Synthesis of inositol phosphate-based competitive antagonists of inositol 1,4,5-trisphosphate receptors.

Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca(2+) channels that are widely expressed in animal cells, where they mediate the release of Ca(2+) from intracellular stores evoked by extracellular stimuli. A diverse array of synthetic agonists of IP3Rs has defined structure-activity relationships, but existing antagonists have severe limitations. We combined analyses of Ca(2+) release with equilibrium competition binding to IP3R to show that (1,3,4,6)IP4 is a full agonist of IP3R1 with lower affinity than (1,4,5)IP3. Systematic manipulation of this meso-compound via a versatile synthetic scheme provided a family of dimeric analogs of 2-O-butyryl-(1,3,4,6)IP4 and (1,3,4,5,6)IP5 that compete with (1,4,5)IP3 for binding to IP3R without evoking Ca(2+) release. These novel analogs are the first inositol phosphate-based competitive antagonists of IP3Rs with affinities comparable to that of the only commonly used competitive antagonist, heparin, the utility of which is limited by off-target effects.Supported by a Senior Investigator Award from the Wellcome Trust 101844 (to C.W.T.), Biotechnology and Biological Sciences Research Council UK and the German Academic Exchange Service (to V.K.). A.E.K. thanks the Research Committee of AUTh for financial support. C.W.T. and V.K. thank Dr S. B. Shears (N.I.E.H.S, U.S.A.) for his helpful advice.This is the final version of the article. It first appeared from the Royal Chemistry Society via http://dx.doi.org/10.1039/C5OB02623

Alkyl and aryl sulfonyl p-pyridine ethanone oximes are efficient DNA photo-cleavage agents

Sulfonyloxyl radicals, readily generated upon UV irradiation of p-pyridine sulfonyl ethanone oxime derivatives, effectively cleave DNA, in a pH independent manner, and under either aerobic or anaerobic conditions. p-Pyridine sulfonyl ethanone oxime derivatives were synthesized from the reaction of p-pyridine ethanone oxime with the corresponding sulfonyl chlorides in good to excellent yields. All compounds, at a concentration of 100 μM, were irradiated at 312 nm for 15 min, after incubation with supercoiled circular pBluescript KS II DNA and resulted in extended single- and double- strand cleavages. The cleavage ability was found to be concentration dependent, with some derivatives exhibiting activity even at nanomolar levels. Besides that, p-pyridine sulfonyl ethanone oxime derivatives showed good affinity to DNA, as it was observed with UV interaction and viscosity experiments with CT DNA and competitive studies with ethidium bromide. The compounds interact to CT DNA probably by non-classical intercalation (i.e. groove-binding) and at a second step they may intercalate within the DNA base pairs. The fluorescence emission spectra of pre-treated EB-DNA exhibited a significant or moderate quenching. Comparing with the known aryl carbonyloxyl radicals the sulfonyloxyl ones are more powerful, with both aryl and alkyl sulfonyl substituted derivatives to exhibit DNA photo-cleaving ability, in significantly lower concentrations. These properties may serve in the discovery of new leads for "on demand" biotechnological and medical applications. © 2016 Elsevier B.V. All rights reserved

Total Synthesis of Enantiopure Potassium Aeshynomate

Potassium aeshynomate (<b>1</b>) is the leaf-opening factor of the nyctinastic plant <i>Aeshynomene indica</i> L. In this article a convenient and efficient strategy for the total synthesis of enantiomerically pure <b>1</b> is described, starting from the l-arabinose derived chiron <i>ent</i>-<b>6</b>. The realized synthetic scheme involves a postcoupling oxidation approach and securely determines the absolute configuration of the targeted natural product, which remained unknown until now

Exploration of the DNA Photocleavage Activity of <i>O</i>-Halo-phenyl Carbamoyl Amidoximes: Studies of the UVA-Induced Effects on a Major Crop Pest, the Whitefly <i>Bemisia tabaci</i>

The DNA photocleavage effect of halogenated O-carbamoyl derivatives of 4-MeO-benzamidoxime under UVB and UVA irradiation was studied in order to identify the nature, position, and number of halogens on the carbamoyl moiety that ensure photoactivity. F, Cl, and Br-phenyl carbamate esters (PCME) exhibited activity with the p-Cl-phenyl derivative to show excellent photocleavage against pBR322 plasmid DNA. m-Cl-PCME has diminished activity, whereas the presence of two halogen atoms reduced DNA photocleavage. The substitution on the benzamidoxime scaffold was irrelevant to the activity. The mechanism of action indicated function in the absence of oxygen, probably via radicals derived from the N-O bond homolysis of the carbamates and in air via hydroxyl radicals and partially singlet oxygen. The UVA-vis area of absorption of the nitro-benzamidoxime p-Cl-PCMEs allowed for the investigation of their potential efficacy as photopesticides under UVA irradiation against the whitefly Bemisia tabaci, a major pest of numerous crops. The m-nitro derivative exhibited a moderate specificity against the adult population. Nymphs were not affected. The compound was inactive in the dark. This result may allow for the development of lead compounds for the control of agricultural insect pests that can cause significant economic damage in crop production

Pyridine and p-Nitrophenyl Oxime Esters with Possible Photochemotherapeutic Activity: Synthesis, DNA Photocleavage and DNA Binding Studies

Compared to standard treatments for various diseases, photochemotherapy and photo-dynamic therapy are less invasive approaches, in which DNA photocleavers represent promising tools for novel “on demand” chemotherapeutics. A series of p-nitrobenzoyl and p-pyridoyl ester conjugated aldoximes, amidoximes and ethanone oximes were subjected to UV irradiation at 312 nm with supercoiled circular plasmid DNA. The compounds which possessed appropriate properties were additionally subjected to UVA irradiation at 365 nm. The ability of most of the compounds to photocleave DNA was high at 312 nm, whereas higher concentrations were required at 365 nm as a result of their lower UV absorption. The affinity of selected compounds to calf-thymus (CT) DNA was studied by UV spectroscopy, viscosity experiments and competitive studies with ethidium bromide (EB) revealing that all compounds interacted with CT DNA. The fluorescence emission spectra of the pre-treated EB-DNA exhibited a moderate to significant quenching in the presence of the compounds indicating the binding of the compounds to CT DNA via intercalation as concluded also by DNA-viscosity experiments. For the oxime esters the DNA photocleavage and affinity studies aimed to clarify the role of the oxime nature (aldoxime, ketoxime, amidoxime) and the role of the pyridine and p-nitrophenyl moieties both as oxime substituents and ester conjugates

Ligand exchange between arylcopper compounds and bis(hypersilyl)tin or bis(hypersilyl)lead: Synthesis and characterization of hypersilylcopper and a stannanediyl complex with a Cu-Sn bond

Bis(hypersilyl)tin (1) and bis(hypersilyl)lead (2) [hypersilyl= Hyp = tris(trimethylsilyl)silyl] undergo ligand exchange reactions with other carbene homologues to yield heteroleptic distannenes or diplumbenes. Here we report the extension of this reaction principle to coordinatively unsaturated arylcopper(I) compounds. The primary reaction products are probably adducts with the carbene homologues as Lewis base and the arylcopper compounds as Lewis acids. This is followed by rearrangement to the adducts HypCu-E-(Hyp)Ar* (E = Sn (6) and Pb (7); Ar* = C(6)H(3)Mes(2)-2,6,) of hypersilylcopper (9) and the heteroleptic stannanediyl or plumbanediyl. The complex may be the final product or may dissociate into its component parts, free hypersilylcopper (9) and the appropriate heteroleptic carbene homologue. The colorless hypersilylcopper forms a trimer (9), in the solid state with short Cu Cu contacts (238.4-241.5 pm). All observed Cu-Si bonds are relatively long. However, shorter distances (234.9-237.4pm) alternate with longer ones (249.2 pm), such that quasi-monomeric hypersilylcopper units can be identified. The dark green complex 6 exhibits a shorter Cu-Si bond (227.3 pm), The Sn-Cu bond length was determined to be 249.9 pm. The turquoise plumbanediyl Pb(Hyp)Ar* (8) is the first strictly monomeric mixed aryl silyl derivative, even in the solid state. The steric repulsions are obviously less than in the parent homoleptic compounds because the Pb-C bond in 8 is shorter (229.0 pm) and the C-Pb-Si angle (109.2 degrees) is markedly smaller