Phenoxazine Ring Research Articles

Synthesis and chemical characterization of N-substituted phenoxazines directed toward reversing vinca alkaloid resistance in multidrug-resistant cancer cells.

A series of 21 N-substituted phenoxazines has been synthesized in an effort to find more specific and less toxic modulators of multidrug resistance (MDR) in cancer chemotherapy. Thus, N-(omega-chloroalkyl)- and N-(chloroacyl)phenoxazines were found to undergo iodide-catalyzed nucleophilic substitution on reaction with various secondary amines, including N,N-diethylamine, N,N-diethanolamine, morpholine, piperidine, pyrrolidine and (beta-hydroxyethyl)piperazine. Products were characterized by UV, IR, 1H-, and 13C-NMR, mass spectral data, and elemental analyses. All of the compounds were examined for cytotoxicity and for their ability to increase the accumulation of the vinca alkaloids, vincristine (VCR) and vinblastine (VLB) in multidrug-resistant GC3/Cl (human colon adenocarcinoma) and KBChR-8-5 (HeLa variant) cell lines. Compounds were compared to the standard modulator verapamil (VRP). Substitutions on the phenoxazine ring at position 10 were associated with an increase in antiproliferative and anti-MDR activities. Modification of the length of the alkyl bridge and the type of amino side chain also influenced the potency of these effects. From among the compounds examined, 10 derivatives were found to increase the accumulation of VCR and VLB in GC3/Cl and KBChR-8-5 cells relative to the effect of VRP, suggesting that with the exception of pyrrolidinyl, the tertiary amine attachments to the phenoxazine nucleus linked through a three- or four-carbon alkyl chain resulted in enhanced anti-MDR activity. On the basis of their 50% growth inhibitory (IC50) values, five of the ten compounds, namely, 10-(3'-chloropropyl)phenoxazine, 10-[3'-[N-bis(hydroxyethyl)- amino]propyl]phenoxazine, 10-(3'-N-morpholinopropyl)phenoxazine, 10-(4'-N-morpholinobutyl)phenoxazine and 10-(N-piperidinoacetyl)phenoxazine were selected as relatively nontoxic chemosensitizers. These modulators, at nontoxic concentrations, potentiated the cytotoxicity of VCR and VLB in GC3/Cl and KBChR-8-5 cells. Further, two compounds 10-(3'-N-morpholinopropyl)phenoxazine, and the butyl derivative, enhanced accumulation of VLB in GC3/Cl, KBChR8-5 and highly resistant KB-V1 cells to a level significantly greater than the maximal level achieved with VRP. Additional experiments to understand the mechanism of action of these agents in modulating MDR are in progress.

Formation of a novel electroactive film by electropolymerization of ortho-aminophenol : Study of its chemical structure and formation mechanism. Electropolymerization of analogous compounds

The anodic oxidation of ortho-aminophenol ( oAP) in acid aqueous media on different electrode materials, leads to the formation of an electroactive polymer, poly( oAP). Cyclic voltammetric studies allow the inference of a quite complex mechanism for the formation of this film. These studies and the spectroscopie data suggest that the structure of poly( oAP) is mainly a polymer of phenoxazine rings. To confirm these studies the electroactive polymer was also prepared by chemical oxidation of oAP and its properties were compared with those of the electrochemically produced poly( oAP). Moreover, a film was obtained by electrooxidation of the cyclic dimer of oAP, the 3-aminophenoxazone (3APZ). The differences between these films are discussed, leading to the conclusion that the actual monomer in the formation of poly( oAP) is 3APZ. However, the fact that the film obtained from pure 3APZ has an ideal nernstian behavior while the one obtained from oAP does not, gives evidence that side reactions and consequently a “side” polymer make the real structure of poly( oAP) more complex. Then the conditions for obtaining reproducible poly( oAP) modified electrodes are proposed. In addition, the electrochemical oxidation of compounds structurally related to oAP was carried out. The studies with m- and p-aminophenol show that o-hydroxy-substitution of anilines is required for the formation of ring chain films like poly( oAP). The o-anisidine gives a linear polymer of the polyaniline type, since the formation of a cyclic dimer is hindered. The mechanism of electropolymerization of o-phenylenediamine and its cyclic dimer (2,3-aminophenazine) seems to have similar features to that of oAP.

“Reverse chromophore” of actinomycin d. Synthesis of 2‐substituted 7‐amino‐8H‐8‐oxo‐oxazolo[4,5‐b] phenoxazine ring system

AbstractThe synthesis and physico‐chemical properties of a new 7‐amino‐8H‐8‐oxo‐oxazolo[4,5‐b]‐phenoxazine ring system (8a and 8b) are reported. These tetracyclic heteroaromatic rings posses an extra oxazolo ring fused to the phenoxazinone chromophore observed in actinomycin D (1b). These tetracyclic compounds (8a‐8b) possess a structure in which the orientation of the A and B rings in 1b are “reversed”. Since DNA binding and the resulting specificity of the antitumor antibiotic 1b is believed to depend on the spatial orientation of P(α) and P(β) relative to the functions on the B ring of 1b, these new compounds represent a novel approach for investigating AMD‐DNA interactions.

Biological, proton-magnetic-resonance- and ultraviolet-spectroscopic evidence for a molecular complex of actinomycin D and 10,11-dihydro-3H-naphth (1,2-g)indazol-7-ol.

A proton-magnetic-resonance study of the complex formed between actinomycin D and 10,11-dihydro-3H-naphth[1,2-g]indazol-7-ol strongly suggests that the indazole lies above the phenoxazine ring of actinomycin D. The complex can be destroyed by addition of dimethyl sulphoxide or dimethylformamide. The actinomycin D-indazole complex inhibits growth of Pseudomonas fluorescens and raises the thermal denaturation response of DNA. These data support the hypothesis that a molecular complex is formed which readily inhibits cell growth and interacts with DNA.

Studies on phenoxazine related compounds. V. Photochemical reaction of 4-tosyl-1,2,3,4-tetrahydro(1,4)diazepino(3,2,1-kl)phenoxazine, 3-tosyl-1,2-dihydro-3H-pyrazino(3,2,1-kl)phenoxazine and 2-tosyl-1,2-dihydroimidazo(4,5,1-kl)phenoxazine

Irradiation of 4-tosyl-1, 2, 3, 4-tetrahydro [1, 4] diazepino [3, 2, 1-kl] phenoxazine (V) in 70% ethanol with 100 W high-pressure mercury lamp in the presence of sodium borohydride and sodium carbonate gave 1, 2, 3, 4-tetrahydro [1, 4] diazepino [3, 2, 1-kl] phenoxazine (VI) and 1-(2'-hydroxyphenyl)-2, 3, 4, 5-tetrahydro-1H-benzo [b]-1, 4-diazepine (VII), accompanied with the opening of the phenoxazine ring. Photochemical reaction of V in dry ethanol or dry benzene afforded VI and 7-tosyl-1, 2, 3, 4-tetrahydro [1, 4] diazepino [3, 2, 1-kl] phenoxazine (XIII), with rearrangement of the tosyl group. Similar reaction of 3-tosyl-1, 2-dihydro-3H-pyrazino [3, 2, 1-kl] phenoxazine (I) gave 1, 2-dihydro-3H-pyrazino [3, 2, 1-kl] phenoxazine (III) and 6-tosyl-1, 2-dihydro-3H-pyrazino [3, 2, 1-kl] phenoxazine (XVII). The synthetic mechanisms of these reaction were examined.