A new approach to the synthesis of 1,4-benzodiazepines and 3-amino-1,4-benzodiazepines, which employs the Pd-catalyzed cross-coupling reaction of an imidoyl chloride with an organometallic reagent as the key step, is described. A five-step synthesis of a key intermediate is described and it is shown that in only four further steps (three couplings and a TFA-mediated BOC-deprotection) a wide variety of N1-, C3-amino-, C5-carbon-, or nitrogen-substituted 1,4-benzodiazepines can be synthesized.
Step by step the first total synthesis was approached: of the zaragozic acids/ squalestatins showing potential therapeutic value for lowering the serum cholesterol concentration, zaragozic acid A/squalestatin SI (1), the most abundant member of a new class of naturally occurring products, has now been synthesized via the key intermediates 2 and 3. Initially the projected final sequence (2 → 1) was achieved, and the side chains attached to C1 and C6 were prepared through efficient asymmetric syntheses. The first synthesis of the highly oxygenated “core”, which is characteristic of this class of natural products, was achieved from a simple prochiral diene via intermediate 3. Finally the synthetic route 3 → 2 was developed to successfully complete the total synthesis. Bn benzyl, PMB para-methoxybenzyl, TMS trimethylsilyl.
The Intramolecular, thermal dipolar cycloadditions of the (Z)-N-alk-4-enyl nitrones 18–21, 34 and 35 bearing a single, allylic substituent were investigated. Certain alkoxy substituted nitrones 18–21 showed a remarkable preference for the formation of axially substituted isoxazolidines 22a-24a, whereas the, propyl and trifluoromethyl substituted nitrones 35 and 34 gave the equatorially substituted cycloadducts 37 and 36a respectively, consistent with the involvement of 'chair-like' transition states 38.
The generation of gamma-secretase inhibitors which block the release of beta-amyloid peptide (Abeta) has long been an attractive therapeutic avenue for treatment or prevention of Alzheimer's disease (AD). Such inhibitors would reduce levels of Abeta available for aggregation into toxic assemblies that lead to the plaque pathology found in affected brain tissue. Cumulative evidence suggests that the S3 cleavage of Notch is also dependent on presenilins (PS) and is carried out by the multimeric PS-containing gamma-secretase complex. It is therefore possible that Notch function could be affected by gamma-secretase inhibitors. To assess the relationship between the cleavage of these substrates in the same system, Western blot cleavage assays have been established using a human cell line stably expressing both the beta-amyloid precursor protein (beta-APP) and the truncated Notch1 receptor fragment NotchDeltaE. Thus, a direct correlation may be made, following inhibitor treatment, of the decrease in the levels of the cleavage products, Abeta peptide and the Notch intracellular domain (NICD), as well as the increase in stabilized levels of both substrates. This analysis has been performed with a range of selected gamma-secretase inhibitors from six distinct structural classes. Changes in all four species usually occur in concert and with remarkably good agreement. A significant cleavage window is not clearly apparent in any case. Thus, these Notch and beta-APP cleavages cannot be dissected apart easily since they show the same pharmacological profile of inhibition. Whether this translates into proportionally reduced Notch signaling in vivo, however, remains to be seen.
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