We developed scintillation proximity assays (SPA) to discover compounds which inhibit phosphopeptide binding toSrchomology 2 (SH2) domain proteinsGrb2andSyk.An assay artifact is reported here as a caveat to others. The SPA used an antibody to couple glutathione-S-transferase SH2 domain fusion proteins to scintillant beads coated with protein A. A pyrazoloquinolone and indolocarbazole inhibited [3H]phosphopeptide binding in both assays. Their potency in the SPA increased with prolonged (2 to 24 h) assay exposure to ambient light. They were inactive in absence of light and in an alternate binding assay. Both compounds absorbed visible light and generated singlet oxygen based on 2-methylfuran-trapping experiments. Their inhibitory activity was suppressed by the singlet oxygen scavengers sodium azide and dithiothreitol. The results suggest that compounds, not previously considered photosensitizers, generated enough singlet oxygen to damage oxidant-sensitive SPA components. Therefore, this SPA should be protected from light to minimize occurrence of false positives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Previous SAR studies of C-3 side chain modified analogs of (−)-SCH 48461, 1,3,4 as well as information concerning the metabolic stability this series, enabled us to design a cholesterol absorption inhibitor (i.e., (−) 2a, SCH 57939) with tenfold higher potency and greatly enhanced metabolic stability. The synthesis and pharmacological profile, including the role of relative stereochemistry at both the C3 and 1′ positions in determining the SAR of these compounds, will be discussed.

Asymmetric induction by several chiral alcohols in the reaction of their bromoacetates with imines in the presence of activated Zn (Reformatsky reaction) was studied. <(Trans)under bar>-2-phenylcyclohexanol and phenyl menthol gave beta-lactam 9, obtained by cyclizing the diastereoisomeric beta-aminoesters 8, in > 99%ee. The resulting chiral 3-unsubstituted azetidin-2-one 9 was converted to 3-substituted products 11, 12, and 13 which exhibit cholesterol absorption inhibitory activity. (C) 1996 Elsevier Science Ltd

Our search for potent cholesterol absorption inhibitors led to the discovery of the p-lactam SCH 48461. Structure activity relationship studies prompted us to this study of gamma-lactams, ring homologs of beta-lactam SCH 48461, to determine their potential as cholesterol absorption inhibitors. The results indicate that the gamma-lactams have moderate cholesterol absorption inhibitory properties.

A variety of 2,6 substituted trihydroxy piperidines 4 was synthesized with stereocontrol from the corresponding 2,6 bis-(Benzotriazolyl) trihydroxy piperidine 9, which in turn was prepared from 1,2-O-isopropylidene-D-glucofuranose 5 employing a simple, two step chemical manipulation. These products are potential glycosidase inhibitors and can be transformed to other useful chiral products.

Indolocarbazole 4 and arcyriaflavin A 19 reacted under basic conditions with 1-benzyl-2,6-bis (benzotriazolyl)-piperidine to give 5 and 20. As an extension of this methodology other related his benzotriazole derivatives were synthesized and coupled with 19 to obtain a variety of aza derivatives 3. N-debenzylation of these compounds gave novel PKC inhibitors.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Attempted transformation of the readily accessible cyclofuransylated indolocarbazole (4) to a cyclopyranosylated compound related to 1 was explored. An unexpected rearranged product (10) was obtained from (9). Compound (10) was converted to (14), a potent PKC inhibitor. The mechanism of the rearrangement was unraveled with a deuterium labeling experiment.

The condensation of indolo[2,3-a]-carbazole (12) with 2,5-dimethoxytetrahydrofuran derivatives gave cyclofuranosylated compounds (e.g. 13), which were converted via dibromocompounds to the dinitriles (e.g. 25). Hydrolysis, hydrolysis-reduction and thiolysis afforded imides, lactams (e.g. 27) and their thio analogs. These compounds were potent inhibitors of the protein kinase C family.

The unsubstituted Eudistomin skeleton containing the oxathiazepine D ring was prepared along with a series of unsubstituted and amino-substituted carba-analogs, using an intramolecular Pictet-Spengler condensation.

AbstractAus Datisca glomerata wurden die Datiscoside (lal‐(lg) bzw. (IIa)‐(IIc) isoliert.

AbstractDie Synthese der Titelverbindung (VII) wird beschrieben.