Phenyl bioisosteres in medicinal chemistry: discovery of novel γ-secretase modulators as a potential treatment for Alzheimer's disease.

Phenyl rings are one of the most prevalent structural moieties in active pharmaceutical ingredients, even if they often contribute to poor physico-chemical properties. Herein, we propose the use of a bridged piperidine (BP) moiety as a phenyl bioisostere, which could also be seen as a superior phenyl alternative as it led to strongly improved drug like properties, in terms of solubility and lipophilicity. Additionally, this BP moiety compares favorably to the recently reported saturated phenyl bioisosteres. We applied this concept to our γ-secretase modulator (GSM) project for the potential treatment of Alzheimer's disease delivering clinical candidates.

[The transformation of gamma-tocopherol to alpha-tocopherol in the animal organism; a generational study in rats]. / Uber die Transformation von gamma-Tocopherol zu alpha-Tocopherol im tierischen Organismus; ein Generationsversuch an Ratten.

The biosynthesis of alpha-tocopherol, the most effective vitamer among the vitamin E-group, is found only in higher plants and microorganisms. Due to the lack of the shikimate pathway, animals are not able to synthesize alpha-tocopherol. Also not found is a whole enteral synthesis; only the conversion of dimethyletocol to trimethyletocol seems to be possible. Using four generations of rats, we sought to determine: Is a transformation of gamma-tocopherol to alpha-tocopherol in the animal body possible? Are there any differences in the transformation rates in organs, tissues, or in the entire body along the generations? Does gut flora play any role in the conversion of gamma-tocopherol? Is it possible to increase the efficiency of the transformation by supplying additional CH3-groups? Wistar rats were fed a semisynthetic basal diet, supplemented with 78.8 mg DL-gamma-tocopherol/kg in the first three generations (F1-F3). In the fourth generation (F4), some of the animals were fed a vitamin E-free diet and gamma-tocopherol (approx. 1.5 mg on alternate days) was injected s.c. Two other groups of animals received the basal diet containing additional methionine (0.25%) or choline (0.45%), as well as gamma-tocopherol (as in F1-F3). alpha- and gamma-tocopherol were analyzed by HPTLC in the whole body and in serum, liver, heart, lung, gut, gonads, and feces. The ratio of alpha-/gamma-tocopherol (micrograms/micrograms) as transformation rate and vitamin E-biopotency (microgram alpha-tocopherol equivalents/g) were calculated. Growth and fertility were normal until the fourth generation; no abnormal developments could be recognized. alpha-tocopherol was found in the whole-body as well as in all tissues and organs. In the whole-body, vitamin E-biopotency decreased 25-70% in F2 and F3. On the other hand, the increase of the transformation rate of gamma- to alpha-tocopherol amounted to 23% (F2) and 168% (F3). Highest conversion rates were found in F2 and F3 for feces, followed by gonads and lungs; the lowest rates were found for serum and liver. Due to the s.c. injection of gamma-tocopherol, feces showed a four-times lower transformation rate in F4 than in F3. There was an increase in heart, gut, lung and serum for both transformation rate and vitamin E-biopotency. These parameters could be improved also by the additional supplements of methionine and choline. Both methyl-group-donators revealed nearly the same positive effect. The results show that the animal organism can adapt to gamma-tocopherol supply over generations.(ABSTRACT TRUNCATED AT 250 WORDS)

Metal ion binding by biological surfaces: voltammetric assessment in the presence of bacteria.

Voltammetric techniques (differential pulse polarography (DPP) and differential pulse anodic stripping voltammetry (DPASV)) were evaluated for their capability to distinguish, without prior separation of the solid phase (e.g. filtration, centrifugation), between dissolved and particulate concentrations of Zn(II), Pb(II) and Cu(II), and to measure the extent of binding of these metals to the surface of a bacterium (Klebsiella pneumonia, formaldehyde treated). From titration curves of bacterial cell suspensions with metals the specific adsorption of metals was determined and quantified in terms of average surface complex formation constants and differential equilibrium functions. The following stability sequence for surface complexes was found: Cu2+ greater than Pb2+ greater than Zn2+ much greater than Ca2+. Simultaneous analytical determination permitted the measurement of both the binding of Cu(II) to the cell surface, and the binding to the solute exudate ligands. The affinity of the metal ions for the functional groups of the cell surface is strongly pH-dependent, and, at a given pH, decreases with increasing metal loading of the bacterial surfaces. This indicates that metal ions bind first to the highest affinity surface ligands and subsequently to those of lesser activity. Copper(II) appears to form stronger surface complexes with the high affinity ligands of the bacterial surface than with the functional groups of hydrous oxides.