Nonconservation of the Valley Density and Its Implications for the Observation of the Valley Hall Effect.

We show that the conservation of the valley density in multivalley insulators is broken in an unexpected way by the electric field that drives the valley Hall effect. This implies that time-reversal-invariant fully gapped insulators, in which no bulk or edge state crosses the Fermi level, can support a valley Hall current in the bulk and yet show no valley density accumulation at the edges. Thus, the valley Hall effect cannot be observed in such systems. If the system is not fully gapped then valley density accumulation at the edges is possible. The accumulation has no contribution from undergap states and can be expressed as a Fermi surface average, for which we derive an explicit formula. We demonstrate the theory by calculating the valley density accumulations in an archetypical valley-Hall insulator: a gapped graphene nanoribbon. Surprisingly, we discover that a net valley density polarization is dynamically generated for certain edge terminations.

Synthetic Routes to Approved Drugs Containing a Spirocycle.

The use of spirocycles in drug discovery and medicinal chemistry has been booming in the last two decades. This has clearly translated into the landscape of approved drugs. Among two dozen clinically used medicines containing a spirocycle, 50% have been approved in the 21st century. The present review focuses on the notable synthetic routes to such drugs invented in industry and academia, and is intended to serve as a useful reference source of synthetic as well as general drug information for researchers engaging in the design of new spirocyclic scaffolds for medicinal use or embarking upon analog syntheses inspired by the existing approved drugs.

Periphery Exploration around 2,6-Diazaspiro[3.4]octane Core Identifies a Potent Nitrofuran Antitubercular Lead.

A small set of twelve compounds of a nitrofuran carboxamide chemotype was elaborated from a readily available 2,6-diazaspiro[3.4]octane building block, exploring diverse variants of the molecular periphery, including various azole substituents. The in vitro inhibitory activities of the synthesized compounds were assessed against Mycobacterium tuberculosis H37Rv. As a result, a remarkably potent antitubercular lead displaying a minimal inhibitory concentration of 0.016 µg/mL was identified.

Replacing the phthalimide core in thalidomide with benzotriazole.

The advent of proteolysis-targeting chimaeras (PROTACs) mandates that new ligands for the recruitment of E3 ligases are discovered. The traditional immunomodulatory drugs (IMiDs) such as thalidomide and its analogues (all based on the phthalimide glutarimide core) bind to Cereblon, the substrate receptor of the CRL4ACRBN E3 ligase. We designed a thalidomide analogue in which the phthalimide moiety was replaced with benzotriazole, using an innovative synthesis strategy. Compared to thalidomide, the resulting "benzotriazolo thalidomide" has a similar binding mode, but improved properties, as revealed in crystallographic analyses, affinity assays and cell culture.

The Use of Aryl-Substituted Homophthalic Anhydrides in the Castagnoli-Cushman Reaction Provides Access to Novel Tetrahydroisoquinolone Carboxylic Acid Bearing an All-Carbon Quaternary Stereogenic Center.

Novel aryl-substituted homophthalic acids were cyclodehydrated to the respective homophthalic anhydrides for use in the Castagnoli-Cushman reaction. With a range of imines, this reaction proceeded smoothly and delivered hitherto undescribed 4-aryl-substituted tetrahydroisoquinolonic acids with remarkable diastereoselectivity, good yields and no need for chromatographic purification. These findings significantly extend the range of cyclic anhydrides employable in the Castagnoli-Cushman reaction and signify access to a novel substitution pattern around the medicinally relevant tetrahydroisoquinolonic acid scaffold.

Ligands for cereblon: 2017-2021 patent overview.

INTRODUCTION: Cereblon (CRBN), the substrate receptor of the CRL4CRBN E3 ubiquitin ligase has been extensively studied due to its involvement in many biological processes. It has also been identified as the target for immunomodulatory drugs (IMiDs). CRBN ligands are also important components of proteolysis-targeting chimeras (PROTACs), special bifunctional constructs capable of targeted degradation of aberrantly acting proteins using the cell's ubiquitin-proteasome machinery. AREAS COVERED: Due to upsurge of the PROTAC technology, the patenting activity of new CRBN ligands has been on the rise in the last 5 years. The present review covers two broadly defined areas of CRBN ligand design. One covers 'thalidomide-like' molecules representing modifications of various parts of classical IMiDs. The other areas - non-thalidomide-like compounds - are compounds that are structurally distinct from the classical IMiDs. Efforts toward creating new CRBN ligands reflected in non-patent literature are briefly discussed with emphasis on the rational, crystallography-driven approaches. EXPERT OPINION: The chemical space of CRBN ligands which is related to the classical IMiDs (thalidomide/lenalidomide/pomalidomide) is comprehensively covered by the current patent literature. The promising area of research is in the identification of non-thalidomide-like chemotypes capable of binding to CRBN. Rational, crystallography-driven approaches currently exploited in academia will significantly aid in this endeavor.

Unexpected Ring Contraction of Homophthalic Anhydrides under Diazo Transfer Conditions.

An attempted Regitz diazo transfer onto homophthalic anhydride led to the discovery of an unexpected ring contraction, which gave N-sulfonyl phthalide-3-carboxamide derivatives. The reaction is thought to proceed via a [3 + 2] cycloaddition of the substrate's enol form and the azide followed by a two-step fragmentation of the intermediate 1,2,3-triazoline with a loss of the nitrogen molecule.

Ambiguities in and completeness of SAS data analysis of membrane proteins: the case of the sensory rhodopsin II-transducer complex.

Membrane proteins (MPs) play vital roles in the function of cells and are also major drug targets. Structural information on proteins is vital for understanding their mechanism of function and is critical for the development of drugs. However, obtaining high-resolution structures of membrane proteins, in particular, under native conditions is still a great challenge. In such cases, the low-resolution methods small-angle X-ray and neutron scattering (SAXS and SANS) might provide valuable structural information. However, in some cases small-angle scattering (SAS) provides ambiguous ab initio structural information if complementary measurements are not performed and/or a priori information on the protein is not taken into account. Understanding the nature of the limitations may help to overcome these problems. One of the main problems of SAS data analysis of solubilized membrane proteins is the contribution of the detergent belt surrounding the MP. Here, a comprehensive analysis of how the detergent belt contributes to the SAS data of a membrane-protein complex of sensory rhodopsin II with its cognate transducer from Natronomonas pharaonis (NpSRII-NpHtrII) was performed. The influence of the polydispersity of NpSRII-NpHtrII oligomerization is the second problem that is addressed here. It is shown that inhomogeneity in the scattering length density of the detergent belt surrounding a membrane part of the complex and oligomerization polydispersity significantly impacts on SAXS and SANS profiles, and therefore on 3D ab initio structures. It is described how both problems can be taken into account to improve the quality of SAS data treatment. Since SAS data for MPs are usually obtained from solubilized proteins, and their detergent belt and, to a certain extent, oligomerization polydispersity are sufficiently common phenomena, the approaches proposed in this work might be used in SAS studies of different MPs.