Optical Control of Glycerolipids and Sphingolipids

Glycerolipids, Sphingolipids, and Sterols are the three major classes of membrane lipids. Both glycerolipids and sphingolipids are comprised of combinations of polar headgroups and fatty acid tails. The fatty acid tail can be chemically modified with an azobenzene photoswitch giving rise to photoswitchable lipids. This approach has yielded a number of photopharmacological tools that allow to control various aspects of lipid assembly, metabolism, and physiology with light

A step toward polytwistane: synthesis and characterization of C-2-symmetric tritwistane

Twistane is a classic hydrocarbon with fascinating stereochemical properties. Herein we describe a series of oligomers of twistane that converges on a chiral nanorod, which we term polytwistane. A member of this series, C-2-symmetric tritwistane, has been synthesized for the first time

Synthetic approaches toward sesterterpenoids

Sesterterpenoids account for many bioactive natural products, often with unusual and complex structural features, which makes them attractive targets for synthetic chemists. This review surveys efforts undertaken toward the synthesis of sesterterpenoids, focusing on completed total syntheses and covering ca. 50 natural products in tota

Natural product anticipation through synthesis

Natural product synthesis remains one of the most vibrant and intellectually rewarding areas of chemistry, although the justifications for pursuing it have evolved over time. In the early years, the emphasis lay on structure elucidation and confirmation through synthesis, as exemplified by celebrated studies on cocaine, morphine, strychnine and chlorophyll. This was followed by a phase where the sheer demonstration that highly complex molecules could be recreated in the laboratory in a rational manner was enough to justify the economic expense and intellectual agonies of a synthesis. Since then, syntheses of natural products have served as platforms for the demonstration of elegant strategies, for inventing new methodology ‘on the fly’ or to demonstrate the usefulness and scope of methods established with simpler molecules. We now add another aspect that we find fascinating, viz. ‘natural product anticipation’. In this Review, we survey cases where the synthesis of a compound in the laboratory has preceded its isolation from nature. The focus of our Review lies on examples where this anticipation of a natural product has triggered a successful search or where synthesis and isolation have occurred independently. Finally, we highlight cases where a potential natural product structure has been suggested as a result of synthetic endeavours but not yet confirmed by isolation, inviting further collaborations between synthetic and natural product chemists

Ligand Photo-Isomerization Triggers Conformational Changes in iGluR2 Ligand Binding Domain

Neurological glutamate receptors bind a variety of artificial ligands, both agonistic and antagonistic, in addition to glutamate. Studying their small molecule binding properties increases our understanding of the central nervous system and a variety of associated pathologies. The large, oligomeric multidomain membrane protein contains a large and flexible ligand binding domains which undergoes large conformational changes upon binding different ligands. A recent application of glutamate receptors is their activation or inhibition via photo-switchable ligands, making them key systems in the emerging field of optochemical genetics. In this work, we present a theoretical study on the binding mode and complex stability of a novel photo-switchable ligand, ATA-3, which reversibly binds to glutamate receptors ligand binding domains (LBDs). We propose two possible binding modes for this ligand based on flexible ligand docking calculations and show one of them to be analogues to the binding mode of a similar ligand, 2-BnTetAMPA. In long MD simulations, it was observed that transitions between both binding poses involve breaking and reforming the T686-E402 protein hydrogen bond. Simulating the ligand photo-isomerization process shows that the two possible configurations of the ligand azo-group have markedly different complex stabilities and equilibrium binding modes. A strong but slow protein response is observed after ligand configuration changes. This provides a microscopic foundation for the observed difference in ligand activity upon light-switching

Synthetic approaches towards alkaloids bearing α-tertiary amines

Alkaloids account for some of the most beautiful and biologically active natural products. Although they are usually classified along biosynthetic criteria, they can also be categorized according to certain structural motifs. Amongst these, the α-tertiary amine (ATA), i.e. a tetrasubstituted carbon atom surrounded by three carbons and one nitrogen, is particularly interesting. A limited number of methods have been described to access this functional group and fewer still are commonly used in synthesis. Herein, we review some approaches to asymmetrically access ATAs and provide an overview of alkaloid total syntheses where those have been employed

Potential energy function for a photo‐switchable lipid molecule

Photo‐switchable lipids are synthetic lipid molecules used in photo‐pharmacology to alter membrane lateral pressure and thus control opening and closing of mechanosensitive ion channels. The molecular picture of how photo‐switchable lipids interact with membranes or ion channels is poorly understood. To facilitate all‐atom simulations that could provide a molecular picture of membranes with photo‐switchable lipids, we derived force field parameters for atomistic computations of the azobenzene‐based fatty acid FAAzo‐4. We implemented a Phyton‐based algorithm to make the optimization of atomic partial charges more efficient. Overall, the parameters we derived give good description of the equilibrium structure, torsional properties, and non‐bonded interactions for the photo‐switchable lipid in its trans and cis intermediate states, and crystal lattice parameters for trans‐FAAzo‐4. These parameters can be extended to all‐atom descriptions of various photo‐switchable lipids that have an azobenzene moiety