5 research outputs found
A Simple, Scalable Synthetic Route to (+)- and (−)-Pseudoephenamine
A three-step synthesis of pseudoephenamine suitable for preparing multigram amounts of both enantiomers of the auxiliary from the inexpensive starting material benzil is described. The sequence involves synthesis of the crystalline monomethylimine derivative of benzil, reduction of that substance with lithium aluminum hydride, and resolution of pseudoephenamine with mandelic acid
Diastereoselective Additions of Allylmetal Reagents to Free and Protected <i>syn</i>-<b>α,β</b>-Dihydroxyketones Enable Efficient Synthetic Routes to Methyl Trioxacarcinoside A
Two routes to the 2,6-dideoxysugar methyl trioxacarcinoside A are described. Each was enabled by an apparent α-chelation-controlled addition of an allylmetal reagent to a ketone substrate containing a free α-hydroxyl group and a β-hydroxyl substituent, either free or protected as the corresponding di-<i>tert</i>-butylmethyl silyl ether. Both routes provide practical access to gram quantities of trioxacarcinose A in a form suitable for glycosidic coupling reactions
Synthesis of Quaternary α‑Methyl α‑Amino Acids by Asymmetric Alkylation of Pseudoephenamine Alaninamide Pivaldimine
The utility of pseudoephenamine as a chiral auxiliary for the alkylative construction of quaternary α-methyl α-amino acids is demonstrated. The method is notable for the high diastereoselectivities of the alkylation reactions, for its versatility with respect to electrophilic substrate partners, and for its mild hydrolysis conditions, which provide α-amino acids without salt contaminants. Alternatively, α-amino esters can be obtained by direct alcoholysis
[3+2] Dipolar Cycloaddition of a Stabilized Azomethine Ylide and an Electron-Deficient Dipolarophile: Revision of Regioselectivity
The regioselectivity of a [3+2] dipolar
cycloaddition reaction
of a stabilized azomethine ylide with an electron-deficient dipolarophile
was found to be counter to a report published in this journal
Interactions of the Natural Product (+)-Avrainvillamide with Nucleophosmin and Exportin‑1 Mediate the Cellular Localization of Nucleophosmin and its AML-Associated Mutants
Nucleophosmin
(NPM1) is a multifunctional phosphoprotein localized
predominantly within the nucleoli of eukaryotic cells. Mutations within
its C-terminal domain are frequently observed in patients with acute
myeloid leukemia (AML), are thought to play a key role in the initiation
of the disease, and result in aberrant, cytoplasmic localization of
the mutant protein. We have previously shown that the electrophilic
antiproliferative natural product (+)-avrainvillamide (<b>1</b>) binds to proteins, including nucleophosmin, by <i>S</i>-alkylation of cysteine residues. Here, we report that avrainvillamide
restores nucleolar localization of certain AML-associated mutant forms
of NPM1 and provide evidence that this relocalization is mediated
by interactions of avrainvillamide with mutant NPM1 and exportin-1
(Crm1). Immunofluorescence and mass spectrometric experiments employing
a series of different NPM1 constructs suggest that a specific interaction
between avrainvillamide and Cys275 of certain NPM1 mutants mediates
the relocalization of these proteins to the nucleolus. Avrainvillamide
treatment is also shown to inhibit nuclear export of Crm1 cargo proteins,
including AML-associated NPM1 mutants. We also observe that avrainvillamide
treatment displaces Thr199-phosphorylated NPM1 from duplicated centrosomes,
leads to an accumulation of supernumerary centrosomes, and inhibits
dephosphorylation of Thr199-phosphorylated NPM1 by protein phosphatase
1. Avrainvillamide is the first small molecule reported to relocalize
specific cytoplasmic AML-associated NPM1 mutants to the nucleolus,
providing an important demonstration of principle that small molecule
induction of a wild-type NPM1 localization phenotype is feasible in
certain human cancer cells