Unusual C-I···O Halogen Bonding in Triazole Derivatives: Gelation Solvents at Two Extremes of Polarity and Formation of Superorganogels.

To investigate the influence of halogen bond (XB) on the gelation of a one-component organogel system, a new family of 5-iodo-1H-1,2,3-triazole and 1H-1,2,3-triazole gelators was designed and synthesized. The iodo gelators (1I, 3I) gelled various solvents at low concentrations and formed many superorganogels, whereas the hydrogenous gelators (1H, 3H) showed much poorer gelling performance. An X-ray analysis of the single crystals of two reference compounds (16I, 16H) reveals that the unusual C-I···O XB interaction is responsible for this difference. The results of spectroscopic examinations (XRD, SEM, 1H NMR, and UV) are well consistent with those of single-crystal analyses. Under the guidance of the XB interaction and the weak π-π interaction, 1I and 3I self-assemble to hexagonal columnar aggregations in the gel state, whereas 1H and 3H, driven by CH-π interactions, feature the formation of gels with a lamellar structure. The mechanical property of iodo gels is much better than that of hydrogenous gels under the same concentration. Gels from 1I respond to the stimuli of Hg2+, Cu2+, Zn2+, and Mg2+ as perchlorate salts, and gels from 1H are selectively responsive to Hg2+ solely.

A prominent bathochromic shift effect of indole-containing diarylethene derivatives.

The potential implication of photochromic materials with absorption and reactivity in the near-infrared region is far-reaching. In this work, three novel bisindole-containing diarylethene derivatives 1o­3o have been successfully synthesized and their photochromic behaviour exhibits a strong bathochromic shift effect compared with bisbenzothiophene diarylethene 4o. These new bisindole-diarylethene compounds 1o­3o are highly sensitive to photo-stimuli both in solution and in poly(methyl methacrylate) films. Besides, 1o­3o exhibit an excellent reversible fluorescence switching behavior modulated by optical stimuli.

Highly efficient enantioselective construction of bispirooxindoles containing three stereocenters through an organocatalytic cascade Michael-cyclization reaction.

Bispirooxindole derivatives containing three stereocenters, including two spiro quaternary centers, were synthesized in a high-yielding, atypically rapid, and stereocontrolled cascade Michael-cyclization reaction between methyleneindolinones and isothiocyanato oxindoles catalyzed by a bi- or multifunctional organocatalyst. Mild conditions were used to construct bispirooxindoles with excellent enantio- and diastereomeric purities within less than 1 min. Catalyst reconfiguration offered access to the opposite enantiomer. This exceptionally highly efficient procedure will allow diversity-oriented syntheses of this intriguing class of compounds with potential biological activities.

Structure-based discovery of potent USP28 inhibitors derived from Vismodegib.

Ubiquitin-specific proteases (USPs) 28 is overexpressed in multiple types of cancers. The development of potent USP28 inhibitors is still in primitive stage. We previously reported our discovery of Vismodegib as a USP28 inhibitor by screening a commercially available drug library. Herein, we report our efforts to solve the cocrystal structure of Vismodegib bound to USP28 for the first time and subsequent structure-based optimization leading to a series of Vismodegib derivatives as potent USP28 inhibitors. Based on the cocrystal structure, elaborative SARs exploration was carried out to afford much more potent USP28 inhibitors than Vismodegib. The representative compounds 9l, 9o and 9p bearing high potency on USP28 showed high selectivity over USP2, USP7, USP8, USP9x, UCHL3 and UCHL5. The detailed cellular assay suggested that compounds 9l, 9o and 9p could cause cytotoxicity in both human colorectal cancer and lung squamous carcinoma cells and significantly enhance the sensitivity of colorectal cancer cells to Regorafenib. Further immunoblotting analysis indicated that compounds 9l, 9o and 9p could dose-dependently down-regulate the cellular level of c-Myc through ubiquitin-proteasome system and anti-cancer effects could mainly be attributed to their inhibition on USP28 but not involving the Hedgehog-Smoothened pathway. Thus, our work provided a series of novel and potent USP28 inhibitors derived from Vismodegib and may contribute to the development of USP28 inhibitors.

A strategy for the late-stage divergent syntheses of scyphostatin analogues.

This account details the synthesis of two scyphostatin analogues exhibiting a reactive polar epoxycyclohexenone core and various amide side chains outfitted for late-stage chemical derivatization into the desirable lipophilic tails. Our efforts highlight a key ipso-dearomatization process and provide new insights regarding the incompatibility and orthogonal reactivity of scyphostatin's functional groups. We further showcase the utility of resorcinol derived 2,5-cyclohexadienones as synthetic platforms capable of participating in selective chemical reactivity, and we further demonstrate their potential for rapid elaboration into complex structural motifs.

Study of naphthopyran derivatives: structure and photochromic properties in solution and in polymer film.

Four naphthopyran derivatives, namely, 3,3-bis(naphthalen-1-yl)-3H-naphtho[2,1-b]pyran, C33H22O, NP1, 3,3-bis([1,1'-biphenyl]-4-yl)-3H-naphtho[2,1-b]pyran, C37H26O, NP2, 3,3-bis(4-phenoxyphenyl)-3H-naphtho[2,1-b]pyran, C37H26O2, NP3, and 3,3-bis(4-methoxy-2-methylphenyl)-3H-naphtho[2,1-b]pyran, C29H26O3, NP4, were synthesized and their photochromic properties investigated. NP1-NP4 exhibited good photochromism in different solutions and in poly(methyl methacrylate) (PMMA) film under UV light irradiation. Solvatochromism and the electronic and steric effects of the substituent group on photochromism were analyzed and decolouration curves were found to fit a monoexponential kinetic decay in most cases. Single-crystal X-ray analysis of NP1 and NP2 revealed the structure-property relationships. Good fatigue resistance of NP1, both in solution and in the PMMA film, endows it with potential value for applications.

Discovery of Investigational Drug CT1812, an Antagonist of the Sigma-2 Receptor Complex for Alzheimer's Disease.

An unbiased phenotypic neuronal assay was developed to measure the synaptotoxic effects of soluble Aß oligomers. A collection of CNS druglike small molecules prepared by conditioned extraction was screened. Compounds that prevented and reversed synaptotoxic effects of Aß oligomers in neurons were discovered to bind to the sigma-2 receptor complex. Select development compounds displaced receptor-bound Aß oligomers, rescued synapses, and restored cognitive function in transgenic hAPP Swe/Ldn mice. Our first-in-class orally administered small molecule investigational drug 7 (CT1812) has been advanced to Phase II clinical studies for Alzheimer's disease.

Diastereoselective syntheses of chroman spiroketals via [4 + 2] cycloaddition of enol ethers and o-quinone methides.

A variety of chroman spiroketals are synthesized via inverse-demand [4 + 2] cycloaddition of enol ethers and ortho-quinone methides (o-QMs). Low temperature o-QM generation in situ allows for the kinetic, diastereoselective construction of these motifs, providing entry to a number of unusual chroman spiroketal natural products.

Synthesis of resorcinol derived spironitronates.

Syntheses of several unique spironitronates are reported. The key transformation involves the first known example of an ipso oxidative cyclization of nitro functionality. Oxidation proceeds from both o- and p-phenols. Reductions of these compounds provide novel spiroisoxazoline derivatives.

Pillararene-Based Aggregation-Induced-Emission-Active Supramolecular System for Simultaneous Detection and Removal of Mercury(II) in Water.

Supramolecular polymers are polymers based on monomeric units held together with directional and reversible noncovalent interactions. Compared with traditional polymers, they possess better processability and better recycling properties, owing to their reversible monomer-to-polymer transition. Herein, we report the construction of a new supramolecular system through self-assembly of a thymine-substituted copillar[5]arene 1 and a tetraphenylethylene (TPE) derivative 2 in the presence of Hg2+. Copillar[5]arene 1 can coordinate with Hg2+ tightly through T-Hg2+-T pairings. On the other hand, 1 can bind with guest molecule 2 through host-guest interactions between the pillararene cavity and the nitrile moiety of 2. These joint interactions generate crisscrossed networks composed of 1, 2, and Hg2+, which eventually wrap into spherical nanoparticles. Due to the aggregation-induced emission (AIE) properties of 2, the formed supramolecular polymer exhibits strong fluorescence which renders convenient the detection of the Hg2+-containing nanoparticles and the subsequent removal procedure. Furthermore, the polymer precipitate can be readily isolated by simple treatment, and the pseudorotaxane 2 ⊂ 1 can be recycled and reused. Our study has demonstrated a practical strategy for the sensing and removal of heavy metal ions in water by the construction of supramolecular polymers.

Synthesis of (+/-)-brazilin using IBX.

[reaction: see text] A short synthesis of (+/-)-brazilin is reported. This synthesis uses several interesting and underutilized transformations including a regioselective dirhodium-catalyzed aryl C-H insertion, a regioselective IBX phenol --> o-quinone oxidation, a tautomerization of an o-quinone to a p-quinone methide, and an intramolecular aryl cyclization with a p-quinone methide.

Simultaneous saccharification and co-fermentation of dry diluted acid pretreated corn stover at high dry matter loading: Overcoming the inhibitors by non-tolerant yeast.

Dry dilute acid pretreatment (DDAP) is a promising method for lignocellulose bioconversion, although inhibitors generated during the pretreatment impede the fermentation severely. We developed the simultaneous saccharification and co-fermentation (SScF) of DDAP pretreated biomass at high solid loading using xylose fermenting Saccharomyces cerevisiae, SyBE005. Effect of temperature on SScF showed that ethanol yield at 34°C was 10.2% higher than that at 38°C. Ethanol concentration reached 29.5 g/L at 15% (w/w) dry matter loading, while SScF almost ceased at the beginning at 25% (w/w) dry matter loading of DDAP pretreated corn stover. According to the effect of the diluted hydrolysate on the fermentation of strain SyBE005, a fed-batch mode was developed for the SScF of DDAP pretreated corn stover with 25% dry matter loading without detoxification, and 40.0 g/L ethanol was achieved. In addition, high yeast inoculation improved xylose utilization and the final ethanol concentration reached 47.2 g/L.

A Cycloaddition Strategy for Use toward Berkelic Acid, an MMP Inhibitor and Potent Anticancer Agent Displaying a Unique Chroman Spiroketal Motif.

A kinetically controlled diastereoselective cycloaddition between a chiral enol ether and an ortho-quinone methide (o-QM) produces a chroman spiroketal motif that is found in the core of berkelic acid, a novel matrix metalloproteinase (MMP) inhibitor and potent anticancer agent. The transformation lays the groundwork for preparation of future inhibitors aimed at distinguishing among the active sites of the twenty-three known MMP. Experimental findings suggest that the stereochemistry that emerges from cycloaddition is opposite that which results from thermodynamic ketalization.