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1.
Fujita Med J ; 9(2): 147-153, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37234392

RESUMEN

Objectives: Agaritine (AGT) is a hydrazine-containing compound derived from the mushroom Agaricus blazei Murill. We previously reported the antitumor effect of AGT on hematological tumor cell lines and suggested that AGT induces apoptosis in U937 cells via caspase activation. However, the antitumor mechanism of AGT has not been fully understood. Methods: Four hematological tumor cell lines (K562, HL60, THP-1, H929) were used in this study. The cells were incubated in the presence of 50 µM AGT for 24 h and analyzed for cell viability, annexin V positivity, caspase-3/7 activity, mitochondrial membrane depolarization, cell cycle, DNA fragmentation, and the expression of mitochondrial membrane-associated proteins (Bax and cytochrome c). Results: In HL60, K562, and H929 cells, AGT reduced cell viability and increased annexin V- and dead cell-positive rates; however, it did not affect THP-1 cells. In K562 and HL60 cells, caspase-3/7 activity, mitochondrial membrane depolarization, and expression of mitochondrial membrane proteins, Bax and cytochrome c, were all increased by AGT. Cell cycle analysis showed that only K562 exhibited an increase in the proportion of cells in G2/M phase after the addition of AGT. DNA fragmentation was also observed after the addition of AGT. Conclusions: These results indicate that AGT induces apoptosis in K562 and HL60 cells, like U937 reported previously, but showed no effect on THP-1 cells. It was suggested that AGT-induced apoptosis involves the expression of Bax and cytochrome c via mitochondrial membrane depolarization.

2.
EMBO J ; 40(4): e105375, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33470442

RESUMEN

Thalidomide causes teratogenic effects by inducing protein degradation via cereblon (CRBN)-containing ubiquitin ligase and modification of its substrate specificity. Human P450 cytochromes convert thalidomide into two monohydroxylated metabolites that are considered to contribute to thalidomide effects, through mechanisms that remain unclear. Here, we report that promyelocytic leukaemia zinc finger (PLZF)/ZBTB16 is a CRBN target protein whose degradation is involved in thalidomide- and 5-hydroxythalidomide-induced teratogenicity. Using a human transcription factor protein array produced in a wheat cell-free protein synthesis system, PLZF was identified as a thalidomide-dependent CRBN substrate. PLZF is degraded by the ubiquitin ligase CRL4CRBN in complex with thalidomide, its derivatives or 5-hydroxythalidomide in a manner dependent on the conserved first and third zinc finger domains of PLZF. Surprisingly, thalidomide and 5-hydroxythalidomide confer distinctly different substrate specificities to mouse and chicken CRBN, and both compounds cause teratogenic phenotypes in chicken embryos. Consistently, knockdown of Plzf induces short bone formation in chicken limbs. Most importantly, degradation of PLZF protein, but not of the known thalidomide-dependent CRBN substrate SALL4, was induced by thalidomide or 5-hydroxythalidomide treatment in chicken embryos. Furthermore, PLZF overexpression partially rescued the thalidomide-induced phenotypes. Our findings implicate PLZF as an important thalidomide-induced CRBN neosubstrate involved in thalidomide teratogenicity.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Citocromo P-450 CYP3A/metabolismo , Proteína de la Leucemia Promielocítica con Dedos de Zinc/metabolismo , Teratogénesis , Talidomida/análogos & derivados , Talidomida/toxicidad , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Embrión de Pollo , Citocromo P-450 CYP3A/genética , Humanos , Ratones , Proteína de la Leucemia Promielocítica con Dedos de Zinc/genética , Proteolisis , Especificidad por Sustrato , Teratógenos/toxicidad , Factores de Transcripción/genética , Ubiquitina-Proteína Ligasas/genética
3.
iScience ; 23(9): 101467, 2020 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-32891056

RESUMEN

Currently, more than 1,200 agrochemicals are listed and many of these are regularly used by farmers to generate the food supply to support the expanding global population. However, resistance to pesticides is an ever more frequently occurring phenomenon, and thus, a continuous supply of novel agrochemicals with high efficiency, selectivity, and low toxicity is required. Moreover, the demand for a more sustainable society, by reducing the risk chemicals pose to human health and by minimizing their environmental footprint, renders the development of novel agrochemicals an ever more challenging undertaking. In the last two decades, fluoro-chemicals have been associated with significant advances in the agrochemical development process. We herein analyze the contribution that organofluorine compounds make to the agrochemical industry. Our database covers 424 fluoro-agrochemicals and is subdivided into several categories including chemotypes, mode of action, heterocycles, and chirality. This in-depth analysis reveals the unique relationship between fluorine and agrochemicals.

4.
Angew Chem Int Ed Engl ; 59(21): 8187-8194, 2020 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-32003516

RESUMEN

The two enantiomers of trifluoromethyl-benzo[c][1,5]oxazonines, (R)-4 and (S)-4, can be selectively accessed with high enantiopurity by the Pd-catalyzed ring-expansion reaction of trifluoromethyl-benzo[d][1,3]oxazinones (1) with vinyl ethylene carbonates (3) using one antipode of a chiral ligand. Initially, the reaction proceeds by a double decarboxylative ring-expansion with kinetic resolution of 1 in the presence of a Pd-catalyst/chiral ligand to provide (R)-4 with high enantiopurity. At the same time, the nonreactive antipode of 1, (S)-1, which was recovered with an impeccable s factor of up to 713 and an ideal chemical yield, was transferred into the antipode of the products, (S)-4, with high enantiopurity by a second run of the Pd-catalyzed double decarboxylation reaction, but this time without any chiral auxiliary. Thus, both antipodes of the chiral trifluoromethyl heterocycles 4 can be obtained in excellent enantiopurity using only a single antipode of the chiral catalyst.

5.
ChemistryOpen ; 8(4): 402, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30976481

RESUMEN

Invited for this month's cover picture is the group of Norio Shibata at the Nagoya Institute of Technology (Japan). The cover picture shows an image related to the perpetual motion machine of the second kind in the eighteenth century, and "alchemy". Our biggest challenge on the path to the results presented in this paper was the creation of alchemy using fluorine chemistry. Read the full text of their Communication at 10.1002/open.201800286.

6.
ChemistryOpen ; 8(4): 406-410, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30976483

RESUMEN

A micro-flow nucleophilic trifluoromethylation of carbonyl compounds using gaseous fluoroform was developed. This method also allows the first micro-flow transformation of N-sulfinylimines into trifluoromethyl amines with excellent diastereoselectivity. To demonstrate the synthetic utility of this micro-flow synthesis, the formal micro-flow synthesis of Efavirenz is described.

7.
Sci Rep ; 8(1): 17131, 2018 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-30459439

RESUMEN

Twenty years after the thalidomide disaster in the late 1950s, Blaschke et al. reported that only the (S)-enantiomer of thalidomide is teratogenic. However, other work has shown that the enantiomers of thalidomide interconvert in vivo, which begs the question: why is teratogen activity not observed in animal experiments that use (R)-thalidomide given the ready in vivo racemization ("thalidomide paradox")? Herein, we disclose a hypothesis to explain this "thalidomide paradox" through the in-vivo self-disproportionation of enantiomers. Upon stirring a 20% ee solution of thalidomide in a given solvent, significant enantiomeric enrichment of up to 98% ee was observed reproducibly in solution. We hypothesize that a fraction of thalidomide enantiomers epimerizes in vivo, followed by precipitation of racemic thalidomide in (R/S)-heterodimeric form. Thus, racemic thalidomide is most likely removed from biological processes upon racemic precipitation in (R/S)-heterodimeric form. On the other hand, enantiomerically pure thalidomide remains in solution, affording the observed biological experimental results: the (S)-enantiomer is teratogenic, while the (R)-enantiomer is not.


Asunto(s)
Talidomida/química , Cromatografía Líquida de Alta Presión , Dimetilsulfóxido/química , Solubilidad , Solventes/química , Espectrofotometría Ultravioleta , Estereoisomerismo
8.
Nat Commun ; 9(1): 4393, 2018 10 22.
Artículo en Inglés | MEDLINE | ID: mdl-30349026

RESUMEN

Direct activation of carbon-fluorine bonds (C-F) to introduce the silyl or boryl groups and generate valuable carbon-silicon (C-Si) or carbon-boron (C-B) bonds is important in the development of synthetically useful reactions, owing to the unique opportunities for further derivatization to achieve more complex molecules. Despite considerable progress of C-F bond activation to construct carbon-carbon (C-C) and carbon-heteroatom (C-X) bond formation, the defluorosilylation via C-F cleavage has been rarely demonstrated. Here, we report an ipso-silylation of aryl fluorides via cleavage of unactivated C-F bonds by a Ni catalyst under mild conditions and without the addition of any external ligand. Alkyl fluorides are also directly converted into the corresponding alkyl silanes under similar conditions, even in the absence of the Ni catalyst. Applications of this protocol in late-stage defluorosilylation of potentially bioactive pharmaceuticals and in further derivatizations are also carried out.

9.
Sci Rep ; 8(1): 11501, 2018 07 31.
Artículo en Inglés | MEDLINE | ID: mdl-30065282

RESUMEN

A simple protocol to overcome the problematic trifluoromethylation of carbonyl compounds by the potent greenhouse gas "HFC-23, fluoroform" with a potassium base is described. Simply the use of glymes as a solvent or an additive dramatically improves the yields of this transformation. Experimental results and DFT calculations suggest that the beneficial effect deals with glyme coordination to the K+ to produce [K(polyether)n]+ whose diminished Lewis acidity renders the reactive anionoid CF3 counterion species more 'naked', thereby slowing down its undesirable decomposition to CF2 and F- and simultaneously increasing its reactivity towards the organic substrate.

10.
Chem Commun (Camb) ; 54(63): 8761-8764, 2018 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-30033470

RESUMEN

A trifluoromethyl analogue of diethylaminosulfur trifluoride (CF3-DAST)-induced deacylative trifluoromethylthiolation of cyclic 1,3-diketones, lactams, and lactones that provides cyclic α-trifluoromethylthioketones, lactams, and lactones is reported. To the best of our knowledge, this method represents the first example of the trifluoromethylthiolation of lactams. A corresponding deacylative pentafluorophenylthiolation using a pentafluorophenyl analogue of diethylaminosulfur trifluoride (C6F5-DAST) was also attempted.

11.
Chem Commun (Camb) ; 54(64): 8881-8884, 2018 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-30043773

RESUMEN

The highly C-selective difluoromethylation of ß-ketoesters was achieved by combining TMSCF2Br/LiOH/N,N,N-trimethylhexadecan-1-ammonium bromide. Compared to other alkali metal salts or organic bases, lithium hydroxide, which served as a difluorocarbene activator from TMSCF2Br, was crucial in the control of high C/O regioselectivity.

12.
Chem Sci ; 9(22): 4931-4936, 2018 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-29938019

RESUMEN

The trans-tetrafluoro-λ6-sulfane (SF4) group has been utilized as a unique three-dimensional building block for the linear connection of two independent N-heterocycles, pyridines and triazoles. The linearly connected heterocyclic compounds were synthesized by thermal Huisgen 1,3-dipolar cycloaddition between previously unknown pyridine SF4-alkynes and readily available azides, providing a series of rod-like SF4-connected N-heterocycles in good to excellent yields. X-ray crystallographic analysis of the target products revealed the trans-geometry of the SF4 group, which linearly connects two independent N-heterocycles. This research will open the field of chemistry of SF4-connected heterocyclic compounds.

13.
Chem Sci ; 9(13): 3276-3281, 2018 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-29732106

RESUMEN

Direct access to pharmaceutically attractive benzo-fused nine-membered heterocyclic alkenes 3 with a trifluoromethyl carbinol moiety was achieved via a palladium-catalyzed double-decarboxylative formal ring-expansion process from six-membered trifluoromethyl benzo[d][1,3]oxazinones 1 to nine-membered trifluoromethyl benzo[c][1,5]oxazonines 3 in the presence of vinylethylene carbonates 2. Generation of a Pd-π-allyl zwitterionic intermediate was proposed in the catalytic cycle. The trifluoromethyl group in the benzoxazinanones 1 plays an important role throughout the transformation. Diastereoselective chemical transformations of products 3 were also demonstrated.

14.
Chem Commun (Camb) ; 54(34): 4294-4297, 2018 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-29632907

RESUMEN

Here we have successfully demonstrated the first stereodivergent direct nucleophilic trifluoromethylation of N-sulfinylimines using the potent greenhouse gas "HFC-23, fluoroform" with an organic-superbase or an organometallic-base in high yields and selectivity.

15.
Beilstein J Org Chem ; 14: 364-372, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29507641

RESUMEN

Conscious of the potential bioactivity of fluorine, an investigation was conducted using various fluorine-containing diaryliodonium salts in order to study and compare their biological activity against human lymphoma U937 cells. Most of the compounds tested are well-known reagents for fluoro-functionalized arylation reactions in synthetic organic chemistry, but their biological properties are not fully understood. Herein, after initially investigating 18 fluoro-functionalized reagents, we discovered that the ortho-fluoro-functionalized diaryliodonium salt reagents showed remarkable cytotoxicity in vitro. These results led us to synthesize more compounds, previously unknown sterically demanding diaryliodonium salts having a pentafluorosulfanyl (SF5) functional group at the ortho-position, that is, unsymmetrical ortho-SF5 phenylaryl-λ3-iodonium salts. Newly synthesized mesityl(2-(pentafluoro-λ6-sulfanyl)phenyl)iodonium exhibited the greatest potency in vitro against U937 cells. Evaluation of the cytotoxicity of selected phenylaryl-λ3-iodonium salts against AGLCL (a normal human B cell line) was also examined.

16.
ChemistryOpen ; 7(2): 204-211, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29497592

RESUMEN

The direct synthesis of aryl triflones, that is, trifluoromethanesulfonyl arenes, was achieved through the trifluoromethanesulfonylation of benzynes. The trifluoromethanesulfonyl group, one of the fluorinated functional groups, is a highly electron-negative and mild lipophilic substituent. Aryl triflones have high potential in the synthesis of bioactive compounds and specialty materials. The treatment of 2-(trimethylsilyl)aryl trifluoromethanesulfonates with cesium fluoride in the presence of 15-crown-5 generated benzynes, which reacted with sodium trifluoromethanesulfinate followed by protonation with tBuOH under heating conditions, provided aryl triflones in moderated to good yields. Both symmetrical and unsymmetrical triflones were nicely accessed under the same reaction conditions. Interestingly, the trifluoromethanesulfonylation of unsymmetrical benzyne precursors proceeded smoothly to furnish corresponding aryl triflones in good yields with good to high regioselectivities. The balance of polarization of electric charge as well as steric hindrance of the benzyne intermediates are central factors to control the outcome of regioselectivity.

17.
Org Lett ; 20(3): 558-561, 2018 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-29320193

RESUMEN

The synthesis of pyrazole triflones containing a triflyl group at the 3-position is disclosed. Treatment of 2-diazo-1-phenyl-2-((trifluoromethyl)sulfonyl)ethan-1-one with nitroalkenes under basic conditions gave pharmaceutically attractive pyrazole 3-triflones in good to high yields. The generation of anionic triflyldiazomethane species followed by the [3 + 2] cycloaddition reaction with nitroalkenes is proposed for this transformation. 3-(Difluoromethanesulfonyl)pyrazoles were also synthesized by using a previously unknown anionic (difluoromethanesulfonyl)diazomethane species under a similar strategy.

18.
Sci Rep ; 8(1): 1294, 2018 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-29358579

RESUMEN

Thalidomide possesses two optical isomers which have been reported to exhibit different pharmacological and toxicological activities. However, the precise mechanism by which the two isomers exert their different activities remains poorly understood. Here, we present structural and biochemical studies of (S)- and (R)-enantiomers bound to the primary target of thalidomide, cereblon (CRBN). Our biochemical studies employed deuterium-substituted thalidomides to suppress optical isomer conversion, and established that the (S)-enantiomer exhibited ~10-fold stronger binding to CRBN and inhibition of self-ubiquitylation compared to the (R)-enantiomer. The crystal structures of the thalidomide-binding domain of CRBN bound to each enantiomer show that both enantiomers bind the tri-Trp pocket, although the bound form of the (S)-enantiomer exhibited a more relaxed glutarimide ring conformation. The (S)-enantiomer induced greater teratogenic effects on fins of zebrafish compared to the (R)-enantiomer. This study has established a mechanism by which thalidomide exerts its effects in a stereospecific manner at the atomic level.


Asunto(s)
Aletas de Animales/efectos de los fármacos , Proteínas del Tejido Nervioso/química , Procesamiento Proteico-Postraduccional , Teratógenos/química , Talidomida/química , Proteínas Adaptadoras Transductoras de Señales , Secuencias de Aminoácidos , Aletas de Animales/anomalías , Aletas de Animales/crecimiento & desarrollo , Animales , Sitios de Unión , Clonación Molecular , Cristalografía por Rayos X , Embrión no Mamífero , Escherichia coli/genética , Escherichia coli/metabolismo , Expresión Génica , Ratones , Simulación del Acoplamiento Molecular , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Unión Proteica , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Estereoisomerismo , Teratógenos/metabolismo , Teratógenos/farmacología , Talidomida/metabolismo , Talidomida/farmacología , Termodinámica , Ubiquitinación , Pez Cebra
19.
Chempluschem ; 83(3): 95-98, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31957336

RESUMEN

X-ray crystallographic analyses of a series of trifluoroethoxy-substituted subphthalocyanines disclosed that a molecule of toluene is clasped at the center of the molecular concave cavity. Twelve trifluoroethoxy substituents, which flexibly surround the toluene molecule to hold it on the 14 π-electron-conjugated surface of the subphthalocyanines, can also catch a molecule of benzene. In contrast, a nonsubstituted subphthalocyanine does not show the same phenomena, and two subphthalocyanine units are required to maintain a small aromatic compound in their concave cavity. DFT calculations of the complexes were conducted to better understand the arene clathrates. Trifluoroethoxy-substituted subphthalocyanines can be used to prepare arene clathrates as a result of their concave space. This is a unique approach to obtaining X-ray crystal structures of small noncrystalline aromatic compounds.

20.
Chempluschem ; 83(3): 93, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31957340

RESUMEN

Invited for this month's cover is the group of Prof. Norio Shibata based at the Nagoya Institute of Technology, Japan. The cover picture shows the crystal structures of trifluoroethoxy-substituted subphthalocyanines which form crystalline clathrates with one small aromatic molecule, such as toluene or benzene, in their concave cavity. Twelve trifluoroethoxy substituents flexibly surround the small molecule to hold it on the 14π-electron conjugated surface of the subphthalocyanines. Read the full text of the article at 10.1002/cplu.201700508.

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