Tandem Suzuki Coupling/Intramolecular Oxetane Ring Opening to Form Polycyclic Ring Systems.

A tandem one-pot reaction featuring a cross-coupling followed by an intramolecular oxetane ring opening by mild nucleophiles is reported. The overall transformation comprises a carbon-carbon bond formation along with a carbon-heteroatom bond construction providing diverse multicyclic ring systems with a pendant hydroxymethyl handle for further elaboration. This approach constitutes a convergent method for rapid access to various scaffolds. Furthermore, a comparison of computed low-energy conformers is presented to rationalize instances in which cyclization was not observed.

Binary Targeting of siRNA to Hematologic Cancer Cells In Vivo using Layer-by-Layer Nanoparticles.

Using siRNA therapeutics to treat hematologic malignancies has been unsuccessful because blood cancer cells exhibit remarkable resistance to standard transfection methods. Herein we report the successful delivery of siRNA therapeutics with a dual-targeted, layer-by-layer nanoparticle (LbL-NP). The LbL-NP protects siRNA from nucleases in the bloodstream by embedding it within polyelectrolyte layers that coat a polymeric core. The outermost layer consists of hyaluronic acid (a CD44-ligand) covalently conjugated to CD20 antibodies. The CD20/CD44 dual-targeting outer layer provides precise binding to blood cancer cells, followed by receptor-mediated endocytosis of the LbL-NP. We use this siRNA delivery platform to silence B-cell lymphoma 2 (BCL-2), a pro-survival protein, in vitro and in vivo. The dual-targeting approach significantly enhanced internalization of BCL-2 siRNA in lymphoma and leukemia cells, which led to significant downregulation of BCL-2 expression. Systemic administration of the dual-targeted, siRNA-loaded nanoparticle induced apoptosis and hampered proliferation of blood cancer cells both in cell culture and in orthotopic non-Hodgkin's lymphoma animal models. These results provide the basis for approaches to targeting blood-borne cancers and other diseases, and suggest that LbL nanoassemblies are a promising approach for delivering therapeutic siRNA to hematopoetic cell types that are known to evade transfection by other means.

Mild Intramolecular Ring Opening of Oxetanes.

Oxetanes have been increasingly used as stable motifs in medicinal chemistry as well as versatile synthetic intermediates. Herein, an intramolecular ring opening of oxetane carboxamides with mild nucleophiles, such as nitrogen heterocycles, is presented. The reaction proceeds under metal-free basic conditions which is highly unusual in ring opening reactions of oxetanes. Amide formation and oxetane ring opening/cyclization in a one-pot approach affords high levels of molecular complexity in a single step from simple, readily available substrates.

Nonpeptide urotensin-II receptor antagonists: a new ligand class based on piperazino-phthalimide and piperazino-isoindolinone subunits.

We have discovered two related chemical series of nonpeptide urotensin-II (U-II) receptor antagonists based on piperazino-phthalimide (5 and 6) and piperazino-isoindolinone (7) scaffolds. These structure types are distinctive from those of U-II receptor antagonist series reported in the literature. Antagonist 7a exhibited single-digit nanomolar potency in rat and human cell-based functional assays, as well as strong binding to the human U-II receptor. In advanced pharmacological testing, 7a blocked the effects of U-II in vitro in a rat aortic ring assay and in vivo in a rat ear-flush model. A discussion of U-II receptor antagonist pharmacophores is presented, and a specifically defined model is suggested from tricycle 13, which has a high degree of conformational constraint.

Phenylpiperidine-benzoxazinones as urotensin-II receptor antagonists: synthesis, SAR, and in vivo assessment.

Various 4-phenylpiperidine-benzoxazin-3-ones were synthesized and biologically evaluated as urotensin-II (U-II) receptor antagonists. Compound 12i was identified from in vitro evaluation as a low nanomolar antagonist against both rat and human U-II receptors. This compound showed in vivo efficacy in reversing the ear-flush response induced by U-II in rats.

Selection of a 2-azabicyclo[2.2.2]octane-based alpha4beta1 integrin antagonist as an inhaled anti-asthmatic agent.

The alpha4beta1 integrin, expressed on eosinophils and neutrophils, induces inflammation in the lung by facilitating cellular infiltration and activation. From a number of potent alpha4beta1 antagonists that we evaluated for safety and efficacy, 1 was selected as a lead candidate for anti-asthma therapy by the inhalation route. We devised an optimized stereoselective synthesis to facilitate the preparation of a sufficiently large quantity of 1 for assessment in vivo. Administration of 1 to allergen-sensitive sheep by inhalation blocked the late-phase response of asthma and abolished airway hyper-responsiveness at 24h following the antigen challenge. Additionally, the recruitment of inflammatory cells into the lungs was inhibited. Administration of 1 to ovalbumin-sensitized guinea pigs intraperitoneally blocked airway resistance and inhibited the recruitment of inflammatory cells.