Fundamental role of the fostriecin unsaturated lactone and implications for selective protein phosphatase inhibition

Key derivatives and analogues of fostriecin were prepared and examined that revealed a fundamental role for the unsaturated lactone and confirmed the essential nature of the phosphate monoester. Thus, an identical 200-fold reduction in protein phosphatase 2A (PP2A) inhibition is observed with either the saturated lactone (7) or with an analogue that lacks the entire lactone (15). This 200-fold increase in PP2A inhibition attributable to the unsaturated lactone potentially may be due to reversible C269 alkylation within the PP beta12-beta13 active site loop accounting for PP2A/4 potency and selectivity.     

Chiral attachment of styrene mediated by surface dimers on Ge100

We have investigated the chiral adsorption configurations of styrene on Ge(100) using scanning tunneling microscopy at 300 K. The chemisorbed styrene on a single Ge dimer reduces the symmetry of the molecule, which produces a chiral center, and leads to the (S) or (R) chiral on-top configuration. We have found that the dimeric adsorption of styrene induced by the Ge surface dimer structure forms the enantiomeric and diastereomeric paired end-bridge configurations. We determine the absolute chirality of adsorbed styrene on Ge(100) and demonstrate a novel method for the achiral molecule to produce dimeric enantiomers and diastereomers attached to the semiconductor surface.     

Antibacterial activities of polystyrene-block-poly(4-vinyl pyridine) and poly(styrene-random-4-vinyl pyridine)

Styrene was polymerized in the presence of benzoyl peroxide (BPO) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) to yield polystyrene-TEMPO (PS-TEMPO) macroinitiator. The PS-TEMPO macroinitiator with different molecular weight was reacted with 4-vinyl pyridine (4-VP) to synthesize polystyrene-block-poly(4-vinyl pyridine) (PS-b-PVP), which was then quaternized with n-octyl iodide. Antibacterial activity of the quaternized copolymers was assessed against a gram negative bacterium (Pseudomonas aeruginosa) and a gram positive one (Staphylococcus aureus) by using the shake flask test method, and the results were compared with those of poly(styrene-random-4-vinyl pyridine) (P(ST-r--VP)). The quaternized copolymers inhibited greatly the growth of the bacteria, and PS-b-PVP was more active than P(ST-r-VP), which was ascribed to the fact that the content of quaternized 4-VP units on the surface of the particles of the former copolymer was higher than that corresponding to the latter one.     

A unified and quantitative receptor model for the microtubule binding of paclitaxel and epothilone

[formula: see text] Paclitaxel and epothilone represent the two major classes of antimicrotubule agents that promote tubulin polymerization and, presumably, mitotic arrest during cell division. A common minireceptor binding site model at beta-tubulin has been constructed for these structurally divergent compounds. Utilizing 20 amino acids identified in photoaffinity labeling experiments, the 3-D model correlates measured and predicted Ki's with r = 0.99 and rms(delta Gcalc-delta Gexp) = 0.2 kcal/mol. In addition, the model predicts the affinity of compounds not used in the training set and explains much of the SAR for the paclitaxel and epothilone families.     

Construction of a 2,6-difunctionalized 2-methyl-2H-1-benzopyran library by using a solid-phase synthesis protocol

[reaction: see text] A library containing 1200 analogues of 2,6-difunctionalized 2-methyl-2H-1-benzopyran was constructed by using a solid-phase synthesis protocol. Polymer-bound 6-amido-, 6-sulfonamido-, and 6-uredo-functionalized 2-hydroxymethyl-2-methylbenzopyrans 10 were prepared as part of a first-generation diversification step by employing reactions of respective acid halides, sulfonyl chlorides, and isocyanates with the amine precursor 7. Transformations of the resin-bound intermediates 10 by reactions with alkyl and acid halides were then used to produce a diverse series of 2,6-difunctionalized 2-methyl-2H-1-benzopyran analogues 12 and 14.