Rainer Albert

Discovery of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione (AEB071), a potent and selective inhibitor of protein kinase C isotypes

A series of novel maleimide-based inhibitors of protein kinase C (PKC) were designed, synthesized, and evaluated. AEB071 (1) was found to be a potent, selective inhibitor of classical and novel PKC isotypes. 1 is a highly efficient immunomodulator, acting via inhibition of early T cell activation. The binding mode of maleimides to PKCs, proposed by molecular modeling, was confirmed by X-ray analysis of 1 bound in the active site of PKCalpha.

Structure-activity relationship and pharmacokinetic studies of sotrastaurin (AEB071), a promising novel medicine for prevention of graft rejection and treatment of psoriasis.

Protein kinase C (PKC) isotypes have emerged as key targets for the blockade of early T-cell activation. Herein, we report on the structure-activity relationship and the detailed physicochemical and in vivo pharmacokinetic properties of sotrastaurin (AEB071, 1), a novel maleimide-based PKC inhibitor currently in phase II clinical trials. Most notably, the preferred uptake of sotrastaurin into lymphoid tissues is an important feature, which is likely to contribute to its in vivo efficacy.

Acetyl Migration in Partially Acetylated D-Glucopyrano-Sides and Acylamidohexopyranosides

Abstract O-4-O-6 Acetyl migrations in partially O-acetylated 2- and 3-acylamidodeoxyhexopyranosides, including derivatives of kanamycin A, were found to be particularly suited to allow the regiospecific accessibility of their respective C-4 OH groups. Partially O-acetylated d-glucopyranosides, compared to the substrates above, showed slightly different aptitudes of migration. However, all O-4-O-6 migrations investigated proved to be irreversible under the conditions applied.

Synthesis of fluorinated kanamycin A derivatives

Abstract Replacement of OH-5 and/or OH-6″ by fluoride in kanamycin A; no substitution of OH-4″ but inversion of configuration when using DAST.

5-Deoxy-5-Fluoro-D-Glucofuranose and -L-Idofuranose Synthesis and NMR Studies

Abstract Starting from 1,2-O-isopropylidene-α-D-gluco- and -β-L-ido-furanurono-6,3-lactone, 5-deoxy-5-fluoro-α/β-D-gluco- and -L-idofuranose, respectively, were prepared by the following sequence of reactions: trifluoromethanesulfonylation, nucleophilic substitution with inversion of configuration, lactone reduction and deprotection. On the basis of H-H-, H-C-, H-F-, and C-F-couplings, the stereochemistry of the products is discussed.

Reaction of 1,2-0-Alkylidenehexofuranurono-6,3-Lactones with Diethylaminosulfur Trifluoride (DAST)

Abstract Reaction of 1,2-0-alkylidenehexofuranurono-6,3-lactones with diethylaminosulfur trifluoride (DAST) led to 1,2-0-alkylidene-5-deoxy-5-fluorohexofuranurono-6,3-lactones (13–30%) together with 1,2-0-alkylidene-3,6-anhydro-6,6-difluorohexofuranoses (45–58%). Evidence was found for participation of the hydroxyl group at C-5 in the formation of the difluorides. Trifluoro compounds could not be prepared by reaction with DAST but were formed from the difluorides by triflate formation and displacement using tetra-n-butylammonium fluoride.

Chemical modifications of kanamycin A Synthesis of 4″-deoxy and 4″-epi-halogenodeoxy kanamycin A☆

Abstract Stereospecific direct placement with inversion of configuration of 4-OH by halogen in kanamycin A. Hydrolysis.

Chemical Modification of Kanamycin A. II. Nucleophilic Displacement Reactions of Kanamycin-A-4″-sulfonates

Abstract Reactions of 2′,3′,4′,2″,6″-penta-O-acetyl-tetra-N-tert-butyloxycarbonyl-kanamycin-A-4″-brosylate (4b) or-4″-triflate (4c) with acetate, thiolacetate, azide, and fluoride, respectively, result in the formation of the corresponding derivatives of 4″-epi-kanamycin A (5a-d). While 4b invariably forms an elimination byproduct (9), the only side—reaction of 4c consists in a neighboring group attack with formation of a 3″-epi-4″-cyclic urethane (7). Removal of the protecting groups yields 4″-epi-(6a), 4″-thio-4″-epi-(6b), 4″-deoxy-4″-fluoro-4″-epi-(6d), 4″-azido-4″-deoxy-4″-epi-(6c), and after hydrogenation of the latter, 4″-amino-4″-deoxy-4″-epi-kanamycin A (6f). Methyl 2,6-di-O-acetyl-3-amino-3-N-tert-butyloxycarbonyl-3-deoxy-4-O-triflyl-β-D-glucopyranoside (1b) served as a model to anticipate preparation, handling, and reactivity of 4c.