- Photolysis of 3-(2-Formylphenyl)-3-chlorodiazirine in an Ar Matrix at Low Temperature
-
Photolysis of 3-(2-formylphenyl)-3-chlorodiazirine in an Ar matrix at 13 K was monitored by IR and UV-vis spectroscopies. Characterization of the products was carried out by comparing the spectra with the theoretical IR spectra obtained by using DFT, which suggested that anti,anti-2-formylphenyl(chloro)carbenes (a,a-2), ketenes (syn- and anti-3), chlorobenzocyclobutenone (4), and chloroisobenzofurane (5) were formed. This indicates that carbene 2 interacts with both hydrogen and oxygen in the formyl group. When the matrix containing a,a-2 was allowed to stand in the dark at 13 K, a gradual increase of the band due to anti-ketene 3 at the expense of 2 was observed. In contrast to its protio analogue, the deuterated carbene 2-d showed almost no changes either for the decay of 2-d or the growth of 3-d within the time range where the protio analogue appreciably decayed. These observations are interpreted in term of a quantum mechanical tunneling mechanism.
- Nakane, Norio,Enyo, Tomonori,Tomioka, Hideo
-
-
Read Online
- The structures of several modified isoindolines, the building blocks of phthalocyanines
-
This report presents the single crystal X-ray structures of several substituted isoindolines that have been frequently used as starting materials for phthalocyanines, phthalocyanine analogs and related chelates. The structures of 1,3-diiminoisoindoline (1), 1,3-bis(hydroxyimino)isoindoline (2), 1,4-diaminophthalazine (3), 1,1,3-trichloroisoindoline (4) and 3-imino-1-oxoisoindoline (5) are reported; compounds 2 and 3 are synthesized from diiminoisoindoline (1) and 4 and 5 are produced from phthalimide. All five compounds are planar macrocycles, and localization of double bonds can be readily determined. We elucidated one of the known structures of 1 at low temperature, and observed two additional new structures of 1. For the crystal forms of 1 and compounds 2, 3, and 5, hydrogen bonding in the solid state was observed. Compounds 1, 2 and 3 form extended hydrogen bonded arrays in the solid state, whereas 5 forms discrete hydrogen bonded dimers.
- Engle, James T.,Allison, Ashley N.,Standard, Joshua M.,Tamgho, Ingrid-Suzy,Ziegler, Christopher J.
-
-
Read Online
- Cyclic acyl amidines as unexpected C4-donors for fully substituted pyridine ring formation in the base mediated reaction with malononitrile
-
A new one-step, pseudo four-component approach for the synthesis of fully substituted pyridines via ring-opening of the cyclic acyl amidine of 3-amino-1H-isoindol-1-one and its aza-analogues during the reaction with malononitrile in the presence of sodium methoxide, followed by pyridine ring closure is reported. This method allows the one-step preparation of previously unknown 2-(pyridin-4-yl)(hetero)aryl carboxamides in good yields under mild reaction conditions.
- Tkachuk, Volodymyr,Merkulova, Vladyslava,Omelchenko,Arrault, Axelle,Hordiyenko, Olga
-
-
Read Online
- Discovery of a Potent and Orally Bioavailable Hypoxia-Inducible Factor 2α (HIF-2α) Agonist and Its Synergistic Therapy with Prolyl Hydroxylase Inhibitors for the Treatment of Renal Anemia
-
Activation of hypoxia-inducible factor 2 (HIF-2) has emerged as a potent renal anemia treatment strategy. Here, the benzisothiazole derivative 26 was discovered as a novel HIF-2α agonist, which first demonstrated nanomolar activity (EC50 = 490 nM, Emax = 349.2%) in the luciferase reporter gene assay. Molecular dynamics simulations indicated that 26 could allosterically enhance HIF-2 dimerization. Furthermore, compound 26 had a good pharmacokinetic profile (the oral bioavailability in rats was 41.38%) and an in vivo safety profile (the LD50 in mice was greater than 708 mg·kg-1). In the in vivo efficacy assays, the combination of 26 and the prolyl hydroxylase inhibitor, AKB-6548, was confirmed for the first time to synergistically increase the plasma erythropoietin level in mice (from 260 to 2296 pg·mL-1) and alleviate zebrafish anemia induced by doxorubicin. These results provide new insights for HIF-2α agonists and the treatment of renal anemia.
- Yu, Yancheng,Yang, Fulai,Yu, Quanwei,Liu, Simeng,Wu, Chenyang,Su, Kaijun,Yang, Le,Bao, Xiaoqian,Li, Zhihong,Li, Xiang,Zhang, Xiaojin
-
p. 17384 - 17402
(2021/11/16)
-
- Insight into the binding mode of HIF-2 agonists through molecular dynamic simulations and biological validation
-
Hypoxia-inducible factor-2 (HIF-2), a heterodimeric transcriptional protein consisting of HIF-2α and aryl hydrocarbon receptor nuclear translocator (ARNT) subunits, has a broad transcriptional profile that plays a vital role in human oxygen metabolism. M1001, a HIF-2 agonist identified by high-throughput screening (HTS), is capable of altering the conformation of Tyr281 of the HIF-2α PAS-B domain and enhancing the affinity of HIF-2α and ARNT for transcriptional activation. M1002, an analog of M1001, shows improved efficacy than M1001. However, the cocrystal structure of M1001 and HIF-2 has some defects in revealing the agonist binding mode due to the relatively low resolution, while the binding mode of M1002 remained unexplored. To in-depth understand agonist binding profiles, herein, the molecular dynamic (MD) simulations was applied to construct a stable agonist-protein model, and a possible binding mode was proposed through the analysis of the binding free energy and hydrogen bonding of the simulation results. Nine compounds were then synthesized and evaluated to verify the proposed binding mode. Among them, compound 10 manifested improved agonistic activity and reduced toxicity compared to M1002. This study provides deep insight into the binding mode of such HIF-2 agonists, which would be useful for designing novel agonists for HIF-2.
- Yu, Yancheng,Yu, Quanwei,Liu, Simeng,Wu, Chenyang,Zhang, Xiaojin
-
-
- A Green One-Pot Synthesis of vic -Amidino (Hetero)aromatic Acids from 1,2-Dinitriles
-
Phthalonitrile undergoes partial hydration in MeOH-H2O media in the presence of an equimolar amount of NaOH to afford 2-carbamimidoylbenzoic acid in good yield in one step. This and similar vic-amidino (hetero)aromatic acids also could be synthesized from corresponding 1,2-dinitriles by hydrolysis in aqueous MeOH catalyzed by an equimolar amount of NaOH of in situ generated 1,1-dimethoxy-1H-isoindol-3-amine or its counterparts. Protonation of the synthesized amidino acids, esterification, and reamination of the parent amidino benzoic acid with N-nucleophiles were performed.
- Tkachuk, Volodymyr A.,Omelchenko, Iryna V.,Hordiyenko, Olga V.
-
supporting information
p. 851 - 857
(2017/04/06)
-
- Novel and mild route to phthalocyanines and 3-iminoisoindolin1-ones via N,N-diethylhydroxylamine-promoted conversion of phthalonitriles and a dramatic solvent-dependence of the reaction
-
Refluxing a mixture of phthalonitrile C6R1R 2R3R4(CN)2 1 (R1-R 4 = H), or its substituted derivatives 2 (R1, R 3, R4 = H, R2 = Me), or 3 (R1, R4 = H, R2, R3 = Cl) (lequiv.) and N,N-diethylhy-droxylamine, Et2NOH, (4 equivs.) in methanol for 4 h results (Route A) in precipitation of the symmetrical (6 and 8) and an isomeric mixture of unsymmetrical (7) phthalocyanines, isolated in good (55-65 % ) yields. The reaction of phthalonitriles 1, 2, or 4 (R1, R 3, R4 = H, R2 = NO2) (4 equivs.) with Et2NOH (8 equivs.) in the presence of a metal salt MCl 2 (M = Zn, Cd, Co, Ni) (1 equiv.) in n-BuOH or without solvent results in the formation of metallated phthalocyanine species (9-17). Upon refluxing in freshlydistilled dry chloroform, phthalonitrile 1 or its substituted analogues 2, 3 or 5 (R1-R4 = F) (1 equiv.) react with N,N-diethylhydroxylamine (2 equivs.) affording 3-iminoisoindolin-1- ones 18-21 (Route B) isolated in good yields (55-80%). All the prepared compounds were characterized with C, H, and N elemental analyses, ESI-MS, IR, and compounds 18-21 also by ID (1H, 13C(1H]), and 2D (1H,15N-HMBC and 1H,13CHMQC, 1H,13C-HMBC) NMR spectroscopy.
- Luzyanin, Konstantin V.,Kukushkin, Vadim Yu.,Kopylovich, Maximilian N.,Nazarov, Alexey A.,Galanski, Markus,Pombeiro, Armando J. L.
-
body text
p. 135 - 142
(2009/04/07)
-
- Structure, polymorphism and thermal properties of phenyliminoisoindolines
-
The crystal and molecular structures of (a) 1-imino-3-phenyliminoisoindoline (2), (b) two polymorphs (3Mono and 3Tric) and a nexane solvate (3Hex) of 1,3-bis(phenylimino)isoindoline (3) and (c) 3-phenyliminoisoindolinone (4) were determined via single-crystal x-ray diffraction. The two polymorphs and solvate of 3 were all obtained by crystallization from hexane. In the solid state, 2 is found as the anti isomer of the amino tautomer, and all forms of 3 exist as either the syn,anti or anti,anti isomers of the diimino tautomer. The 3Tric and 3Mono polymorphs represent a rare example in which the phenomena of conformational polymorphism and conformational isomorphism occur for the same substance. Compound 4 crystallizes as the anti isomer of the keto form. Differential scanning calorimetry and thermogravimetric analysis were performed to characterize the thermal properties of samples of 2-4. X-ray powder diffraction studies on 2, 3 and 4 reveal that, whereas specimens of 2 are a single phase, none of the samples of 3 and 4 crystallize as single phases under the conditions of the experiments. Copyright
- Zhang, Zhi-Qin,Uth, Samnang,Sandman, Daniel J.,Foxman, Bruce M.
-
p. 769 - 776
(2007/10/03)
-
- Use of diiminoisoindoline derivatives or 3-aminoisoindolone derivatives for dyeing keratin fibers, and dye compositions containing them
-
Diiminoisoindoline derivatives or 3-aminoisoindolone derivatives, or tautomeric forms thereof, used as oxidizing-agent-free dye precursors in dyeing keratin fibers, in particular human keratin fibers such as the hair, without an oxidizing agent, in the presence of compounds containing a primary or secondary amine function; dye compositions containing these compounds and to the dyeing devices and processes used.
- -
-
-
- Novel Spirosuccinimides with Incorporated Isoindolone and Benzisothiazole 1,1-Dioxide Moieties as Aldose Reductase Inhibitors and Antihyperglycemic Agents
-
Compounds from two novel series of spirosuccinimides were prepared.Analogs of series 2 possessed a spiro-fused isoindolone moiety while those of series 3 contained a spiro-fused benzisothiazole S,S-dioxide group.These compounds were evaluated as aldose reductase inhibitors (ARI) in vitro by their ability to inhibit glyceraldehyde reduction using a partially purified bovine lens aldose reductase preparation and in vivo as inhibitors of galactitol accumulation in the lens, sciatic nerve, and diaphragm of galactose-fed rats.Many members from the isoindolone series 2,particularly those containing an isoindolone N-methyl moiety, showed good in vitro and in vivo potency.The most potent member, the 6-chloro analog 32, was resolved, and aldose reductase activity was found to reside almost exclusively in the (+)-enantiomer.Compound 32 was approximately equipotent in the sciatic nerve of the galactose-fed rat to other cyclic imide ARI's of similar in vitro activity, namely sorbinil and ADN-138 and also to tolrestat, an acetic acid-based ARI (ED50's 4-8 mg/kg).Compounds from both series, 2 and 3, were also found to lower plasma glucose levels of genetically obese db/db and ob/ob mice with potency similar to that of ciglitazone.However, members from these series failed to lower insulin levels of the ob/ob mouse at the doses tested.
- Wrobel, Jay,Dietrich, Arlene,Woolson, Shiela A.,Millen, Jane,McCaleb, Michael,et al.
-
p. 4613 - 4627
(2007/10/02)
-
- NMR STUDIES ON IMIDINES. III. (1)H AND (13)C NUCLEAR MAGNETIC RESONANCE STUDY ON THE TAUTOMERISM AND GEOMETRICAL ISOMERISM OF 3-IMINOISOINDOLINONE AND SOME ALKYLATED DERIVATIVES. OBSERVATION OF E AND Z ISOMERS ABOUT A FREE IMINO GROUPING
-
3-Iminoisoindolinone (1) and some N-alkyl derivatives (8, 9, 10, 11, 12, 16 and 17) have been fully examined by (1)H and (13)C NMR spectroscopy. 3-(Methylimino)isoindolinone (12) cannot be obtained by reaction of 1 with methylamine, because it rearranges to 3-imino-2-methylisoindolinone (11), which reacts further to 2-methyl-3-(methylimino)isoindolinone (10).Both compounds have been shown to adopt the E configuration predominantly (88 percent for 11 at -55 deg C (CDCl3); 100 percent for 10). 3-(Methylimino)isoindolinone (12) favours the Z configuration (96 percent). Analogous results are found for the butyl derivatives (16, 17). 3-Imino isoindolinone (1) is present as the imino tautomer for 70 percent in DMSO-d6 solution as established by comparison of (13)C NMR chemical shift values of 1 with those of model compounds, 3-imino-2-methyl isoindolinone (11) and 3-(dimethylamino)isoindolinone (8).The tautomeric equilibrium is more extreme towards the imino form for the N-methyl and N-butyl derivatives 12 and 16. 2,3,4,5-tetrahydroisoindolinopyrimidin-6-one served as the imino model compound together with 10. (1)H and(13)C NMR data are given for several phthalic acid derivatives.
- Spiessens, Luc I.,Anteunis, Marc J. O.
-
p. 965 - 994
(2007/10/02)
-