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Ziad T I Alkayar, Iain Coldham
A cascade or domino sequence of condensation of hydroxylamine and an aldehyde to give an oxime, cyclization to a nitrone, and intramolecular 1,3-dipolar cycloaddition has been successfully employed where there is branching at C-4 as a route to the iboga alkaloids. Cyclization occurs with displacement of chloride as a leaving group and intramolecular cycloaddition occurs with an alkene as a dipolarophile. The reaction gives an azabicyclo[2.2.2]octane product containing a fused isoxazolidine as a single stereoisomer and this was converted to an isoquinuclidine that completed a formal synthesis of the alkaloid (±)-19-hydroxyibogamine...
December 12, 2018: Organic & Biomolecular Chemistry
Amit Kumar, Krista Kinneer, Luke Masterson, Ebele Ezeadi, Philip Howard, Herren Wu, Changshou Gao, Nazzareno Dimasi
Experimental procedures and 1 H and 13 C NMR of the heterotrifunctional linker used for preparation of dual drug conjugates and PBD payload are included. Procedure for carrying preparation of antibody linker conjugate via thiol maleimide conjugation and antibody drug conjugates (ADCs) using copper assisted click reaction and oxime ligation, their cell viability assay and western blotting procedures of the resultant conjugates are detailed. Also, reduced mass spectroscopy results and in vitro cytotoxicity of antibody drug conjugates used in this article are shown...
December 2018: Data in Brief
Takeru Miyakoshi, Hiroyuki Konno
Many pyridine syntheses have been developed to date. In this study, we focused on pyridine synthesis with 1,5-diketone derivatives and hydroxylamine. Treatment of simple 1,5-diketoalkanes and hydroxylamine in basic or acidic conditions gave aldol adducts without any pyridine compounds. However, by screening the reaction conditions, we found that acidic conditions produced via the formation of oxime intermediates derived from 1,5-diketoalkanes allowed the formation of the corresponding pyridine derivatives. This is the first example of 2,4,6-trialkylpyridine synthesis from quite simple 1,5-diketoalkanes...
December 5, 2018: Organic & Biomolecular Chemistry
Verena Hampel, Martin Knaus, Jürgen Schäfer, Frederic Beugnet, Steffen Rehbein
The efficacy of NexGard® and NexGard Spectra® against sarcoptic mange in dogs was evaluated in a clinical field study. Skin scrapings from dogs presenting signs suggestive of sarcoptic mange were examined to confirm infestation. A total of 106 dogs were screened at eight sites in Portugal and Germany. In all, 80 dogs that had demonstrated ≥5 live Sarcoptes mites in five skin scrapings were enrolled, scored for specific clinical signs (pruritus; papules and crusts; alopecia), and allocated at random to receive either NexGard® or NexGard Spectra® twice, one month apart per label instructions...
2018: Parasite: Journal de la Société Française de Parasitologie
Mahmoud S Abdelbaset, Mohamed Abdel-Aziz, Gamal El-Din A Abuo-Rahma, Mostafa H Abdelrahman, Mohamed Ramadan, Bahaa G M Youssif
Novel quinoline derivatives carrying nitrones and oxime as nitric oxide donors were prepared and characterized using different spectroscopic techniques. Nitrones can release nitric oxide in larger amounts compared to corresponding oximes. Antiproliferative screening results showed that the 2-benzylthioquinoline nitrones 6e and 6f and the 2-methylthio analogues 6g and 6h exhibited promising antiproliferative activity especially against leukemia and colon cancer cell lines. Compounds 6c, 6e, and 6f exhibited higher potency as anticancer agents compared to doxorubicin, with IC50 ranging from 0...
November 30, 2018: Archiv der Pharmazie
Mingchuang He, Zhaohua Yan, Fuyuan Zhu, Sen Lin
A copper-catalyzed iminyl radical-mediated C-C bond cleavage/cross-coupling tandem reaction of cyclobutanone oxime esters with aryl thiols in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature was developed and aryl cyanopropyl sulfides were smoothly synthesized in 20-88% yields. By altering copper reagent and the molar ratio of cyclobutanone oxime ester/aryl thiol/DBU, substitutional products N-arylthio cyclobutanone imines were selectively generated in 50-91% yields. Using this protocol, C-S bond and N-S bond formations using aryl thiols as sulfur sources were realized under very mild conditions without the use of photocatalysis and electrocatalysis techniques...
November 30, 2018: Journal of Organic Chemistry
Eloi P Coutant, Vincent Hervin, Glwadys Gagnot, Candice Ford, Racha Baatallah, Yves L Janin
We have explored here the scope of the age-old diethyl malonate-based accesses to α-amino esters involving Knoevenagel condensations of diethyl malonate on aldehydes, reductions of the resulting alkylidenemalonates, the preparation of the corresponding α-hydroxyimino esters and their final reduction. This synthetic pathway turned out to be general although some unexpected limitations were encountered. The synthetic modifications of some of the intermediates - using Suzuki-Miyaura coupling or cycloadditions - before undertaking the oximation step - provided accesses to further α-amino esters...
2018: Beilstein Journal of Organic Chemistry
Ronald B Pringle, Edward C Meek, Howard W Chambers, Janice E Chambers
The nerve agents are extremely toxic organophosphates which lead to massive inhibition of acetylcholinesterase (AChE) in both the central and peripheral nervous systems. The currently approved pyridinium oxime reactivators of organophosphate-inhibited AChE (eg, 2-PAM in the United States) cannot penetrate the blood-brain barrier because of the permanent positive charge in the pyridinium ring. Therefore these current oximes cannot rescue inhibited AChE in the brain. Our laboratories have invented and patented a platform of substituted phenoxyalkyl pyridinium oximes that have been tested for efficacy as therapy within the brains of adult male rats which were challenged with a high sublethal dosage of highly relevant surrogates of sarin (nitrophenyl isopropyl methylphosphonate, NIMP) and VX (nitrophenyl ethyl methylphosphonate, NEMP)...
December 1, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
Simone K Huber, Georg Höfner, Klaus T Wanner
In this study, pyrrolidine-3-acetic acid derived oxime libraries were applied to the concept of library screening by MS Binding Assays, as a powerful technique to reveal new potent murine γ-aminobutyric acid transporter subtype (mGAT1) inhibitors. Library generation was accomplished by condensation of an excess of pyrrolidine-3-acetic acid bearing a hydroxylamine unit with various libraries, each composed of eight different aldehydes. The oxime libraries have been screened by means of competitive MS Binding Assays and, as a consequence, the most active libraries were further investigated through deconvolution experiments to identify single oximes responsible for the observed activity on the target mGAT1...
November 28, 2018: ChemMedChem
Jiahua Cui, Xu Zhang, Guang Huang, Qijing Zhang, Jinyun Dong, Gege Sun, Qingqing Meng, Shao-Shun Li
In order to reduce the pervasive toxicity of natural shikonin, alkannin and their synthetic analogues and to enhance the selectivity of these chemotherapeutics towards cancer cells, a novel 5,8-dimethyl alkannin oxime derivative (DMAKO-20) was designed, synthesized and evaluated for its strong antitumor activity both in vitro and in vivo. It showed potent growth inhibitory effects against HCT-15, HCT-116 and K562 cells (IC50 < 1μM), moderate anti-proliferative activity towards MDA-MB-231, HepG2, PANC, Bel7402 and MGC803 cancer cells (IC50 < 10μM), and was nontoxic to the human normal VEC and HSF cells...
November 27, 2018: Molecular Pharmaceutics
Yasumasa Kuwahara, Yayoi Ichiki, Masashi Morita, Tsutomu Tanabe, Yasuhisa Asano
The defense allomones of two haplodesmid millipedes, Eutrichodesmus elegans and E. armatus (Polydesmida: Haplodesmidae), are known as a mixture of the following three nitro compounds: (2-nitroethyl)benzene and ( Z )- and ( E )-(2-nitroethenyl)benzenes. Administrations of a mixture of 2 H-labeled ( Z )- and ( E )-phenylacetaldoximes and of 2 H-labeled phenylacetonitrile as precursors resulted in the same production of three 2 H-labeled nitro compounds, [2'-nitroethyl][2,3,4,5,6-2 H5 ]benzene and [( Z )- and ( E )-2'-nitroethenyl][2,3,4,5,6-2 H5 ]benzenes, in both species...
November 20, 2018: Journal of Pesticide Science
Zeynep Özdemir, Suat Sari, Arzu Karakurt, Sevim Dalkara
Hit, Lead & Candidate Discovery Preclinical Research & Development In this study, 15 new oxime ether derivatives were synthesized and their anticonvulsant activities were screened in vivo. The compounds were synthesized by the reaction of various alkyl halides with 1-(2-naphthyl)-2-(1H-imidazol-1-yl)ethanone oxime. Their anticonvulsant activities were determined using acute (maximal electroshock, subcutaneous metrazol [SCM], and 6 Hz seizure test) and chronic (corneal-kindled mouse) seizure models, their neurotoxic effects were evaluated by models of behavioral toxicity according to the Epilepsy Therapy Screening Program protocol of the NIH...
November 25, 2018: Drug Development Research
Rubina Siddiqui, Zafar Saied Saify, Shamim Akhter, Syed-Muhammad Ghufran Saeed, Shazia Haider, Qurratul-Ain Leghari
In search of potent molecules having antioxidant activity the present work was designed to synthesize 2, 6-diphenylpiperidine-4-one compounds (1a and 1b) and their imine derivatives (2a, 2b, 3a, and 3b). Compounds 1a and 1b were synthesized by Mannich condensation reaction. The method was found to be simple, convenient with high yield and products were easily separated. Compounds 1a and 1b serves as an intermediate for the preparation of highly functionalized novel imine derivatives. Oxime (2a, 2b) and carbothioamide (3a, 3b) derivatives of 1a and 1b compounds were produced by condensation reaction with hydroxyl amine hydrochloride and thiosemicarbazide respectively...
November 2018: Pakistan Journal of Pharmaceutical Sciences
Yue Yuan, Lalita Subedi, Daesung Lim, Jae-Kyung Jung, Sun Yeou Kim, Seung-Yong Seo
Novel isoxazole and pyrazole analogs based on natural biphenyl-neolignan honokiol were synthesized and evaluated for their inhibitory activities against nitric oxide production in lipopolysaccharide-activated BV-2 microglial cells. The isoxazole skeleton was constructed via nitrile oxide cycloaddition from oxime 3 and pyrazole was generated by condensation of 4-chromone and alkylhydrazine. Among the analogs, 13b and 14a showed stronger inhibitory activities with IC50 values of 8.9 and 1.2 µM, respectively, than honokiol...
November 9, 2018: Bioorganic & Medicinal Chemistry Letters
Zhongwei Zhu, Alexander M Genaev, George E Salnikov, Konstantin Yu Koltunov
1-Nitronaphthalene smoothly reacts with benzene and undergoes selective reduction with cyclohexane in the presence of aluminum chloride to give 2,4,4-triphenyl-3,4-dihydronaphthalen-1(2H)-one oxime and 5,6,7,8-tetrahydro-1-naphthylamine, respectively. The mechanistic aspects of these and related reactions are discussed on the basis of DFT, providing insight into the protonation behavior of 1-nitronaphthalene coordinated to AlCl3.
November 21, 2018: Organic & Biomolecular Chemistry
Zrinka Kovarik, Jarosław Kalisiak, Nikolina Maček Hrvat, Maja Katalinić, Tamara Zorbaz, Suzana Žunec, Carol Green, Zoran Radić, Valery V Fokin, K Barry Sharpless, Palmer Taylor
Acetylcholinesterase (AChE), an enzyme that degrades the neurotransmitter acetylcholine, when covalently inhibited by organophosphorus compounds (OPs), such as nerve agents and pesticides, can be reactivated by oximes. However, tabun remains among the most dangerous nerve agents due to the low reactivation efficacy of standard pyridinium aldoxime antidotes. Therefore, finding an optimal reactivator for prophylaxis against tabun toxicity and for post-exposure treatment is a continued challenge. In this study, we analyzed the reactivation potency of 111 novel nucleophilic oximes mostly synthesized using the CuAAC triazole ligation between alkyne and azide building blocks...
November 20, 2018: Chemistry: a European Journal
Andrew J Franjesevic, Sydney B Sillart, Jeremy M Beck, Shubham Vyas, Christopher S Callam, Christopher M Hadad
Organophosphorus (OP) nerve agents and pesticides present significant threats to civilian and military populations. OP compounds include the nefarious G and V chemical nerve agents, but more commonly, civilians are exposed to less toxic OP pesticides, while resulting in the same negative toxicological effects and thousands of deaths on an annual basis. After decades of research, no new therapeutics have been realized since the mid-1900s. Upon phosphylation of the catalytic serine residue, known as inhibition, there is an accumulation of acetylcholine (ACh) in the brain synapses and neuromuscular junctions, leading to a cholinergic crisis and eventually death...
November 16, 2018: Chemistry: a European Journal
Ligia R Gomes, Marcus V N de Souza, Cristiane F Da Costa, James L Wardell, John Nicolson Low
The crystal structures of four ( E )-meth-oxy-benzaldehyde oxime derivatives, namely (2-meth-oxy-benzaldehyde oxime, 1 , 2,3-di-meth-oxy-benzaldehyde oxime, 2 , 4-di-meth-oxy-benzaldehyde oxime, 3 , and 2,5-di-meth-oxy-benzaldehyde oxime, 4 , are discussed. The arrangements of the 2-meth-oxy group and the H atom of the oxime unit are s-cis in compounds 1 - 3 , but in both independent mol-ecules of compound 4 , the arrangements are s-trans . There is also a difference in the conformation of the two mol-ecules in 4 , involving the orientations of the 2- and 5-meth-oxy groups...
November 1, 2018: Acta Crystallographica. Section E, Crystallographic Communications
Reuel L de Paula, Joyce S F D de Almeida, Samir F A Cavalcante, Arlan S Gonçalves, Alessandro B C Simas, Tanos C C Franca, Martin Valis, Kamil Kuca, Eugenie Nepovimova, José M Granjeiro
The present work aimed to compare the small, neutral and monoaromatic oxime, isatin-3-oxime (isatin-O), to the commercial ones, pralidoxime (2-PAM) and obidoxime, in a search for a new potential reactivator for acetylcholinesterase (AChE) inhibited by the pesticide paraoxon (AChE/POX) as well as a novel potential scaffold for further synthetic modifications. The multicriteria decision methods (MCDM) allowed the identification of the best docking poses of those molecules inside AChE/POX for further molecular dynamic (MD) studies, while Ellman's modified method enabled in vitro inhibition and reactivation assays...
November 12, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Sabine Schuster, Beáta Biri-Kovács, Bálint Szeder, László Buday, János Gardi, Zsuzsanna Szabó, Gábor Halmos, Gábor Mező
Receptors for gonadotropin releasing hormone (GnRH) are highly expressed in various human cancers including breast, ovarian, endometrial, prostate and colorectal cancer. Ligands like human GnRH-I or the sea lamprey analogue GnRH-III represent a promising approach for the development of efficient drug delivery systems for targeted tumor therapy. Here, we report on the synthesis and cytostatic effect of 14 oxime bond-linked daunorubicin GnRH-III conjugates containing a variety of unnatural amino acids within the peptide sequence...
November 9, 2018: Pharmaceutics
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