Acetohydroxamatoiron(III) Complexes: Thermodynamics of Formation and Temperature Dependent Speciation

Studies of the thermodynamics of formation of the acetohydroxamatoiron(III) complexes were carried out in acidic media at temperatures ranging from 293 to 323 K. Through the isolation of the unique UV–visible spectra of all three complexes, it was possible to determine their formation constants and deduce enthalpies and entropies of formation as well as their molar absorptivities. The enthalpies of formation of the mono-, bis- and trisacetohydroxamatoiron(III) complexes were found to be −56.4, −17.09 and +19.74 kJ⋅mol⁻¹, respectively. Following the determination of the enthalpy and entropy of formation of these complexes, speciation diagrams were calculated for the complexes at temperatures ranging from 293 to 323 K.     

Validation of a simple HPLC method for assay of haplamine and its metabolites in plasma suitable for pharmacokinetic application in rats

A simple HPLC method with ultraviolet detection has been developed and validated for the simultaneous determination of haplamine and its metabolites (trans/cis-3,4-dihydroxyhaplamine) in rat. A liquid-liquid extraction was used to extract the compounds from rat plasma. The analysis was performed on a C(18) Nucleosil Nautilus column. The mobile phase consisted of water (A) and a mixture of methanol and acetonitrile (85:15; v/v) (B) used in gradient mode (38-40% B for 10 min, 40-58% B for 49 min, 58-38% B for 1 min, and 38% for 5 min) pumped at 1 mL/min. The calibration curves showed good linearity with correlation coefficients greater than 0.999 for the analytes in the investigated concentration range. The lower limit of detection was 0.007, 0.008 and 0.009 microg/mL and the lower limit of quantification was 0.014, 0.017 and 0.018 microg/mL for haplamine, and trans/cis-3,4-dihydroxyhaplamine, respectively. The method was applied to a preliminary pharmacokinetic study in rats. This method proved to meet fully the standards required of experimental pharmacokinetic studies and should be used in further preclinical investigation.     

Natural products as an inspiration in the diversity-oriented synthesis of bioactive compound libraries

The purpose of diversity-oriented synthesis is to drive the discovery of small molecules with previously unknown biological functions. Natural products necessarily populate biologically relevant chemical space, since they bind both their biosynthetic enzymes and their target macromolecules. Natural product families are, therefore, libraries of pre-validated, functionally diverse structures in which individual compounds selectively modulate unrelated macromolecular targets. This review describes examples of diversity-oriented syntheses which have, to some extent, been inspired by the structures of natural products. Particular emphasis is placed on innovations that allow the synthesis of compound libraries that, like natural products, are skeletally diverse. Mimicking the broad structural features of natural products may allow the discovery of compounds that modulate the functions of macromolecules for which ligands are not known. The ability of innovations in diversity-oriented synthesis to deliver such compounds is critically assessed.     

Pyrroles as antioxidants: solvent effects and the nature of the attacking radical on antioxidant activities and mechanisms of pyrroles, dipyrrinones, and bile pigments

The absolute rate constants, k(inh), and stoichiometric factors, n, of pyrroles, 2-methyl-3-ethylcarboxy-4,5-di-p-methoxyphenylpyrrole, 6, 2,3,4,5-tetraphenylpyrrole, 7, and 2,3,4,5-tetra-p-methoxyphenylpyrrole, 8, compared to the phenolic antioxidant, di-tert-butylhydroxyanisole, DBHA, during inhibited oxidation of cumene initiated by AIBN at 30 degrees C gave the relative antioxidant activities (k(inh)) DBHA > 8 > 7 > 6 and n = 2, whereas in styrene, 8 > DBHA. These results are explained by hydrogen atom transfer, HAT, from the N-H of pyrroles to ROO(*) radicals. The k(inh) values in styrene of dimethyl esters of the bile pigments of bilirubin ester (BRDE), of biliverdin ester (BVDE), and of a model compound (dipyrrinone, 1) gave k(inh) in the order pentamethylhydroxychroman (PMHC) > BRDE > 1 > BVDE. These antioxidant activities for BVDE and the model compound, 1, and PMHC dropped dramatically in the presence of methanol due to hydrogen bonding at the pyrrolic N-H group. In contrast the k(inh) of BRDE increased in methanol. We now show that pyrrolic compounds may react by HAT, proton-coupled electron transfer, PCET, or single electron transfer, SET, depending on their structure, the nature of the solvent, and the attacking radical. Compounds BVDE and 1 react by the HAT or PCET pathway (HAT/PCET) in styrene/chlorobenzene with ROO(*) and with the DPPH(*) radical in chlorobenzene according to N-H/N-D kH/kD of 1.6, whereas the DKIE with BRDE was only 1.2 with ROO(*). The antioxidant properties of polypyrroles of the BVDE class and model compounds (e.g., 1) are controlled by intramolecular H bonding which stabilizes an intermediate pyrrolic radical in HAT/PCET. According to kinetic polar solvent effects on the monopyrrole, 8, and BRDE, which gave increased rates in methanol, some pyrrolic structures are also susceptible to SET reactions. This conclusion is supported by some calculated ionization potentials. The antioxidant mechanism for BRDE with peroxyl radicals is described by the PCET reaction. Experiments using the 2,6-di-tert-butyl-4-(4'-methoxyphenyl)phenoxyl radical (DBMP(*)) showed this to be a better radical to monitor HAT activities in stopped-flow kinetics compared to the use of the more popular DPPH(*) radical.     

A computational study of chlorocarbene additions to cyclooctyne

Dichloro- and phenylchlorocarbene (CCl2 and PhCCl) add to cyclooctyne via a barrierless process (MP2/6-311+G*, B3LYP/6-311+G*, B3LYP/6-31G*) to yield the expected corresponding cyclopropene adducts. A three-dimensional potential energy surface (PES) for CCl2 addition to cyclooctyne (B3LYP/6-31G*) shows the formation of the cyclopropene product and also possible formation of a vinylcarbene. Residing in a shallow energy well, the vinylcarbene easily rearranges to the cyclopropene product, or to an exocyclic vinyl bicyclo[3.3.0]octane. Although the calculated three-dimensional PES indicates possible dynamic control of the cyclooctyne-chlorocarbene system through the putative formation of a vinylcarbene (in addition to the expected cyclopropene), additional calculations and preliminary experimental work show paths through the vinylcarbene to be unlikely. If the additions of chlorocarbenes to cyclooctyne are controlled by reaction dynamics, we predict that the vast majority of the reactions proceed via traditional carbene cycloaddition with only a very minor amount of products formed from the alternative pathway.     

2-Position base-modified analogues of adenophostin A as high-affinity agonists of the D-myo-inositol trisphosphate receptor: in vitro evaluation and molecular modeling

Adenophostin A (AdA) is a potent agonist of the d-myo-inositol 1,4,5-trisphosphate receptor (Ins(1,4,5)P3R). Various 2-aminopurine analogues of AdA were synthesized, all of which (guanophostin 5, 2,6-diaminopurinophostin 6, 2-aminopurinophostin 7, and chlorophostin 8) are more potent than 2-methoxy-N6-methyl AdA, the only benchmark of this class. The 2-amino-6-chloropurine nucleoside 11, from Vorbrüggen condensation of 2-amino-6-chloropurine with appropriately protected disaccharide, served as the advanced common precursor for all the analogues. Alcoholysis provided the precursor for 5, ammonolysis at high temperature the precursor for 6, and ammonolysis under mild conditions the precursor for synthesis of 7 and 8. For 8, the debenzylation of precursor leaving the chlorine untouched was achieved by judicious use of BCl3. The reduced potency of chlorophostin 8 and higher potency of guanophostin 5 in assays of Ca2+ release via recombinant Ins(1,4,5)P3R are in agreement with our model suggesting a cation-pi interaction between AdA and Ins(1,4,5)P3R. The similar potencies of 2,6-diaminopurinophostin (6) and 2-aminopurinophostin (7) concur with previous reports that the 6-NH2 moiety contributes negligibly to the potency of AdA. Molecular modeling of the 2-amino derivatives suggests an interaction between the carboxylate side chain of Glu505 of the receptor and the 2-NH2 of the ligand, but for 2-methoxy-N6-methyl AdA the carboxylate group of Glu505 is deflected away from the methoxy group. A helix-dipole interaction between the 1-phosphate of Ins(1,4,5)P3 and the 2'-phosphate of AdA with alpha-helix 6 of Ins(1,4,5)P3R is postulated. The results support a proposed model for high-affinity binding of AdA to Ins(1,4,5)P3R.     

Bis(pyrazole)- and bis(pyrazolyl)-palladium complexes as phenylacetylene polymerization catalysts

Two types of pyrazole-based palladium complexes were used to catalyze the polymerization of phenylacetylene. Catalysts with electron-withdrawing linkers, [{1,3-(3,5-R₂pzCO)₂C₆H₄}Pd₂Cl₂(μ-Cl)₂] (R = ^tBu (1), Ph (2), Me (3), [{2,6-(3,5-R₂pzCO)₂C₅H₃N)}PdCl₂] (R = ^tBu (4), Me (5)), show high conversion; whilst those with simple pyrazole ligands, [(3,5-R₂pz)₂PdCl₂] (R = H (6), Me (7), ^tBu (8)), [(3,5-^tBu₂pz)₂PdCl(Me)] (9), have much lower conversions. Conversion greatly improved when 9 was used to catalyze the co-polymerization of sulfur dioxide and phenylacetylene. Both types of catalysts produce predominantly trans–cisoidal polyphenylacetylene.     

Five Years of ChemRxiv: Where We Are and Where We Go From Here**

ChemRxiv was launched on August 15, 2017 to provide researchers in chemistry and related fields a home for the immediate sharing of their latest research. In the past five years, ChemRxiv has grown into the premier preprint server for the chemical sciences, with a global audience and a wide array of scholarly content that helps advance science more rapidly. On the service's fifth anniversary, we would like to reflect on the past five years and take a look at what is next for ChemRxiv.     

Electrochemical sensing of heavy metals in biological media: A review

Trace metals are required in the body as they play a significant role in several biochemical processes. Moreover, certain heavy metals are beneficial at appropriate levels. Copper (Cu), for example, is essential for red blood cell formation, bone strength, and infant growth. Despite these fundamental roles, Cu can become toxic at high levels. Other heavy metals such as lead (Pb), cadmium (Cd), manganese (Mn), and mercury (Hg), have been identified to cause acute and chronic health complications. For these reasons, rapid, real-time quantification of such metals in biological media is of interest to improving human health outcomes. Electrochemical methods offer numerous advantages, such as portability, capability to be miniaturized, low cost, and ease-of-use. In this review, we examine recent developments in electrochemical sensing for the detection of heavy metals in biological media. To meet the requirements for inclusion in this review, the electrochemical sensor must have been evaluated in biological media (blood, serum, sweat, saliva, urine, brain tissue/cells). Several applications are explored to examine recent advancements in electrochemical sensing within these matrices. Addressing the challenges through materials, device, and system innovations, it is expected that electrochemical sensing of heavy metals in biological media will facilitate future diagnoses and treatments in healthcare.