TRPA1 Inhibition Effects by 3-Phenylcoumarin Derivatives.

Transient receptor potential ankyrin 1 (TRPA1) protein plays an important role in the inflammatory response, and it has been associated with different pain conditions and pain-related diseases, making TRPA1 a valid target for painkillers. In this study, we identified potential TRPA1 inhibitors and located their binding sites utilizing computer-aided drug design (CADD) techniques. The designed 3-phenylcoumarin-based TRPA1 inhibitors were successfully synthesized using a microwave assisted synthetic strategy.

Structural Diversity in Antiosteolytic Bisphosphonates: Deciphering Structure-Activity Trends in Ultra Long Controlled Release Phenomena.

Bisphosphonate (BP)-based treatments have been extensively prescribed for bone-related conditions, particularly for osteoporosis. Their low bioavailability creates the need for prescribed dosage increase to reach therapeutic levels but generates a plethora of undesirable side effects. A viable approach to alleviating these issues is to design and exploit controlled release strategies.

Simple and User-Friendly Methodology for Crystal Water Determination by Quantitative Proton NMR Spectroscopy in Deuterium Oxide.

In drug research and development, knowledge of the precise structure of an active ingredient is crucial. However, it is equally important to know the water content of the drug molecule, particularly the number of crystal waters present in its structure. Such knowledge ensures the avoidance of drug dosage and formulation errors since the number of water molecules affects the physicochemical and pharmaceutical properties of the molecule.

Surface-Modified Silica Hydrogels for the Programmable Release of Bisphosphonate Anti-Osteoporosis Drugs: The Case of Etidronate.

Bisphosphonate drugs constitute the primary treatment for bone diseases such as Paget's disease and osteoporosis. Despite their effectiveness, they also exhibit severe drawbacks, such as rapid excretion and limited oral bioavailability. High doses are usually administered to counterbalance these drawbacks.

Synthesis of the biologically important dideuterium-labelled adenosine triphosphate analogue ApppI( ).

The chemical synthesis of the dideuterium-labelled ATP analogue 1-adenosin-5'-yl-3-(3-methylbut-3-en-1,1- -1-ol) triphosphoric acid diester (ApppI( )) is described. ApppI has been reported to be an important mevalonate pathway metabolite, induced by nitrogen-containing bisphosphonates used for the treatment of several diseases related to the calcium metabolism, of which osteoporosis is the most well-known. The availability of ApppI( ) opens possibilities to quantitative measurements of ApppI in biological samples by mass spectrometry.

Drug-Inclusive Inorganic-Organic Hybrid Systems for the Controlled Release of the Osteoporosis Drug Zoledronate.

Bisphosphonates (BPs) are common pharmaceutical treatments used for calcium- and bone-related disorders, the principal one being osteoporosis. Their antiresorptive action is related to their high affinity for hydroxyapatite, the main inorganic substituent of bone. On the other hand, the phosphonate groups on their backbone make them excellent ligands for metal ions.

Real-Time On-Site Multielement Analysis of Environmental Waters with a Portable X-ray Fluorescence (pXRF) System.

Strict regulations are in place to control the effluents of mining sites and other industries. Heavy metal contamination of aquatic systems caused by leakages is difficult to mitigate as it takes time to detect and localize the leak. Dynamic sampling would drastically reduce the time to locate leakages and allow faster actions to reduce the impact on the environment.

Self-sacrificial MOFs for ultra-long controlled release of bisphosphonate anti-osteoporotic drugs.

In this paper we report drug delivery systems that are based on phosphonate MOFs. These employ biologically-acceptable metal ions (e.g.

()-Di-iodination of Alkynes Using Dried Dowex H/NaI Approach.

We investigated the usefulness of the dried Dowex H/NaI approach for the selective di-iodination of alkynes. The Dowex H/NaI approach selectively produces only ()-di-iodinated products; it is very straightforward and nontoxic. The utilization of 2-propanol as a solvent in the reactions can be considered as a "green" approach and the method maybe extended to radio-iodination.

Green and Efficient Esterification Method Using Dried Dowex H/NaI Approach.

The usefulness of dried Dowex H cation-exchange resin with or without sodium iodide (NaI) as a catalyst system for different kinds of esterifications using carboxylic acids and alcohols as starting materials has been systematically investigated. The Dowex H/NaI approach is very effective, generally high yielding, energy-efficient, and nontoxic, and the Dowex H resin is reusable. Since the whole procedure from start to product isolation is also very simple, these features make the method environmentally friendly.

Synthesis of a Biologically Important Adenosine Triphosphate Analogue, ApppD.

The chemical synthesis of a adenosine triphosphate analogue, 1-adenosin-5'-yl 3-(3-methylbut-2-enyl) triphosphoric acid diester (ApppD), is described. ApppD is known to be an active metabolite of the mevalonate pathway in the human body like its structural isomer isopentenyl ester of ATP (ApppI). Very recently, ApppI has been found to possess novel function(s); now it will also be possible to examine the effects of ApppD more precisely because it can be synthesized in reasonable amounts.

Bisphosphonate-Generated ATP-Analogs Inhibit Cell Signaling Pathways.

Bisphosphonates are a major class of drugs used to treat osteoporosis, Paget's disease, and cancer. They have been proposed to act by inhibiting one or more targets including protein prenylation, the epidermal growth factor receptor, or the adenine nucleotide translocase. Inhibition of the latter is due to formation in cells of analogs of ATP: the isopentenyl ester of ATP (ApppI) or an AppXp-type analog of ATP, such as AMP-clodronate (AppCClp).

Integrated analysis of isopentenyl pyrophosphate (IPP) toxicity in isoprenoid-producing Escherichia coli.

Isopentenyl pyrophosphate (IPP) toxicity presents a challenge in engineered microbial systems since its formation is unavoidable in terpene biosynthesis. In this work, we develop an experimental platform to study IPP toxicity in isoprenol-producing Escherichia coli. We first characterize the physiological response to IPP accumulation, demonstrating that elevated IPP levels are linked to growth inhibition, reduced cell viability, and plasmid instability.

Semi-preparative high-performance countercurrent chromatography method for the purification of chemically synthesized ATP analogue, ApppI.

An efficient high-performance countercurrent chromatography (HPCCC) based method has been developed for the purification of chemically synthesized 1-adenosin-5'-yl 3-(3-methylbut-3-enyl)triphosphoric acid diester (ApppI). ApppI is an adenosine triphosphate (ATP) analogue with biological significance due to its varied actions in the body. ApppI was synthesized and purified as its tetrabutylammonium (TBA) salt and converted successfully into its more practical sodium salt form after purification.

Correction to "Synthesis of a Biologically Important Adenosine Triphosphate Analogue, ApppD".

[This corrects the article DOI: 10.1021/acsomega.7b00531.

Smart, programmable and responsive injectable hydrogels for controlled release of cargo osteoporosis drugs.

Easy-to-prepare drug delivery systems, based on smart, silica gels have been synthesized, characterized, and studied as hosts in the controlled release of bisphosphonates. They exhibit variable release rates and final % release, depending on the nature of bisphosphonate (side-chain length, hydro-philicity/-phobicity, water-solubility), cations present, pH and temperature. These gels are robust, injectable, re-loadable and re-usable.

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

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.

Synthesis of medronic acid monoesters and their purification by high-performance countercurrent chromatography or by hydroxyapatite.

We achieved the synthesis of important medronic acid monoalkyl esters via the dealkylation of mixed trimethyl monoalkyl esters of medronic acid. Two methods were developed for the purification of medronic acid monoesters: 1) small scale (10-20 mg) purification by using hydroxyapatite and 2) large scale (tested up to 140 mg) purification by high-performance countercurrent chromatography (HPCCC).

Two strategies for the synthesis of the biologically important ATP analogue ApppI, at a multi-milligram scale.

Two strategies for the synthesis of the ATP (adenosine triphosphate) analogue ApppI [1-adenosin-5'-yl 3-(3-methylbut-3-enyl)triphosphoric acid diester] (1) are described. ApppI is an active metabolite of the mevalonate pathway and thus is of major biological significance. Chemically synthezised ApppI was purified by using triethylammonium bicarbonate as the counter ion in ion-pair chromatography and characterized by (1)H, (13)C, (31)P NMR and MS spectroscopical methods.

Structural requirements for bisphosphonate binding on hydroxyapatite: NMR study of bisphosphonate partial esters.

Eighteen different bisphosphonates, including four clinically used bisphosphonate acids and their phosphoesters, were studied to evaluate how the bisphosphonate structure affects binding to bone. Bisphosphonates with weak bone affinity, such as clodronate, could not bind to hydroxyapatite after the addition of one ester group. Medronate retained its ability to bind after the addition of one ester group, and hydroxy-bisphosphonates could bind even after the addition of two ester groups.

Advanced material and approach for metal ions removal from aqueous solutions.

A Novel approach to remove metals from aqueous solutions has been developed. The method is based on a resin free, solid, non-toxic, microcrystalline bisphosphonate material, which has very low solubility in water (59 mg/l to ion free Milli-Q water and 13 mg/l to 3.5% NaCl solution).

Synthesis of triple-bond-containing 1-hydroxy-1,1-bisphosphonic acid derivatives to be used as precursors in "click" chemistry: two examples.

The synthesis of novel (ω-alkynyl-1-hydroxy-1,1-diyl)bisphosphonic acid tetramethyl esters (1a-c), their P,P'-dimethyl esters (2a-c), and two trimethyl ester derivatives (3a and 3b) is reported. The prepared compounds can be attached to many kinds of molecules containing azide (-N3) functionalities using a "click" chemistry approach. As an example, bisphosphonate trimethyl ester 3a and P,P'-dimethyl ester 2b were attached to triethylene glycol to form triethylene glycol-bisphosphonate conjugates 4 and 5 as model compounds for further studies in, for example, nanoparticle targeting.

Firefly luciferase inhibitor-conjugated peptide quenches bioluminescence: a versatile tool for real time monitoring cellular uptake of biomolecules.

In this paper, novel firefly luciferase-specific inhibitor compounds (FLICs) are evaluated as potential tools for cellular trafficking of transporter conjugates. As a proof-of-concept, we designed FLICs that were suitable for solid phase peptide synthesis and could be covalently conjugated to peptides via an amide bond. The spacer between inhibitor and peptide was optimized to gain efficient inhibition of recombinant firefly luciferase (FLuc) without compromising the activity of the model peptides.