Cytotoxic nucleosides have proven to be ineffective for the treatment of hepatocellular carcinoma (HCC) due, in part, to their inadequate conversion to their active nucleoside triphosphates (NTP) in the liver tumor and high conversion in other tissues. These characteristics lead to poor efficacy, high toxicity, and a drug class associated with an unacceptable therapeutic index. Cyclic 1-aryl-1,3-propanyl phosphate prodrugs selectively release the monophosphate of a nucleoside (NMP) into CYP3A4-expressing cells, such as hepatocytes, while leaving the prodrug intact in plasma and extrahepatic tissues. This prodrug strategy was applied to the monophosphate of the well-known cytotoxic nucleoside cytosine-1-beta-D-arabinofuranoside (cytarabine, araC). Compound 19S (MB07133), in mice, achieves good liver targeting compared to araC, generating >19-fold higher cytarabine triphosphate (araCTP) levels in the liver than levels of araC in the plasma and >12-fold higher araCTP levels in the liver than in the bone marrow, representing a >120-fold and >28-fold improvement, respectively, over araC administration.
The described approach provides calix [4]arene scaffolds that can be coupled to amino acids using standard solid phase peptide synthesis, providing a route for the rapid preparation of combinatorial libraries of this class of molecular hosts. In addition, we report the first example of a tetrapeptido-calix[4]arene in which the amino acids are attached to the upper rim through the carboxy termini. Specifically, a tetra-nitrocalix[4]arene was prepared, attached to solid support, and the nitro groups were reduced to the corresponding amines by treatment with SnCl 2 ·H 2 O. This was followed by three successive couplings with alanine to provide the tetra(trialanine)calix[4]arene. The final product was cleaved from the solid support and shown by LCMS to elute as one peak with the expected mass.
diastereoselective syntheses, enantioselective syntheses diastereoselective syntheses, enantioselective syntheses (incl. cis/trans-isomerism) O 0031
-033Reactive Ketenes Through a Carbonate/Amine Shuttle Deprotonation Strategy: Catalytic, Enantioselective α-Bromination of Acid Chlorides.-Acid chlorides undergo a tandem catalytic, enantioselective α-bromination-esterification in a two-step reaction. In the first step, ketenes are generated using chiral nucleophilic amines as catalysts. The further addition of the brominating agent occurs in moderate yields and high enantioselectivities. -(HAFEZ, AHMED M.; TAGGI, ANDREW E.; WACK, HARALD; ESTER-
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