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 the 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 occurred independently. Finally, we highlight cases where such a possibility has been suggested but not yet confirmed, inviting further collaborations between synthetic and natural product chemists. The total synthesis of natural products has always been a major factor in the development of organic chemistry. The reasons for pursuing it have evolved as the field has progressed. In its early history, total synthesis mostly served to confirm the constitution and configuration of readily available natural products. With the advent of X-ray crystallography, NMR spectroscopy, and mass spectrometry, this aspect has become less important, although numerous recent cases exist where the structure of a natural product was settled through total synthesis. [1,2] As a consequence, the emphasis has shifted more toward reaction development and the definition of efficient synthetic strategies. In some cases, the desire to achieve a particular transformation has led to the invention of new reactions or reagents that did not exist before. [3] If a total synthesis is sufficiently efficient, it can also be used to deliver a prized natural product on scale that can otherwise only be procured at great expense or by ignoring environmental concerns. [4] Many other motivations for total synthesis exist, ranging from its value as a training ground for medicinal chemists to the satisfaction that comes with solving the sheer intellectual challenge that it represents. [5,6] In this account, we wish to highlight yet another reason to pursue it: Natural Product Anticipation.In the early days of organic synthesis, there must have been many cases where a compound was prepared in the laboratory and considered "synthetic" that was subsequently identified as a natural product. For instance, Gabriel made aminoacetone (1) in 1893 using his eponymous method. [7,8]...
α‐Galactosylceramides are glycosphingolipids that show promise in cancer immunotherapy. After presentation by CD1d, they activate natural killer T cells (NKT), which results in the production of a variety of pro‐inflammatory and immunomodulatory cytokines. Herein, we report the synthesis and biological evaluation of photochromic derivatives of KRN‐7000, the activity of which can be modulated with light. Based on established structure–activity relationships, we designed photoswitchable analogues of this glycolipid that control the production of pro‐inflammatory cytokines, such as IFN‐γ. The azobenzene derivative α‐GalACer‐4 proved to be more potent than KRN‐7000 itself when activated with 370 nm light. Photolipids of this type could improve our mechanistic understanding of cytokine production and could open new directions in photoimmunotherapy.
G protein-coupled receptors (GPCRs) are the most common targets of drug discovery. However, the similarity between related GPCRs combined with the complex spatiotemporal dynamics of receptor activation in vivo has hindered drug development. Photopharmacology offers the possibility of using light to control the location and timing of drug action by incorporating a photoisomerizable azobenzene into a GPCR ligand, enabling rapid and reversible switching between an inactive and active configuration. Recent advances in this area include (i) photoagonists and photoantagonists that directly control receptor activity but are nonselective because they bind conserved sites, and (ii) photoallosteric modulators that bind selectively to nonconserved sites but indirectly control receptor activity by modulating the response to endogenous ligand. In this study, we designed a photoswitchable allosteric agonist that targets a nonconserved allosteric site for selectivity and activates the receptor on its own to provide direct control. This work culminated in the development of aBINA, a photoswitchable allosteric agonist that selectively activates the G i/o -coupled metabotropic glutamate receptor 2 (mGluR2). aBINA is the first example of a new class of precision drugs for GPCRs and other clinically important signaling proteins.
Serotonin receptors play central roles in neuromodulation and are critical drug targets for psychiatric disorders. Optical control of serotonin receptor subtypes has the potential to greatly enhance our understanding of the spatiotemporal dynamics of receptor function. While other neuromodulatory receptors have been successfully rendered photoswitchable, reversible photocontrol of serotonin receptors has not been achieved, representing a major gap in GPCR photopharmacology. Herein, we develop the first tools that allow for such control. Azo5HT‐2 shows light‐dependent 5‐HT2AR agonism, with greater activity in the cis‐form. Based on docking and test compound analysis, we also develop photoswitchable orthogonal, remotely‐tethered ligands (PORTLs). These BG‐Azo5HTs provide rapid, reversible, and repeatable optical control following conjugation to SNAP‐tagged 5‐HT2AR. Overall, this study provides a foundation for the broad extension of photopharmacology to the serotonin receptor family.
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