Intramolecular Photoreactions of (5<i>S</i>)‑5-Oxymethyl-2(5<i>H</i>)‑furanones as a Tool for the Stereoselective Generation of Diverse Polycyclic Scaffolds

The photoactivated evolution of a series of enantiomerically pure 5-oxymethyl-2­(5<i>H</i>)-furanones has been investigated. The observed intramolecular photoreactions have proven to be a straightforward entry to diverse and stereochemically rich fragment-molecules, most of which contain the privileged tetrahydropyran (THP) scaffold. The formation of the THP involves a 1,5-hydrogen atom transfer process, leading to a diradical intermediate that recombines to form a new σ C–C bond. These reactions take place under both sensitized and nonsensitized conditions, and they are highly stereoselective. When the substrate contains an allyl residue, the intramolecular [2 + 2] cycloaddition leading to cyclobutanes competes advantageously. When the substrate contains a THP residue, the cyclization involves the concomitant formation of [6,6]-spiroketals with nonanomeric relationships

Nanoscale Capillary Interactions in Dynamic Atomic Force Microscopy

Standard models accounting for capillary interactions typically involve expressions that display a significant decay in force with separation. These forces are commonly investigated in the nanoscale with the atomic force microscope. Here we show that experimental observations are not predicted by these common expressions in dynamic interactions. Since in dynamic atomic force microscopy methods the cantilever is vibrated over the surface, the nanoscopic tip is submitted to nonlinear interactions with the sample in a periodic fashion. That is, the force dependencies involved in dynamic interactions in the nanoscale can be probed. We describe two extreme experimental scenarios in these dynamic interactions and interpret them as single and multiple asperity cases. In both extremes there is a predominantly attractive component of the net force that is relatively independent of distance and that ranges several nanometers above the surface. The distance dependence approximates that of a square well. Experimental data have been acquired for cantilevers of different stiffness and fundamental resonant frequency indicating that the distance dependencies provided here are valid for a relatively large range of frequencies. The reproducibility of our experiments and the accurate prediction of the experimental data that we present imply that future investigations should take the phenomena that we report into account to describe and interpret dynamic capillary interactions

Stereodivergent Synthesis of (+)- and (−)-Isolineatin

A stereodivergent approach to (+)- and (−)-isolineatin using (<i>S</i>)-4-methyl-5-pivaloyloxymethyl-2­(5<i>H</i>)-furanone as the single source of asymmetry by exploiting the inherent chirality at the C-5 stereocenter is described

Flexible Approach to <i>Stemona</i> Alkaloids: Total Syntheses of (−)-Stemospironine and Three New Diastereoisomeric Analogs

Total syntheses of (−)-stemospironine and three new diastereoisomeric analogs have been completed through a flexible strategy devised for <i>Stemona</i> alkaloids. The azabicycle <b>7</b> is the pivotal intermediate, from which the sequence splits according to each particular target. The most remarkable differential feature for stemospironine is the installation of the spiranic γ-lactone through an intramolecular Horner–Wadsworth–Emmons olefination. The configuration of the stereogenic center at C-11 was controlled by fine-tuning of the synthetic sequence

Flexible Approach to <i>Stemona</i> Alkaloids: Total Syntheses of (−)-Stemospironine and Three New Diastereoisomeric Analogs

Total syntheses of (−)-stemospironine and three new diastereoisomeric analogs have been completed through a flexible strategy devised for <i>Stemona</i> alkaloids. The azabicycle <b>7</b> is the pivotal intermediate, from which the sequence splits according to each particular target. The most remarkable differential feature for stemospironine is the installation of the spiranic γ-lactone through an intramolecular Horner–Wadsworth–Emmons olefination. The configuration of the stereogenic center at C-11 was controlled by fine-tuning of the synthetic sequence

Establishing Nanoscale Heterogeneity with Nanoscale Force Measurements

Establishing the presence or absence of nanoscale compositional heterogeneity with nanoscale resolution is becoming instrumental for the development of many fields of science. Force versus distance measurements and parameters directly or indirectly derived from these profiles can be potentially employed for this purpose with sophisticated instruments such as the atomic force microscope (AFM). On the other hand, standards are necessary to reproducibly and conclusively support hypothesis from experimental data and these standards are still emerging. Here, we define a set of standards for providing data originating from atomic force measurements to be employed to compare between sample properties, parameters, or, more generally, compositional heterogeneity. We show that reporting the mean and standard deviation only might lead to inconsistent conclusions. The fundamental principle behind our investigation deals with the very definition of reproducibility and repeatability in terms of accuracy and precision, and we establish general criteria to ensure that these hold without the need of restricting assumptions

Establishing Nanoscale Heterogeneity with Nanoscale Force Measurements

Establishing the presence or absence of nanoscale compositional heterogeneity with nanoscale resolution is becoming instrumental for the development of many fields of science. Force versus distance measurements and parameters directly or indirectly derived from these profiles can be potentially employed for this purpose with sophisticated instruments such as the atomic force microscope (AFM). On the other hand, standards are necessary to reproducibly and conclusively support hypothesis from experimental data and these standards are still emerging. Here, we define a set of standards for providing data originating from atomic force measurements to be employed to compare between sample properties, parameters, or, more generally, compositional heterogeneity. We show that reporting the mean and standard deviation only might lead to inconsistent conclusions. The fundamental principle behind our investigation deals with the very definition of reproducibility and repeatability in terms of accuracy and precision, and we establish general criteria to ensure that these hold without the need of restricting assumptions

Monoterpene Glycoside ESK246 from <i>Pittosporum</i> Targets LAT3 Amino Acid Transport and Prostate Cancer Cell Growth

The l-type amino acid transporter (LAT) family consists of four members (LAT1–4) that mediate uptake of neutral amino acids including leucine. Leucine is not only important as a building block for proteins, but plays a critical role in mTORC1 signaling leading to protein translation. As such, LAT family members are commonly upregulated in cancer in order to fuel increased protein translation and cell growth. To identify potential LAT-specific inhibitors, we established a function-based high-throughput screen using a prefractionated natural product library. We identified and purified two novel monoterpene glycosides, ESK242 and ESK246, sourced from a Queensland collection of the plant <i>Pittosporum venulosum</i>. Using <i>Xenopus laevis</i> oocytes expressing individual LAT family members, we demonstrated that ESK246 preferentially inhibits leucine transport via LAT3, while ESK242 inhibits both LAT1 and LAT3. We further show in LNCaP prostate cancer cells that ESK246 is a potent (IC₅₀ = 8.12 μM) inhibitor of leucine uptake, leading to reduced mTORC1 signaling, cell cycle protein expression and cell proliferation. Our study suggests that ESK246 is a LAT3 inhibitor that can be used to study LAT3 function and upon which new antiprostate cancer therapies may be based