3-(3-Bromophenyl)-7-acetoxycoumarin

In natural product synthesis, the procurement of easily accessible starting materials is crucial. Chromenones and their subclass, coumarins, are a wide family of small, oxygen-containing aromatic heterocycles. Phenylcoumarins offer a particularly excellent starting point for a diverse chemical space of natural products, and thus are excellent staring materials for more complex natural products. Herein, we report an efficient synthesis of an easily accessible 3-phenylcoumarin bearing two orthogonally substitutable groups, bromine, and an acetyl-protected phenylic hydroxyl group

Selective Calcium-Dependent Inhibition of ATP-Gated P2X3 Receptors by Bisphosphonate-Induced Endogenous ATP Analog ApppI

Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics. Pain is the most unbearable symptom accompanying primary bone cancers and bone metastases. Bone resorptive disorders are often associated with hypercalcemia, contributing to the pathologic process. Nitrogen-containing bisphosphonates (NBPs) are efficiently used to treat bone cancers and metastases. Apart from their toxic effect on cancer cells, NBPs also provide analgesia via poorly understood mechanisms. We previously showed that NBPs, by inhibiting the mevalonate pathway, induced formation of novel ATP analogs such as ApppI [1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) triphosphoric acid diester], which can potentially be involved in NBP analgesia. In this study, we used the patch-clamp technique to explore the action of ApppI on native ATP-gated P2X receptors in rat sensory neurons and rat and human P2X3, P2X2, and P2X7 receptors expressed in human embryonic kidney cells. We found that although ApppI has weak agonist activity, it is a potent inhibitor of P2X3 receptors operating in the nanomolar range. The inhibitory action of ApppI was completely blocked in hypercalcemia-like conditions and was stronger in human than in rat P2X3 receptors. In contrast, P2X2 and P2X7 receptors were insensitive to ApppI, suggesting a high selectivity of ApppI for the P2X3 receptor subtype. NBP, metabolite isopentenyl pyrophosphate, and endogenous AMP did not exert any inhibitory action, indicating that only intact ApppI has inhibitory activity. Ca2+-dependent inhibition was stronger in trigeminal neurons preferentially expressing desensitizing P2X3 subunits than in nodose ganglia neurons, which also express nondesensitizing P2X2 subunits. Altogether, we characterized previously unknown purinergic mechanisms of NBP-induced metabolites and suggest ApppI as the endogenous pain inhibitor contributing to cancer treatment with NBPs

Large glucosylthioureidocalixarenes: selective hosts for mono- and bisphosphonates

Non-covalent complexation of mono- and bisphosphonates by hexaglucosylthioureidocalix[6]arene and octaglucosylthioureidocalix[ 8]arene was studied by electrospray ionisation Fourier transform ion cyclotron resonance mass spectrometry. Glucosylthioureidocalix[8]arene formed 1:1 and 1:2 complexes with bisphosphonates, with a marked preference towards risedronate, clodronate, zoledronate and etidronate. In contrast, up to four guest molecules were bound in the case of monophosphonates, suggesting a different type of binding in comparison to bisphosphonates. Hexaglucosylthioureidocalix[ 6]arene also formed complexes with phosphonates with a somewhat similar binding selectivity. Interestingly, the addition of calcium ions into the sample of etidronate–glucosylthioureidocalix[8]arene complex resulted in a complete release of the guest due to the very high affinity between calcium and bisphosphonate. In the gas-phase hydrogen/deuterium exchange reactions, glucosylthioureidocalix[8]arene exhibited a number of exchangeable hydrogens and a bimodal exchange distribution was observed, suggesting a presence of multiple gas-phase conformations. Surprisingly, no exchange or very slow exchange for the complexes of glucosylthioureidocalix[8]arene was observed

Selective Calcium-Dependent Inhibition of ATP-Gated P2X3 Receptors by Bisphosphonate-Induced Endogenous ATP Analog ApppI

Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics. Pain is the most unbearable symptom accompanying primary bone cancers and bone metastases. Bone resorptive disorders are often associated with hypercalcemia, contributing to the pathologic process. Nitrogen-containing bisphosphonates (NBPs) are efficiently used to treat bone cancers and metastases. Apart from their toxic effect on cancer cells, NBPs also provide analgesia via poorly understood mechanisms. We previously showed that NBPs, by inhibiting the mevalonate pathway, induced formation of novel ATP analogs such as ApppI [1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) triphosphoric acid diester], which can potentially be involved in NBP analgesia. In this study, we used the patch-clamp technique to explore the action of ApppI on native ATP-gated P2X receptors in rat sensory neurons and rat and human P2X3, P2X2, and P2X7 receptors expressed in human embryonic kidney cells. We found that although ApppI has weak agonist activity, it is a potent inhibitor of P2X3 receptors operating in the nanomolar range. The inhibitory action of ApppI was completely blocked in hypercalcemia-like conditions and was stronger in human than in rat P2X3 receptors. In contrast, P2X2 and P2X7 receptors were insensitive to ApppI, suggesting a high selectivity of ApppI for the P2X3 receptor subtype. NBP, metabolite isopentenyl pyrophosphate, and endogenous AMP did not exert any inhibitory action, indicating that only intact ApppI has inhibitory activity. Ca2+-dependent inhibition was stronger in trigeminal neurons preferentially expressing desensitizing P2X3 subunits than in nodose ganglia neurons, which also express nondesensitizing P2X2 subunits. Altogether, we characterized previously unknown purinergic mechanisms of NBP-induced metabolites and suggest ApppI as the endogenous pain inhibitor contributing to cancer treatment with NBPs

Rapid synthesis of nanostructured porous silicon carbide from biogenic silica

International audienceNanostructured silicon carbide (SiC) is an exceptional material with numerous applications e.g. in catalysis, biomedicine, high performance composites, and sensing. In this study, a fast and scalable method of producing nanostructured SiC from plant materials by magnesiothermic reduction via self-propagating high-temperature synthesis (SHS) route was developed. The produced biogenic material possessed a high surface area above 200 m 2 /g with a SiC crystallite size below 10 nm, which has not been done previously by SHS. This method enables affordable synthesis of the material plant-based precursors in a reaction that only takes a few seconds, thereby paving a way for nanostructured silicon carbide production in high volumes using renewable resources. The material was also functionalized with carboxylic acid and bisphosphonate moieties, and its use as metal adsorbent in applications such as wastewater remediation was demonstrated