Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain.

Polycomb repressive complex 1 (PRC1) is an essential chromatin-modifying complex that monoubiquitinates histone H2A and is involved in maintaining the repressed chromatin state. Emerging evidence suggests PRC1 activity in various cancers, rationalizing the need for small-molecule inhibitors with well-defined mechanisms of action. Here, we describe the development of compounds that directly bind to RING1B-BMI1, the heterodimeric complex constituting the E3 ligase activity of PRC1. These compounds block the association of RING1B-BMI1 with chromatin and inhibit H2A ubiquitination. Structural studies demonstrate that these inhibitors bind to RING1B by inducing the formation of a hydrophobic pocket in the RING domain. Our PRC1 inhibitor, RB-3, decreases the global level of H2A ubiquitination and induces differentiation in leukemia cell lines and primary acute myeloid leukemia (AML) samples. In summary, we demonstrate that targeting the PRC1 RING domain with small molecules is feasible, and RB-3 represents a valuable chemical tool to study PRC1 biology.

A novel stereoselective [8+2] double cycloaddition route to hydronaphthalene ring systems.

Substituted hydronaphthalenes where each of the ten carbons of the two-ring system contains functionality were obtained through a tandem [8+2] cycloaddition and base-catalyzed rearrangement process using dienylfurans and electron-deficient alkynes. If the [8+2] process is conducted under solvent-free conditions the process could be conducted in a single reaction flask without isolation of the chromatographically sensitive [8+2] cycloadducts. A mechanism involving base catalysed alkene positional isomerization followed by disrotatory electrocyclic ring closure was proposed for the key reaction step that converts [8+2] cycloadducts to hydronaphthalenes. The products undergo selective ring opening-isomerization processes upon treatment with Lewis acids.

New synthesis of α'-hydroxydienones.

Herein, attempted oxidation of selected allenols with PCC affording α'-hydroxydienones rather than simple oxidation products is described. The formation of the products observed is rationalized via a series of sigmatropic shifts, followed by hydrolysis.

Total synthesis of (+)-antofine and (-)-cryptopleurine.

The tylophorine alkaloid anticancer compounds antofine and cryptopleurine have been synthesized in optically active form. Both syntheses employ optically pure α-amino acids as the starting materials, require only seven steps from known 2-ethynylpyrrolidine or 2-ethynylpiperidine derivatives, and are free of protecting groups. Key steps include an alkyne hydration and a chromium carbene complex based net [5+5]-cycloaddition step. Alkyne hydration was accompanied by racemization of the resulting ß-aminoketone under most of the conditions examined, and successful minimization of this side reaction was achieved through careful pH control and choice of metal additive. Final ring closure involves a Bischler-Napieralski reaction using a carbamate (antofine) or urea (cryptopleurine) precursor.

Toward the total synthesis of elisapterosin B: A Hg(OTf)(2)-promoted diastereoselective intramolecular Friedel-Crafts alkylation reaction.

As part of an approach to the synthesis of the antitubercular agent elisapterosin B, we prepared two different chiral, non-racemic olefinic substrates and examined their diastereoselective ring closure using mercury salts. The effort yielded potential precurors to elisapterosin B in good yield with good to excellent diastereocontrol.

Oxidation of 4-methoxyanilines to 1,4-benzoquinones using ceric ammonium nitrate (CAN).

Treatment of substituted 4-methoxyanilines with ceric ammonium nitrate in a 1:1 mixture of water and acetonitrile resulted in formation of 1,4-benzoquinones in acceptable yields.

Radiosynthesis of 6'-Deoxy-6'[18F]Fluorosucrose via Automated Synthesis and Its Utility to Study In Vivo Sucrose Transport in Maize (Zea mays) Leaves.

Sugars produced from photosynthesis in leaves are transported through the phloem tissues within veins and delivered to non-photosynthetic organs, such as roots, stems, flowers, and seeds, to support their growth and/or storage of carbohydrates. However, because the phloem is located internally within the veins, it is difficult to access and to study the dynamics of sugar transport. Radioactive tracers have been extensively used to study vascular transport in plants and have provided great insights into transport dynamics. To better study sucrose partitioning in vivo, a novel radioactive analog of sucrose was synthesized through a completely chemical synthesis route by substituting fluorine-18 (half-life 110 min) at the 6' position to generate 6'-deoxy-6'[(18)F]fluorosucrose ((18)FS). This radiotracer was then used to compare sucrose transport between wild-type maize plants and mutant plants lacking the Sucrose transporter1 (Sut1) gene, which has been shown to function in sucrose phloem loading. Our results demonstrate that (18)FS is transported in vivo, with the wild-type plants showing a greater rate of transport down the leaf blade than the sut1 mutant plants. A similar transport pattern was also observed for universally labeled [U-(14)C]sucrose ([U-(14)C]suc). Our findings support the proposed sucrose phloem loading function of the Sut1 gene in maize, and additionally demonstrate that the (18)FS analog is a valuable, new tool that offers imaging advantages over [U-(14)C]suc for studying phloem transport in plants.

Chemical synthesis of 1'-deoxy-1'-fluorosucrose.

The first chemical synthesis of 1'-deoxy-1'-fluorosucrose has been accomplished in eight steps from sucrose by an unlikely, but ultimately successful, SN2 displacement reaction.

Benzotriazole-bridged sensitizers containing a furan moiety for dye-sensitized solar cells with high open-circuit voltage performance.

Two new benzotriazole-bridged sensitizers are designed and synthesized (BTA-I and BTA-II) containing a furan moiety for dye-sensitized solar cells (DSSCs). Two corresponding dyes (BTA-III and BTA-IV) with a thiophene spacer were also synthesized for comparison. All of these dyes performed as sensitizers for DSSCs, and the photovoltaic performance data of these benzotriazole-bridged dyes showed a high open-circuit voltage (V(oc): 804-834 mV). Among the four dyes, DSSCs based on BTA-II, with a furan moiety and branched alkyl chain, showed the highest V(oc) (834 mV), a photocurrent density (J(sc)) of 12.64 mA cm(-2), and a fill factor (FF) of 0.64, corresponding to an overall conversion efficiency (η) of 6.72%. Most importantly, long-term stability of the BTA-I-IV-based DSSCs with ionic-liquid electrolytes under 1000 h light-soaking was demonstrated, and BTA-II exhibited better photovoltaic performance of up to 5.06% power conversion efficiency.

Series of new D-A-π-A organic broadly absorbing sensitizers containing isoindigo unit for highly efficient dye-sensitized solar cells.

In this work, six new D-A-π-A sensitizers (ID1-ID6), with triarylamine as the electron donor; isoindigo as a auxiliary electron withdrawing unit; thiophene, furan, and benzene as the linker; and cyanoacrylic acid as the anchoring group, were synthesized through simple synthetic procedures and with low cost. Their absorption spectra were broad with long wavelength absorption maximum approximately at 589 nm and the absorption onset at 720 nm on the TiO(2) film. Electrochemical experiments indicate that the HOMO and LUMO energy levels can be conveniently tuned by alternating the donor moiety and the linker. All of these dyes performed as sensitizers for the DSSCs test under AM 1.5 similar experimental conditions, and a maximum overall conversion efficiency of 5.98% (J(sc) = 14.77 mA cm(-2), V(oc) = 644 mV, ff = 0.63) is obtained for ID6-based DSSCs when TiO(2) films were first immersed for 6 h in 20 mM CDCA ethanol solution followed by 12 h of dipping in the dye CH(2)Cl(2) solution. Electrochemical impedance measurement data implies that the electron lifetime can be increased by coadsorption of CDCA, which leads to a lower rate of charge recombination and thus improved V(oc).

Expedient synthesis of sulfinamides from sulfonyl chlorides.

Sulfinamides were synthesized from sulfonyl chlorides using a procedure involving in situ reduction of sulfonyl chlorides. The reaction is broad in scope and easy to perform.