A Naphthalimide‐Based Cd2+ Fluorescent Probe with Carbamoylmethyl Groups Working as Chelators and PET‐Promoters under Neutral Conditions

We have developed a novel naphthalimide‐based Cd²⁺ fluorescent probe ( 1 ), featuring almost no background response, high sensitivity and selectivity toward Cd²⁺ through its high association constant [K=(2.10±0.423)×10⁶], and a practical working pH range. Membrane‐permeability was conferred on 1 by replacing the imide and amide substituents with n‐butyl groups, and hence the derivative ( 4 ) has found practical utility on fluorescent imaging of Cd²⁺ in HeLa cells. Comparison of fluorescent properties between various compounds derived from 1 has demonstrated that the carbamoylmethyl groups in 1 function not only as Cd²⁺ chelators but also as promoters for photoinduced electron transfer (PET) by lowering the basicity of the two tertiary amino groups. As a result, 1 and 4 exhibited highly practical performance as Cd²⁺ probes under neutral conditions.     

Practical and efficient synthesis of the (R)-atropisomer of a 4-phenyl 1,2,4-triazole derivative as a selective GlyT1 inhibitor

Herein we describe a novel and efficient method for synthesizing the (R)-atropisomer of 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile 1, a novel GlyT1 inhibitor. The diastereomeric salt formation of 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzoic acid 7 with (1R,2S)-(?)-2-amino-1,2-diphenylethanol afforded the desired (R)-atropisomer. We also report the determination of the absolute configuration of (R)-7 by powder X-ray diffraction.     

Local response dispersion method in periodic systems: Implementation and assessment

We report the implementation of the local response dispersion (LRD) method in an electronic structure program package aimed at periodic systems and an assessment combined with the Perdew–Burke–Ernzerhof (PBE) functional and its revised version (revPBE). The real‐space numerical integration was implemented and performed exploiting the electron distribution given by the plane‐wave basis set. The dispersion‐corrected density functionals revPBE+LRD was found to be suitable for reproducing energetics, structures, and electron distributions in simple substances, molecular crystals, and physical adsorptions. © 2014 Wiley Periodicals, Inc.     

Isolation of amoenamide A and five antipodal prenylated alkaloids from Aspergillus amoenus NRRL 35600

A new prenylated alkaloid, Amoenamide A (6), was isolated from the fungus Aspergillus amoenus NRRL 35600. Previously, 6 was postulated to be a precursor of Notoamide E4 (21) converted from Notoamide E (16), which was a key precursor of the prenylated indole alkaloids in the fungi of the genus Aspergillus. We previously succeeded in the isolation of two pairs of antipodes, Stephacidin A (1) and Notoamide B (2), from A. amoenus and A. protuberus MF297-2 and expected the presence of other antipodes in the culture of A. amoenus. We here report five new antipodes (7–11) along with a new metabolite (12), which was isolated as a natural compound for the first time, from A. amoenus.     

Enantioselective Synthesis of Chiral Isotopomers of 1‐Alkanols by a ZACA–Cu‐Catalyzed Cross‐Coupling Protocol

Chiral compounds arising from the replacement of hydrogen atoms by deuterium are very important in organic chemistry and biochemistry. Some of these chiral compounds have a non‐measurable specific rotation, owing to very small differences between the isotopomeric groups, and exhibit cryptochirality. This particular class of compounds is difficult to synthesize and characterize. Herein, we present a catalytic and highly enantioselective conversion of terminal alkenes to various β and more remote chiral isotopomers of 1‐alkanols, with ≥99 % enantiomeric excess (ee), by the Zr‐catalyzed asymmetric carboalumination of alkenes (ZACA) and Cu‐catalyzed cross‐coupling reactions. ZACA‐in situ iodinolysis of allyl alcohol and ZACA‐in situ oxidation of TBS‐protected ω‐alkene‐1‐ols protocols were applied to the synthesis of both (R)‐ and (S)‐difunctional intermediates with 80–90 % ee. These intermediates were readily purified to provide enantiomerically pure (≥99 % ee) compounds by lipase‐catalyzed acetylation. These functionally rich intermediates serve as very useful synthons for the construction of various chiral isotopomers of 1‐alkanols in excellent enantiomeric purity (≥99 % ee) by introducing deuterium‐labeled groups by Cu‐catalyzed cross‐coupling reactions without epimerization.     

Ultrasensitive method to quantify intracellular zidovudine mono‐, di‐ and triphosphate concentrations in peripheral blood mononuclear cells by liquid chromatography–tandem mass spectrometry

Although zidovudine (AZT) is not the preferred antiretroviral drug for adult HIV‐infected patients, it is still widely used in infants for both prevention of mother‐to‐infant HIV‐1 transmission and treatment of HIV‐infected children. However, it is difficult to measure intracellular concentrations of AZT metabolites in small blood samples due to their extremely low concentrations in peripheral blood mononuclear cells and interference by endogenous nucleotide triphosphates, residual plasma phosphates and electrolytes. We developed an ultrasensitive assay using liquid chromatography–tandem mass spectrometry (LC–MS/MS) for measurement of intracellular concentrations of zidovudine (AZT)‐monophosphate (AZT‐MP), ‐diphosphate (AZT‐DP) and ‐triphosphate (AZT‐TP). The high sensitivity was due to the improvement of peripheral blood mononuclear cells extraction for complete removal of plasma and electrolytes, alkalization of LC buffer and use of alkaline‐stable high performance liquid chromatography column and tetrabutylammonium hydroxide as the ion pair. Using this method, the lower limits of quantification of AZT, AZT‐MP, ‐DP and ‐TP were 6, 6, 10 and 10 fmol per sample, respectively. Accuracy ranged 89–115% and precision was lower than 15% in the quantification range of 6–6000 fmol/sample for plasma AZT and intracellular AZT‐MP and 10–10 000 fmol/sample for AZT‐DP and ‐TP. The validation parameters met the international requirements. Among nine AZT‐treated HIV‐infected adult patients, five had low AZT‐TP levels (<10 fmol/10⁶ cells). Our assay has high sensitivity and is advantageous for evaluation of AZT phosphates in children and infants based on minimum blood sampling requirement. Copyright © 2015 John Wiley & Sons, Ltd.     

Inactivation of Saccharomyces cerevisiae by ultrasonic irradiation

We have investigated the inactivation of Saccharomyces cerevisiae (yeast cells) by ultrasonic irradiation. The amplitude on the vibration face contacting the sample solution was used as an indication of the ultrasonic power intensity. The effects of the amplitude on the vibration face and the initial cell numbers on the sonolytic inactivation of yeast cells have been investigated using a horn-type sonicator (27.5 kHz). The inactivation of the yeast cells by ultrasonic irradiation shows pseudo first-order behavior. The inactivation rate constant varied from 0.0007 to 0.145 s(-1) when the amplitude on the vibration face was in the range of 1-7 microm(p-p). The change in the inactivation rate constant as a function of the amplitude on the vibration face was similar to that of the OH radical formation rate under the same conditions. The threshold of this sonicator was 3 microm(p-p) with the amplitude on the vibration face. The initial cell numbers (from 10(2) to 10(5) mL(-1)) had an influence on the inactivation of the yeast cells by ultrasonic irradiation. The inactivation rate constants varied from 0.023 to 6.4 x 10(-3) s(-1), and the inactivation by ultrasonic irradiation was fastest at the lowest initial cell numbers. In a squeeze-film-type sonicator (26.6 kHz), 90% inactivation of the yeast cells was achieved by ultrasonic irradiation for 60 min.     

Collective Synthesis and Biological Evaluation of Tryptophan‐Based Dimeric Diketopiperazine Alkaloids

A concise two one‐pot synthesis of WIN 64821, eurocristatine, 15,15′‐bis‐epi‐eurocristatine, ditryptophenaline, ditryptoleucine A, WIN 64745, cristatumin C, asperdimin, naseseazine A, and naseseazine B is detailed, based on a unique bioinspired dimerization reaction of tryptophan derivatives in aqueous acidic solution and a one‐pot procedure for the construction of diketopiperazine rings. Total yields of these alkaloid syntheses were from 10 up to 27 %. In addition, 1′‐(2‐phenylethylene)‐ditryptophenaline was synthesized by using three one‐pot operations. The studies detailed herein provided synthesized natural products for inhibitory activities of ubiquitin‐specific protease 7 (USP7) and foam cell formation in macrophages. The newly listed biological evaluation for tryptophan‐based dimeric diketopiperazine alkaloids discovered 15,15′‐bis‐epi‐eurocristatine, 1′‐(2‐phenylethylene)‐ditryptophenaline, and WIN 64745 as new drug candidates.     

Taichunamides: Prenylated Indole Alkaloids from Aspergillus taichungensis (IBT 19404)

Seven new prenylated indole alkaloids, taichunamides A–G, were isolated from the fungus Aspergillus taichungensis (IBT 19404). Taichunamides A and B contained an azetidine and 4‐pyridone units, respectively, and are likely biosynthesized from notoamide S via (+)‐6‐epi‐stephacidin A. Taichunamides C and D contain endoperoxide and methylsulfonyl units, respectively. This fungus produced indole alkaloids containing an anti‐bicyclo[2.2.2]diazaoctane core, whereas A. protuberus and A. amoenus produced congeners with a syn‐bicyclo[2.2.2]diazaoctane core. Plausible biosynthetic pathways to access these cores within the three species likely arise from an intramolecular hetero Diels–Alder reaction.