The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.

Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design.

This Perspective illustrates the defining characteristics of free radical chemistry, beginning with its rich and storied history. Studies from our laboratory are discussed along with recent developments emanating from others in this burgeoning area. The practicality and chemoselectivity of radical reactions enable rapid access to molecules of relevance to drug discovery, agrochemistry, material science, and other disciplines. Thus, these reactive intermediates possess inherent translational potential, as they can be widely used to expedite scientific endeavors for the betterment of humankind.

Radicals: Reactive Intermediates with Translational Potential

Fatty acid synthase (FASN) is a key enzyme involved in neoplastic lipogenesis Overexpression of FASN is common in many cancers, and accumulating evidence suggests that it is a metabolic oncogene with an important role in tumor growth and survival, making it an attractive target for cancer therapy Early small-molecule FASN inhibitors such as cerulenin, C75 and orlistat have been shown to induce apoptosis in several cancer cell lines and to induce tumor growth delay in several cancer xenograft models but their mechanism is still not well understood These molecules suffer from pharmacological limitations and weight loss as a side effect that prevent their development as systemic drugs Several potent inhibitors have recently been reported that may help to unravel and exploit the full potential of FASN as a target for cancer therapy in the near future Furthermore, novel sources of FASN inhibitors, such as green tea and dietary soy, make both dietary manipulation and chemoprevention potential alternative modes of therapy in the future

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Fatty acid synthase as a potential therapeutic target in cancer

Catalysed X–H insertion reactions into diazo compounds (where X is any heteroatom) are a powerful yet underutilized class of transformations. The following review will explore the historical development of X–H insertion and give an up-to-date account of the metal catalysts most often employed, including an assessment of their strengths and weaknesses. Despite decades of development, recent work on enantioselective variants, as well as applying catalytic X–H insertion towards problems in chemical biology indicate that this field has ample room for innovation.

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Catalytic X–H insertion reactions based on carbenoids

Introduction: Ten years ago, we put forward the metabolo-oncogenic nature of fatty acid synthase (FASN) in breast cancer. Since the conception of this hypothesis, which provided a model to ...

Fatty acid synthase (FASN) as a therapeutic target in breast cancer.

As lung cancer is the most common malignancy worldwide and high mortalities are the result of metastasis, novel information surpassing the treatment strategies and therapeutic agents focusing on cancer dissemination are of interest Lung cancer metastasis involves increased motility, survival in circulation and ability to form new tumors Metastatic cells increase their aggressive features by utilizing several mechanisms to overcome hindrances of metastasis, including epithelial to mesenchymal transition (EMT), increased in cellular survival and migratory signals Sufficient amounts of natural product-derived compounds have been shown to have promising anti-metastasis activities by suppressing key molecular features upholding such cell aggressiveness The knowledge regarding molecular mechanisms rendering cell dissemination together with the anti-metastasis information of natural product-derived compounds may lead to development of novel therapeutic strategies

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Potential Anti-metastasis Natural Compounds for Lung Cancer.

Introduction: At present, the key public health concern is to define the way in which the next influenza pandemic should be controlled. While influenza vaccines are available, their effectiveness could be significantly reduced if new strains differ significantly from those of the vaccines. Therefore, antiviral drugs play an important role in the prevention and management of influenza. The influenza neuraminidase (NA), a surface-glycoprotein enzyme involved in releasing the virus from the host cell, has been considered as an essential therapeutic target for treatment and prophylaxis of influenza infection. It is a highly conserved feature of the active site across all influenza A and B viruses and is of particular interest because compounds NA inhibitors (NAIs) can be cross-reactive against multiple types and subtypes of influenza. Currently, there are two NAI drugs which are licensed worldwide: oseltamivir and zanamivir, and two more drugs which have received recent approval in Japan: peramivir and lanina...

Recent progress and challenges in the discovery of new neuraminidase inhibitors.

Natural products are essential tools for basic cellular studies leading to the identification of medically relevant protein targets and the discovery of potential therapeutic leads. The development of methods that enable mild and selective derivatization of natural products continues to be of significant interest for mining their information-rich content. Herein, we describe novel diazo reagents for simultaneous arming and structure–activity relationship (SAR) studies of alcohol-containing natural products with a small steric footprint, namely, an α-trifluoroethyl (HTFB) substituted reagent. The Rh(II)-catalyzed O–H insertion reaction of several natural products, including the potent translation inhibitor lactimidomycin, was investigated, and useful reactivity and both chemo- and site (chemosite) selectivities were observed. Differential binding to the known protein targets of both FK506 and fumagillol was demonstrated, validating the advantage of the smaller steric footprint of α-trifluoroethyl derivativ...

Diazo reagents with small steric footprints for simultaneous arming/SAR studies of alcohol-containing natural products via O-H insertion.

Background Neuraminidase (NA), a major glycoprotein found on the surface of the influenza virus, is an important target for the prophylaxis and treatment of influenza virus infections. Recently, several plant-derived polyphenols, especially caffeic acid analogs, have been reported to exert the inhibitory activity against NA. Objective Herein, we aimed to investigate the anti-influenza NA activity of caffeic acid and its hydroxycinnamate analogues, rosmarinic acid and salvianolic acid A, in comparison to a known NA inhibitor, oseltamivir. Methods In vitro MUNANA-based NA inhibitory assay was used to evaluate the inhibitory activity of the three interested hydroxycinnamic compounds towards the influenza NA enzyme. Subsequently, allatom molecular dynamics (MD) simulations and binding free energy calculations were employed to elucidate the structural insights into the protein-ligand complexations. Results Rosmarinic acid showed the highest inhibitory activity against NA with the IC50 of 0.40 μM compared to caffeic acid (IC50 of 0.81 μM) and salvianolic acid A (IC50 of >1 μM). From 100-ns MD simulations, the binding affinity, hot-spot residues, and H-bond formations of rosmarinic acid/NA complex were higher than those of caffeic acid/NA model, in which their molecular complexations was driven mainly by electrostatic attractions and H-bond formations from several charged residues (R118, E119, D151, R152, E227, E277, and R371). Notably, the two hydroxyl groups on both phenyl and phenylacetic rings of rosmarinic acid play a crucial role in stabilizing NA through a strongly formed Hbond( s). Conclusion Our findings shed light on the potentiality of rosmarinic acid as a lead compound for further development of a potential influenza NA inhibitor.

Supakarn Chamni

Papers

Potential Anti-metastasis Natural Compounds for Lung Cancer.

Recent progress and challenges in the discovery of new neuraminidase inhibitors.

Diazo reagents with small steric footprints for simultaneous arming/SAR studies of alcohol-containing natural products via O-H insertion.

Rosmarinic Acid as a Potent Influenza Neuraminidase Inhibitor: In Vitro and In Silico Study.

β-Lactam congeners of orlistat as inhibitors of fatty acid synthase