Isomerization Mechanism in Hydrazone-Based Rotary Switches: Lateral Shift, Rotation, or Tautomerization?

Landge, Shainaz M.; Tkatchouk, Ekatarina; Benítez, Diego; Lanfranchi, Don Antoine; Elhabiri, Mourad; Goddard, William A.; Aprahamian, Ivan

doi:10.1021/ja200699v

Cited by 176 publications

(128 citation statements)

References 147 publications

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“…As reported in the literature for E/Z mixtures of acylhydrazones and phenylhydrazones, the signals of the olefinic protons of the Z isomers are observed at higher ppm values than those of the E isomers [30]; furthermore, the signals of the hydrazone NH proton of Z -phenylhydrazones are observed at lower ppm values than those of the E isomers [31]. On this basis, in the NMR spectra of phenylhydrazones 6a and 7a, the signals of the vinyl proton and of the hydrazone NH were assigned to the Z isomers (6a: =CH: 8.69 ppm, NH: 9.69 ppm; 7a: =CH: 9.40 ppm, NH: 9.75 ppm).…”

Section: Stereochemisty Assignementsupporting

confidence: 68%

Synthesis and biological evaluation of (acyl)hydrazones and thiosemicarbazones obtained via in situ condensation of iminium salts with nitrogen-containing nucleophiles

et al. 2015

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An unprecedented, highly convergent, high-yielding, one-pot synthesis of (acyl)hydrazones and thiosemicarbazones was carried out by the in situ condensation of isolable iminium chlorides of imidazolidin-2-(thio)one, tetrahydropyrimidin-2-thione and indole derivatives with nitrogen nucleophiles in the presence of a base. The developed reaction procedure is largely advantageous. It is highly parallelizable, no intermediates need to be isolated and minimal sample handling is required during the purification steps. Some relevant reaction parameters including reaction temperature and p[Formula: see text] of the base are discussed. NMR analysis was carried out to assess the stereochemistry of the obtained compounds. The stereochemical outcome of the reaction was found to be affected by the nature of the nitrogen-containing nucleophile being the majority of the derivatives isolated as single geometric isomers. The cytotoxicity and antiviral activities of the prepared compounds have been preliminary assessed. In cell-based screenings some of the derivatives proved to be cytotoxic at low micromolar concentrations and interesting anti-Reo-1 properties have been detected.

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Section: Stereochemisty Assignementsupporting

confidence: 68%

Synthesis and biological evaluation of (acyl)hydrazones and thiosemicarbazones obtained via in situ condensation of iminium salts with nitrogen-containing nucleophiles

et al. 2015

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“…5 (top pathway). 26,30 Neutralizing with excess Et 3 N gave a mixture of Z-2- (Fig. 4, step c) to yield EZ-1-right.…”

Section: Synthesis and Characterizationmentioning

confidence: 99%

Pick-up, transport and release of a molecular cargo using a small-molecule robotic arm

et al. 2015

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Modern day factory assembly lines often feature robots that pick up, reposition and connect components in a programmed manner. The idea of manipulating molecular fragments in a similar way has to date only been explored using biological building blocks (DNA). Here we report on a wholly artificial small-molecule robotic arm capable of selectively transporting a molecular cargo in either direction between two spatially distinct, chemically similar, sites on a molecular platform. The arm picks up/releases a 3-mercaptopropanehydrazide cargo by formation/breakage of a disulfide bond, while dynamic hydrazone chemistry controls the cargo binding to the platform. Transport is controlled by selectively inducing conformational and configurational changes within an embedded hydrazone rotary switch that steers the robotic arm. In a three-stage operation 79-85 % of 3-mercaptopropanehydrazide molecules are transported in either (chosen) direction between the two platform sites, without the cargo at any time fully dissociating from the machine nor exchanging with other molecules in the bulk.The mechanical manipulation of matter at atomic length-scales has fascinated scientists since it was proposed by Feynman in 'There's Plenty of Room at the Bottom'.

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“…The two isomers can be separated by RP-flash chromatography (Methanol/ Water/ 0.1% Formic acid) and stored at 4°C as stable solids for several months. Pure E -isomers undergoes E -to- Z isomerization at different rates and generate different equilibrium mixtures when dissolved in polar solvents [20]. These variations might be due to the different nature of substituents on rings A and C .…”

Section: Resultsmentioning

confidence: 99%

Structure–activity relationship study of 4EGI-1, small molecule eIF4E/eIF4G protein–protein interaction inhibitors

Takrouri¹,

Chen²,

Papadopoulos³

et al. 2014

European Journal of Medicinal Chemistry

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Protein-protein interactions are critical for regulating the activity of translation initiation factors and multitude of other cellular process, and form the largest block of untapped albeit most challenging targets for drug development. 4EGI-1, (E/Z)-2-(2-(4-(3,4-dichlorophenyl)thiazol-2-yl)hydrazono)-3-(2-nitrophenyl)propanoic acid, is a hit compound discovered in a screening campaign of small molecule libraries as an inhibitor of translation initiation factors eIF4E and eIF4G protein-protein interaction; it inhibits translation initiation in vitro and in vivo. A series of 4EGI-1-derived thiazol-2-yl hydrazones have been designed and synthesized in order to delineate the structural latitude and improve its binding affinity to eIF4E, and increase its potency in inhibiting the eIF4E/eIF4G interaction. Probing a wide range of substituents on both phenyl rings comprising the 3-phenylpropionic acid and 4-phenylthiazolidine moieties in the context of both E- and Z-isomers of 4EGI-1 led to analogs with enhanced binding affinity and translation initiation inhibitory activities.

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Isomerization Mechanism in Hydrazone-Based Rotary Switches: Lateral Shift, Rotation, or Tautomerization?

Cited by 176 publications

References 147 publications

Synthesis and biological evaluation of (acyl)hydrazones and thiosemicarbazones obtained via in situ condensation of iminium salts with nitrogen-containing nucleophiles

Synthesis and biological evaluation of (acyl)hydrazones and thiosemicarbazones obtained via in situ condensation of iminium salts with nitrogen-containing nucleophiles

Pick-up, transport and release of a molecular cargo using a small-molecule robotic arm

Structure–activity relationship study of 4EGI-1, small molecule eIF4E/eIF4G protein–protein interaction inhibitors

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