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1.
Molecules ; 24(2)2019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30646524

RESUMO

7-Oxo-1,2,4-benzotriazines (benzo[1,2,4]triazin-7-ones) are reversible thioredoxin reductase inhibitors that exhibit very strong correlations to pleurotin. In this article, we provide the first synthesis of fluorinated derivatives. Fluorination using Selectfluor of benzo[1,2,4]triazin-7-ones occurs regioselectively and in high yield at the enamine-activated position. This electron N-lone pair activation overrides the activation/deactivation effects of some other substituents. The reaction time was significantly reduced with the use of microwave irradiation at 120 °C and 7 bar. The cytotoxicity and cyclic voltammetry measurements for 8-fluoro-1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (2) are presented and compared with its synthetic precursor, 1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (1a).


Assuntos
Compostos de Diazônio/química , Triazinas/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Halogenação , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Relação Estrutura-Atividade , Triazinas/farmacologia
2.
J Org Chem ; 83(16): 9391-9402, 2018 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-29940730

RESUMO

Modifying the para-quinonimine 1,3-diphenyl-1,2,4-benzotriazin-7(1 H)-one (2a) ( E1/2-1/0 -1.20 V), by replacing the N1-phenyl by pentafluorophenyl, the C3-phenyl by trifluoromethyl, or the C7 carbonyl by ylidenemalononitrile, led to improved electron affinities as determined by cyclic voltammetry and computational studies. Combining structural changes further improved electron accepting abilities: the most electron deficient analogues ( E1/2-1/0 ∼ -0.65 V) involved combining the ylidenemalononitrile groups at C7 with the trifluoromethyl groups at C3. 1,2,5-Thiadiazolo fusion at C5-C6 did not affect the redox behavior but did enhance the UV-vis absorption profile. During the synthesis of the thiadiazolo analogues, 1,4-thiazino-fused analogues 6 were obtained in low yield, which thermally ring contract to the triazafluoranthenones 7. Compounds are fully characterized, and X-ray data are provided for selected analogues.

3.
Molecules ; 23(6)2018 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-29795048

RESUMO

Thermolysis of 4,4'-dichloro-, 4,4'-diaryl-, and 4,4'-di(thien-2-yl)-5,5'-bi(1,2,3-dithiazol-ylidenes) affords the respective 3,6-dichloro-, 3,6-diaryl- and 3,6-di(thien-2-yl)isothiazolo[5,4-d]-isothiazoles in low to high yields. The transformation of the 4,4'-diaryl- and 4,4'-di(thien-2-yl)-5,5'-bi(1,2,3-dithiazolylidenes) occurs at lower temperatures in the presence of the thiophiles triphenylphosphine or tetraethylammonium iodide. Optimized reaction conditions and a mechanistic rationale for the thiophile-mediated ring transformation are presented.


Assuntos
Tiazóis/síntese química , Modelos Moleculares , Estrutura Molecular , Temperatura , Tiazóis/química
4.
Molecules ; 23(5)2018 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-29783765

RESUMO

We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors.


Assuntos
Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Tiadiazóis/síntese química , Tiadiazóis/farmacologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/química , Domínio Catalítico , Cristalografia por Raios X , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Tiadiazóis/química , Água/química
5.
J Org Chem ; 83(8): 4754-4761, 2018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29595269

RESUMO

Isodiphenylfluorindone 6 and isodiphenylfluorindinone 7 are synthesized. The former reacts with NaOMe to give the 13-methoxyisodiphenylfluorindone 22 (95%), while the latter reacts with 70% perchloric acid to give the bisperchlorate 21 (87%) and with MnO2 dimerizes to give 13,13'-bi(isodiphenylfluorindone) 4 (60%). UV-vis, NMR, CV, and DFT computational studies support the structural assignments of all products. Single-crystal X-ray diffraction studies are reported for isodiphenylfluorindinone 7.

6.
Molecules ; 23(3)2018 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-29510488

RESUMO

Cell viability studies for benzo[1,2,4]triazin-7-ones and 1,2,4-benzotriazinyl (Blatter-type) radical precursors are described with comparisons made with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). All of the stable free radicals were several orders of magnitude less cytotoxic than the benzo[1,2,4]triazin-7-ones. The synthesis and evaluation of two new pyrid-2-yl benzo[1,2,4]triazin-7-ones are described, where altering the 1,3-substitution from phenyl to pyrid-2-yl increased cytotoxicity against most cancer cell lines, as indicated using National Cancer Institute (NCI) one-dose testing. COMPARE analysis of five-dose testing data from the NCI showed very strong correlations to the naturally occurring anti-cancer compound pleurotin. COMPARE is program, which analyzes similarities in cytotoxicity data of compounds, and enables quantitative expression as Pearson correlation coefficients. Compounds were also evaluated using the independent MTT assay, which was compared with SRB assay data generated at the NCI.


Assuntos
Antineoplásicos/farmacologia , Derivados de Benzeno/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Triazinas/farmacologia , Antineoplásicos/síntese química , Derivados de Benzeno/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Radicais Livres , Células HT29 , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Humanos , Células MCF-7 , Relação Estrutura-Atividade , Triazinas/síntese química
7.
Org Lett ; 20(3): 844-847, 2018 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-29350037

RESUMO

Isodiphenylfluorindine (5) reacts with K2Cr2O7/H+ to give 13-oxoisodiphenylfluorindinium perchlorate (7) (75%), but with phenyliodine bis(trifluoroacetate) (PIFA) or MnO2 it gives the zwitterionic and quinoidal cruciform 13,13'-dimers 11 (85%) and 12 (89%), respectively. The zwitterionic 13,13'-dimer 11 can be rapidly converted with MnO2 into the quinoidal 13,13'-dimer 12 (100%). UV-vis, NMR, single-crystal X-ray diffraction, and density functional theory studies support the structural assignments of all products. The electrochemical behavior of the compounds is also presented.

8.
J Org Chem ; 82(14): 7564-7575, 2017 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-28628743

RESUMO

Reacting N-aryliminophosphoranes with 1-(het)aroyl-2-aryldiazenes in preheated diphenyl ether at ca. 150-250 °C for 5-25 min affords in most cases the 1,3-diaryl-1,4-dihydrobenzo[e][1,2,4]triazin-4-yls (aka Blatter radicals) in moderate to good yields. All new compounds are fully characterized, including EPR and CV studies for the radicals. Single-crystal X-ray structures of 1-benzoyl-2-(perfluorophenyl)diazene and 1-(perfluorophenyl)-3-phenyl-1,4-dihydrobenzo[e][1,2,4]triazinyl are also presented.

9.
Org Lett ; 19(1): 174-177, 2017 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-27966997

RESUMO

A Pd(0)-catalyzed double C-N coupling of 5,5'-dibromo-2,2'-bithiazoles with (het)arylamines and subsequent in situ Ag2O-mediated oxidation provides access to cross-conjugated quinoidal 5,5'-diarylimino-2,2'-bithiazoles in moderate to high yield. The highly colored quinoidal 2,2'-bithiazoles were studied by UV/vis spectroscopy, cyclic voltammetry and computational methods.

10.
Molecules ; 21(9)2016 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-27626399

RESUMO

Electrospun nanocomposite fibers consisting of crosslinked polyvinylpyrrolidone (PVP) chains and gold nanoparticles (Au NPs) were fabricated, starting from highly stable PVP/Au NP colloidal solutions with different NP loadings, followed by thermal treatment. Information on the morphological characteristics of the fibers and of the embedded Au NPs was obtained by electron microscopy. Cylindrical, bead-free fibers were visualized by Scanning Electron Microscopy (SEM) while Transmission Electron Microscopy (TEM) and Energy Diffraction X-ray (EDX) analysis supported the presence of Au NPs within the fibers and gave information on their morphologies and average diameters. These materials were briefly evaluated as heterogeneous catalytic supports for the gold-catalyzed intramolecular cyclisation of 2­(phenylethynyl)aniline to form 2-phenyl-1H-indole. The performance of the gold catalyst was strongly dependent on the Au NP size, with the system containing the smallest Au NPs being the more effective. Moreover, a slight drop of their catalytic efficiency was observed after three consecutive reaction runs, which was attributed to morphological changes as a consequence of fiber merging.


Assuntos
Compostos de Anilina/química , Ouro/química , Indóis , Nanopartículas Metálicas/química , Povidona/química , Indóis/síntese química , Indóis/química
11.
Org Lett ; 18(16): 4056-9, 2016 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-27483200

RESUMO

A near-quantitative acid and/or thermal mediated ring contraction of 3',5'-diarylspiro(benzo[d][1,3]dioxole-2,4'-[1,2,6]thiadiazines) affords 3-aryl-4-(2-arylbenzo[d][1,3]dioxol-2-yl)-1,2,5-thiadiazoles. The reaction scope was studied providing 11 examples of this ring contraction. A double Wagner-Meerwein reaction mechanism is proposed.

12.
Bioorg Med Chem ; 24(16): 3565-70, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27290691

RESUMO

The thioredoxin (Trx)-thioredoxin reductase (TrxR) system plays a key role in maintaining the cellular redox balance with Trx being over-expressed in a number of cancers. Inhibition of TrxR is an important strategy for anti-cancer drug discovery. The natural product pleurotin is a well-known irreversible inhibitor of TrxR. The cytotoxicity data for benzo[1,2,4]triazin-7-ones showed very strong correlation (Pearson correlation coefficients ∼0.8) to pleurotin using National Cancer Institute COMPARE analysis. A new 3-CF3 substituted benzo[1,2,4]triazin-7-one gave submicromolar inhibition of TrxR, although the parent compound 1,3-diphenylbenzo[1,2,4]triazin-7-one was more cytotoxic against cancer cell lines. Benzo[1,2,4]triazin-7-ones exhibited different types of reversible inhibition of TrxR, and cyclic voltammetry showed characteristic quasi-reversible redox processes. Cell viability studies indicated strong dependence of cytotoxicity on substitution at the 6-position of the 1,3-diphenylbenzo[1,2,4]triazin-7-one ring.


Assuntos
Antineoplásicos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Triazinas/farmacologia , Antineoplásicos/química , Linhagem Celular Transformada , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Triazinas/química
13.
Molecules ; 21(5)2016 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-27187349

RESUMO

3-Adamantyl-1-phenyl-1,4-dihydrobenzo[e][1,2,4]triazin-4-yl (4) crystallizes as chains of radicals where the spin bearing benzotriazinyl moieties are isolated from each other. Magnetic susceptibility studies in the 5-300 K temperature region indicate that radical 4 demonstrates typical paramagnetic behavior stemming from non-interacting S = ½ spins.


Assuntos
Triazinas/química , Cristalografia por Raios X , Modelos Moleculares , Marcadores de Spin
14.
Org Lett ; 18(5): 1116-9, 2016 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-26866391

RESUMO

Tetraphenylhexaazaanthracene (TPHA), a fluorescent zwitterionic biscyanine with a closed-shell singlet ground state, on treatment with manganese dioxide or phenyliodine bis(trifluoroacetate) (PIFA), undergoes oxidative dimerization to give a near-zero dipole scissor 5,5'-dimer DI-TPHA. Both acene components of the new dimer DI-TPHA maintain their biscyanine closed-shell singlet ground state motifs, as judged by analysis of both single crystal X-ray crystallographic and density functional theory computational studies; however, unlike TPHA, DI-TPHA is only very weakly fluorescent.

16.
J Org Chem ; 81(2): 615-31, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26671065

RESUMO

N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)anilines react with DABCO in hot PhCl to give N-{4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}anilines in high yields (70-92%). The reaction also works with 4-chloro-5H-1,2,3-dithiazol-5-one and -thione, giving the corresponding products in 85% and 76% yields, respectively. While the reaction of several (4-chloro-5H-1,2,3-dithiazol-5-ylidene)methanes with DABCO failed to give {4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}methanes, these can be prepared in moderate yields via classical cycloaddition-retrocycloaddition strategies from 4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazole-5-thione. The 2-chloroethyl moiety on selected dithiazoles was also modified without cleavage of the 1,2,3-dithiazole by reaction with various nucleophiles, giving access to 4-[N-(2-substituted)piperazin-1-yl]-5H-1,2,3-dithiazoles in moderate to high yields.

17.
Chemistry ; 21(44): 15843-53, 2015 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-26493885

RESUMO

A series of d-block metal complexes of the recently reported coordinating neutral radical ligand 1-phenyl-3-(pyrid-2-yl)-1,4-dihydro-1,2,4-benzotriazin-4-yl (1) was synthesized. The investigated systems contain the benzotriazinyl radical 1 coordinated to a divalent metal cation, Mn(II) , Fe(II) , Co(II) , or Ni(II) , with 1,1,1,5,5,5-hexafluoroacetylacetonato (hfac) as the auxiliary ligand of choice. The synthesized complexes were fully characterized by single-crystal X-ray diffraction, magnetic susceptibility measurements, and electronic structure calculations. The complexes [Mn(1)(hfac)2 ] and [Fe(1)(hfac)2 ] displayed antiferromagnetic coupling between the unpaired electrons of the ligand and the metal cation, whereas the interaction was found to be ferromagnetic in the analogous Ni(II) complex [Ni(1)(hfac)2 ]. The magnetic properties of the complex [Co(1)(hfac)2 ] were difficult to interpret owing to significant spin-orbit coupling inherent to octahedral high-spin Co(II) metal ion. As a whole, the reported data clearly demonstrated the favorable coordinating properties of the radical 1, which, together with its stability and structural tunability, make it an excellent new building block for establishing more complex metal-radical architectures with interesting magnetic properties.

18.
Molecules ; 20(8): 14576-94, 2015 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-26274946

RESUMO

The high yielding transformations of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine into 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (up to 85%) and 2-(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)malononitrile (up to 83%) have been investigated and compared to the analogous transformations of the closely-related 4,5-dichloro-1,2,3-dithiazolium chloride (Appel's salt) into 4-chloro-5H-1,2,3-dithiazol-5-one and 2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)malononitrile. Furthermore, cyclocondensation of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine with 2-aminophenol and 1,2-benzenediamines gave fused 4H-1,2,6-thiadiazines in 68%-85% yields.


Assuntos
Tiadiazinas/química , Tiazóis/química , Fenômenos Químicos , Hidrocarbonetos Clorados/química , Tiadiazinas/síntese química , Tiazóis/síntese química
19.
Org Lett ; 17(16): 4118-21, 2015 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-26261875

RESUMO

Condensation of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine with a range of anilines gave 22 N-aryl-3,5-dichloro-4H-1,2,6-thiadiazin-4-imines in 43-96% yields. The scope and limitations of this condensation are briefly investigated. Furthermore, mono- and bis-substitution of the C-3 and C-5 chlorines of 3,5-dichloro-N-phenyl-4H-1,2,6-thiadiazin-4-imine by amine and alkoxide nucleophiles is explored. Finally, Stille coupling chemistry is used to prepare several N-phenyl-3,5-diaryl-4H-1,2,6-thiadiazin-4-imines.

20.
J Org Chem ; 80(16): 8329-40, 2015 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-26252396

RESUMO

Benzo[4,5]imidazo[1,2-c]quinazoline-6-carbonitriles are prepared in high yields via three new routes: (1) a Cu(OTf)2 (0-5 mol %) catalyzed hypervalent iodine [PhI(OTf)2] mediated oxidative coupling of 4-anilinoquinazoline-2-carbonitriles in neat trifluoroacetic acid (TFA); (2) a Pd(OAc)2 (10 mol %) or CuI (10 mol %) mediated nonoxidative coupling of 4-(2-bromoanilino)quinazoline-2-carbonitrile; and (3) a nonoxidative Pd(Ar3P)3 [Ar = 3,5-(F3C)2C6H3] [aka Superstable Pd(0) Catalyst] (10 mol %) mediated intramolecular C-N cyclization of 3-(2-bromophenyl)-4-imino-3,4-dihydroquinazoline-2-carbonitriles. All new compounds are fully characterized.

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