylaminoalkylenyl)benzamide residue.
- Vivier, Magali,Rapp, Maryse,Galmier, Marie-Josephe,Jarrousse, Anne-Sophie,Miot-Noirault, Elisabeth,Leal, Fernand,Weber, Valérie,Métin, Jacques,Sauzire, Jacques,Chezal, Jean-Michel,Madelmont, Jean-Claude
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supporting information; experimental part
p. 5705 - 5710
(2011/12/21)
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- Syntheses of R and S isomers of AF-DX 384, a selective antagonist of muscarinic M2 receptors
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Enantiomers of 5,11-dihydro-11-[2-[2-[(N,N-dipropylaminomethyl)piperidin-1-yl]ethylamino]-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (AF-DX 384) 1, have been synthesized from (S)-(+) and (R)-(-)-2-[N,N-dipropylaminomethyl]piperidine 4. The enantiomeric excess of 1 has been determined by capillary electrophoresis by using the α-highly sulphated cyclodextrin (α-HSCD) as chiral selector within the running electrolyte. (S)-(+)-(4) was prepared from (S)-(-)-pipecolic acid in a 4-step procedure (overall yield: 30%, ee: 99%) and (R)-(-)-AF-DX 384 from (R)-(+)-pipecolic acid. The (R)-(-) isomer exhibited in vitro a 23-fold higher affinity than its enantiomer (S)-(+) towards muscarinic receptors of subtype 2. Copyright (C) 2000.
- Martin, Juliette,Deagostino, Annamaria,Perrio, Cecile,Dauphin, Francois,Ducandas, Christophe,Morin, Christophe,Desbene, Paul-Louis,Lasne, Marie Claire
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p. 591 - 600
(2007/10/03)
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