Phenoxazine structure

Phenoxazine-1,9-dicarboxylie acid, 2-amino-4,6-dimethyI-3-oxo-occurrence, 3, 1037 Phenoxazines arylation, 3, 1011 electrophilic reactions, 3, 1012 nitration, 3, 1012 nomenclature, 3, 996 oxidation, 3, 1010 reactions, 3, 1011 structure, 2, 4, 7-8 3, 1010 synthesis, 3, 1033... 

Oxidation of P-nicotinamide adenine dinucleotide (NADH) to NAD+ has attracted much interest from the viewpoint of its role in biosensors reactions. It has been reported that several quinone derivatives and polymerized redox dyes, such as phenoxazine and phenothiazine derivatives, possess catalytic activities for the oxidation of NADH and have been used for dehydrogenase biosensors development [1, 2]. Flavins (contain in chemical structure isoalloxazine ring) are the prosthetic groups responsible for NAD+/NADH conversion in the active sites of some dehydrogenase enzymes. Upon the electropolymerization of flavin derivatives, the effective catalysts of NAD+/NADH regeneration, which mimic the NADH-dehydrogenase activity, would be synthesized [3]. 

Fig. 6.8. Structures of some common fluorophores. DPH = diphenylhexatriene NBD = nitrobenzoxadiazole Tb-DTPA-csl24 = terbium diethylenetriaminepentacetate-carbostyril 124, DAPI = 4, 6-diamidino-2-phenylindole Nile red = 9-(diethylamino)-5H-benzo-[a]phenoxazin-5-one.

Thimmaiah, K.N., Horton, J.K., Qian, X.D., Beck, W.T., Houghton, J.A. and Houghton, J. (1990) Structural determinants of phenoxazine type compounds required to modulate the accumulation of vinblastine and vincristine in multidrug-resistant cell lines. Cancer Communications, 2, 249-259. 

It is interesting to compare the biphenylamine substituted compounds with the corresponding carbazoles, phenoxazines, and phenothiazines. For the triaryla-mino-based structures, the carbazole 24 has the highest oxidation potential (0.69 V vs. Ag/0.01 Ag+) [102], followed by the phenoxazine 25a (0.46 V vs. Ag/0.01 Ag+) [166]. A similar observation was made for the corresponding derivatives of 36a the phenothiazine (0.27 V vs. Fc/Fc+) and the phenoxazine (0.29 V vs. Fc/Fc+) have higher oxidation potentials than the parent compound. The carbazole 37 has an even higher oxidation potential, but in this case the oxidation is not reversible [234]. The redox properties of carbazoles are not fully understood yet. In some devices, a carbazole such as CBP (10) was used as an interface layer on the cathode side, suggesting a lower barrier for electron injection [50]. 

A group at Lilly reported that phenoxazine (89) is a potent inhibitor of cRBL (0.02 iM) [237]. Substitution at the 1-position by carboxylic acid, ester, or hydroxamic acid groups decreased potency 10- to 30-fold. Substitution at the 2-position was less destructive of inhibition as long as the substituent was lipophilic (ester, acrylate ester) carboxylate caused a 200-fold loss of potency. Activity in rat neutrophils has been disclosed for related structures in patents from Bayer [238]. The second aromatic ring is not required, as shown by the activity of series exemplified by (90)-(92) [239-242]. Antiasthmatic activity was indicated for these compounds, but few details were given. 

It seems likely that aromatic amines which are found in liquefaction products have been produced by a combination of thermolysis and hydrogenation. There is no evidence for aromatic amines in coals from either selective oxidation degradations (22) or from direct X-ray Photoelectron Spectroscopy measurements (23). Oxidations would produce very stable nitroaromatics which are not seen. Another possible structure for this formula is phenoxazine(Vb). Such a molecule would not survive high temperature combined with long reaction times. Although annelated thiophene with a pyrrole(VI) would appear to be a likely structure in coal, there is no evidence for its existence in any of the coal derived materials. 

In addition, there is evidence that a class of compounds including thianthrene(II), phenoxathiin(VIIb) and phenoxazine(Vb) may be present in this coal. These compounds are thermally quite reactive and would probably not survive extended pyrolysis or liquefaction conditions. Instead, they will convert into the more stable dibenzothiophenes. This would suggest that chemical or biological removal of these compounds could be more efficient than a thermal process. Work is in progress to better characterize these structures by among other approaches HRMS/MS. 

Some of the structures reported from this laboratory for making CMEs for electrocatalytic oxidation of NADH are summarized in Figure 5. We have found that a positively charged paraphenylene-diimine is the best basic catalytic structure (55,83,84-87,89,91,92). When it is incorporated as a part of a phenoxazine or a phenothiazine (see Figure 5) some very beneficial properties are added to the mediator. The E° values are decreased with some 300 to 400 mV compared with the free paraphenylenediimine structure (57,58,102) and they strongly adsorb on graphite electrodes to form CMEs allowing NADH to be electrocatalytically oxidized well below 0 mV (55,83,84-87,89,91,92). 

Figure 5. Some structural formulae of phenazine, phenoxazine, and phenothiazine mediators used at this laboratory for making CMEs used for electrocatalytic oxidation with NADH. continued on next page.

Actinomycin D has been clinically used for the treatment of many cancers and is known to be a DNA intercalator. The structure of actinomycin D is based on a phenoxazine ring bound to two cyclic pentapeptides [33]. The presence of the phenoxazine ring in the structure of actinomycin D suggests that phenoxazine derivatives may possess anticancer activity. Phenoxazine derivatives are known to be effective multidrug resistance (MDR) modulators in cancer cells [34], potent inhibitors of Akt signaling in cells [35], inhibitors of human plasma cholinesterase [36], and photo-chemotherapeutic agents in cancer cells [37]. Recent studies also show that the relatively water-soluble phenox-azines, such as 2-amino-4,4a-dihydro-4a,7-dimethyl-2H-phenoxazine-3-one and 2-aminophenoxazine-3-one, exert antitumor effects on various cancer cells in vitro and in vivo. [38]. We have investigated 24 phenoxazines [23,39] (Fig. 4). 

The electron spin resonance spectra of the positive radical ion formed by phenoxazine in acid solution have been reported by Tuck and Schieser.48 This radical is similar in structure to the free radical ion formed with anthracene (which, however, is strictly planar), but it is considerably more stable, owing to the greater possibilities of resonance due to the presence of nitrogen in the central ring. For this... 

The radical ion of phenoxazine has a uniformly spaced four-line spectra with the line intensities in the ratio 1 2 2 1. The measured coupling constant was 9.83 gauss, the line width 8.19 gauss, and the g value 2.0049. This hyperfine structure can be interpreted as a basic three-line splitting by the nitrogen-14 nucleus (nuclear spin 1) and a doublet splitting with nearly identical spacing due to the attached acidic proton (nuclear spin ). 

The condensation of phenoxazine in refluxing benzene with thio-phosgene, in order to obtain the 10-thiocarbonyl chloride, gave only a black unidentified precipitate, while the filtrate yielded a yellow compound to which structure 41 was assigned.77 Phenoxazine treated... 

Electrodes doped with mediators are also successful in analyses using NAD (P)-dependent dehydrogenases (86-88). In these cases, the mediator is firmly adsorbed to the electrode. The cofactor is oxidized by the mediator, which becomes reduced. The mediator is reoxidized by an electrochemical process on the electrode. This technology makes it possible to reduce the amount of cofactor needed, for example, in flow injection analysis and also eliminates the need for enzymatic regeneration systems. A further successful development uses a carbon paste chemically modified with a dehydrogenase, the coenzyme, and a phenoxazine mediator. This complex structure is then coated with a polyester sulfonic acid cation exchanger (86). The mediators used are of aromatic polycyclic structure and are firmly bound to graphite or other carbon electrodes (Fig. 2) (89). 

It would be interesting to investigate whether or not such configurational effects are also encountered in other structurally related molecules, like phenoxazine, phenoselenazine, etc. The paper of Malrieu and Pullman on isoalloxazines is a start in this direction. 

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