Discovery of anti-cancer activity for benzo[1,2,4]triazin-7-ones : very strong correlation to pleurotin and thioredoxin reductase inhibition

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.F.A. thanks the Irish Research Council (IRC) for a Government of Ireland Postgraduate Scholarship for Martin Sweeney and College of Science, National University of Ireland Galway (NUI Galway) for a postgraduate scholarship for Robert Coyle. We thank the National Cancer Institute (USA), Development Therapeutic Program for providing us with a small quantity of pleurotin. P.A.K. thanks the Cyprus Research Promotion Foundation [Grants: NEAYPODOMH/NEKYP/0308/02 and YGEIA/BIOS/0308(BIE)/13], the University of Cyprus (Medium Sized Grant), and the following organizations in Cyprus for generous donations of chemicals and glassware: the State General Laboratory, the Agricultural Research Institute, the Ministry of Agriculture, Medochemie Ltd and Biotronics Ltd. Furthermore, P.A.K. thanks the A. G. Leventis Foundation for helping to establish the NMR facility in the University of Cyprus.2018-05-3

N1-(5-Fluoro-2,4-dinitrophenyl)-N2-phenyl-4-(trifluoromethyl)benzene-1,2-diamine

Treating 1,5-difluoro-2,4-dinitrobenzene (1) with N1-phenyl-5-(trifluoromethyl)benzene-1,2-diamine (4) and N,N-diisopropylethylamine in EtOH at ca. 0 °C for 4 h affords a mixture of N1-(5-ethoxy-2,4-dinitrophenyl)-N2-phenyl-4-(trifluoromethyl)benzene-1,2-diamine (5) (38%) and N1-(5-fluoro-2,4-dinitrophenyl)-N2-phenyl-4-(trifluoromethyl)benzene-1,2-diamine (6) (51%) that can be separated by chromatography. Repeating the reaction in dichloromethane led to the sole formation of N1-(5-fluoro-2,4-dinitrophenyl)-N2-phenyl-4-(trifluoromethyl)benzene-1,2-diamine (6) in 96% yield

N1-(5-Fluoro-2,4-dinitrophenyl)-N2-phenyl-4-(trifluoromethyl)benzene-1,2-diamine

Treating 1,5-difluoro-2,4-dinitrobenzene (1) with N1-phenyl-5-(trifluoromethyl)benzene-1,2-diamine (4) and N,N-diisopropylethylamine in EtOH at ca. 0 °C for 4 h affords a mixture of N1-(5-ethoxy-2,4-dinitrophenyl)-N2-phenyl-4-(trifluoromethyl)benzene-1,2-diamine (5) (38%) and N1-(5-fluoro-2,4-dinitrophenyl)-N2-phenyl-4-(trifluoromethyl)benzene-1,2-diamine (6) (51%) that can be separated by chromatography. Repeating the reaction in dichloromethane led to the sole formation of N1-(5-fluoro-2,4-dinitrophenyl)-N2-phenyl-4-(trifluoromethyl)benzene-1,2-diamine (6) in 96% yield

5,6,7,8-Tetrafluoro-1-(2-nitrophenyl)-3-phenyl-1H-benzo[e][1,3,4]oxadiazine

Treating 1-fluoro-2-nitrobenzene (6) with N′-pentafluorophenylbenzohydrazide (7) and K2CO3 (1.1 equiv) in EtOH at ca. 110 °C (sealed tube) for 24 h affords 5,6,7,8-tetrafluoro-1-(2-nitrophenyl)-3-phenyl-1H-benzo[e][1,3,4]oxadiazine (5) (36%) and N′-(2-nitrophenyl)-N′-(perfluorophenyl)benzohydrazide (3) (37%). The X-ray crystallography of 5,6,7,8-tetrafluoro-1-(2-nitrophenyl)-3-phenyl-1H-benzo[e][1,3,4]oxadiazine (5) is provided. Microwave irradiation (100 W) of perfluorophenylbenzohydrazide 3 with K2CO3 (1.1 equiv) in THF at ca. 120 °C (sealed tube, 80 PSI) for 3 h gives oxadiazine 5 (85%), while reduction of the nitro group using Sn (4 equiv) in glacial acetic acid at ca. 20 °C for 30 min, followed by cyclodehydration at ca. 118 °C for 20 min and treatment with 2 M NaOH for 24 h resulted in 1-(perfluorophenyl)-3-phenyl-1,2,4-benzotriazin-4-yl (4) with 93% yield

Synthesis and Characterization of Isodiphenylfluorindone and Isodiphenylfluorindinone

Isodiphenylfluorindone <b>6</b> and isodiphenylfluorindinone <b>7</b> are synthesized. The former reacts with NaOMe to give the 13-methoxyisodiphenylfluorindone <b>22</b> (95%), while the latter reacts with 70% perchloric acid to give the bisperchlorate <b>21</b> (87%) and with MnO₂ dimerizes to give <b>13</b>,13′-bi­(isodiphenylfluorindone) <b>4</b> (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 <b>7</b>

Synthesis and Characterization of Isodiphenylfluorindone and Isodiphenylfluorindinone

Isodiphenylfluorindone <b>6</b> and isodiphenylfluorindinone <b>7</b> are synthesized. The former reacts with NaOMe to give the 13-methoxyisodiphenylfluorindone <b>22</b> (95%), while the latter reacts with 70% perchloric acid to give the bisperchlorate <b>21</b> (87%) and with MnO₂ dimerizes to give <b>13</b>,13′-bi­(isodiphenylfluorindone) <b>4</b> (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 <b>7</b>

Oxidation of Isodiphenylfluorindine: Routes to 13‑Oxoisodiphenylfluorindinium Perchlorate and Fluorindine Cruciform Dimers

Isodiphenylfluorindine (<b>5</b>) reacts with K₂Cr₂O₇/H⁺ to give 13-oxoisodiphenylfluorindinium perchlorate (<b>7</b>) (75%), but with phenyliodine bis­(trifluoroacetate) (PIFA) or MnO₂ it gives the zwitterionic and quinoidal cruciform 13,13′-dimers <b>11</b> (85%) and <b>12</b> (89%), respectively. The zwitterionic 13,13′-dimer <b>11</b> can be rapidly converted with MnO₂ into the quinoidal 13,13′-dimer <b>12</b> (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

Toward N-<i>peri</i>-Annulated Planar Blatter Radical through aza-Pschorr and Photocyclization

Preparation of the elusive N-peri-annulated planar Blatter radicals was attempted using aza-Pschorr and photocyclization methods. In both methods, substrates containing N–Me and N–Ac groups yielded a zwitterionic heterocycle lacking the N-substituent as the main product, while in one of them a carbazole derivative representing a new heterocyclic system was also obtained. The formation of the zwitterion and the carbazole suggests the formation of the desired planar Blatter radical, which undergoes facile fragmentation through homolysis of the N–R bond. This mechanism is supported by DFT computational results, which also suggest that N-Ar derivatives should be sufficiently stable for isolation. Electronic structures of three planar Blatter radicals annulated with the O, S, and N–Ph groups are compared