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

On the Development of Catalytic Carba-6π Electrocyclizations

Hexatriene substrates substituted in the 2-position with carbonyl groups were studied in the context of catalytic 6π electrocyclizations. The nature of the carbonyl group and the substitution pattern on the hexatriene have significant effects on the ability of these substrates to succumb to catalysis. A novel 2-formyl hexatriene dimerization was observed. The first example of a catalytic asymmetric carba-6π electrocyclization is reported along with the discovery of an unusual kinetic resolution via a catalytic photochemical electrocyclic ring-opening

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

Optical control of NMDA-receptors with a diffusible photoswitch

N-methyl-D-aspartate receptors (NMDARs) play a central role in synaptic plasticity, learning and memory, and are implicated in various neuronal disorders. We synthesized a diffusible photochromic glutamate analogue, azobenzene-triazole-glutamate (ATG), which is specific for NMDARs and functions as a photoswitchable agonist. ATG is inactive in its dark-adapted trans-isoform, but can be converted into its active cis-isoform using one-photon (near UV) or two-photon (740 nm) excitation. Irradiation with violet light photo-inactivates ATG within milliseconds, allowing agonist removal on the timescale of NMDAR deactivation. ATG is compatible with Ca2+ imaging and can be used to optically mimic synaptic coincidence detection protocols. Thus, ATG can be used like traditional caged glutamate compounds, but with the added advantages of NMDAR specificity, low antagonism of GABAR-mediated currents, and precise temporal control of agonist delivery

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

Tunable Oscillations in the Purkinje Neuron

In this paper, we study the dynamics of slow oscillations in Purkinje neurons in vitro, and derive a strong association with a forced parametric oscillator model. We demonstrate the precise rhythmicity of the oscillations in Purkinje neurons, as well as a dynamic tunability of this oscillation using a photo-switchable compound. We show that this slow oscillation can be induced in every Purkinje neuron, having periods ranging between 10-25 seconds. Starting from a Hodgkin-Huxley model, we also demonstrate that this oscillation can be externally modulated, and that the neurons will return to their intrinsic firing frequency after the forced oscillation is concluded. These results signify an additional functional role of tunable oscillations within the cerebellum, as well as a dynamic control of a time scale in the brain in the range of seconds.Comment: 12 pages, 5 figure

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