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PubMed1988

Metabolites of microorganisms. 247. Phenazines from Streptomyces antibioticus, strain Tü 2706.

From a strain of Streptomyces antibioticus seven yellow phenazines were isolated. The antibacterially most active antibiotic was identified as (-)-saphenamycin, a second one with compound DC-86-Y (saphenic acid). Three compounds were new: Saphenic acid methyl ether, 6-acetylphenazine-1-carboxylic acid and an inseparable mixture of fatty acid esters of saphenic acid. Two simple phenazines were phenazine-1-carboxylic acid (tubermycin B) and unsubstituted phenazine, which was isolated for the first time from a microorganism.

Microbial Sensitivity Tests↗
PubMed2001

Growth of Pseudomonas aureofaciens PGS12 and the Dynamics of HHL and Phenazine Production in Liquid Culture, on Nutrient Agar, and on Plant Roots.

The growth of Pseudomonas aureofaciens PGS12 was followed in nutrient broth (NB), on nutrient agar (NA), and on plant roots by monitoring cell numbers, the production of the autoinducer hexanoyl-homoserine lactone (HHL), and the antibiotic phenazine-1-carboxylic acid (PCA). In NB, as the growth rate declined in transition phase, HHL synthesis increased rapidly, shortly followed by PCA production. During stationary phase, HHL concentration declined rapidly while PCA concentration continued to increase slowly. The luxAB reporter genes were inserted in the phzB gene of the phenazine operon and phenazine transcriptional activity was monitored using measurement of luminescence. Levels and pattern of light output were similar to HHL accumulation and indicated that gene expression was maximal in transition phase and silenced in stationary phase. PCA production continued in stationary phase, suggesting that the protein products of the phenazine operon were maintained in the cell after down regulation. HHL accumulation was 60 times higher on NA than in NB per equivalent volume because of a 60-fold increase in cell density on NA. Higher levels of PCA per cell (6.8 times) and per equivalent volume (360-fold) accumulated in a colony compared to that found in broth. HHL remained at a high concentration in a colony for a longer period compared to a short burst in NB, and this may explain the increased PCA production. In contrast, on wheat seedlings and bean plant roots, bacterial growth was observed, but neither HHL nor PCA was detected; however, transcriptional activity of the phzB::luxAB reporter occurred on the bean plant roots.

Journal Article↗
PubMed1986

Cyclic voltammetry of phenazines and quinoxalines including mono- and di-N-oxides. Relation to structure and antimicrobial activity.

Cyclic voltammetry data were obtained for eight phenazines and phenazine-N-oxides, and eleven quinoxalines and quinoxaline-N-oxides: 1,6-phenazine-diol-5,10-dioxide (iodinin), iodinin copper complex, 6-methoxy-1-phenazinol-5,10-dioxide 1,6-dimethoxyphenazine-5-oxide, 1,6-phenazinediol, 1,6-dimethoxyphenazine, quinoxaline-1,4-dioxide, 2-methylquinoxaline-1,4-dioxide, 2,3-diphenylquinoxaline-1,4-dioxide, 2-carboxyquinoxaline-1,4-dioxide, 5-hydroxyquinoxaline-1,4-dioxide, 5-hydroxy-8-methoxyquinoxaline-1,4-dioxide, 2-methylquinoxaline, 2,3-diphenylquinoxaline, 5-hydroxyquinoxaline, 5-hydroxy-8-methoxyquinoxaline and 2-(2-quinoxalinylmethylene)hydrazine carboxylic acid methyl ester-1,4-dioxide (Carbadox). The di-N-oxides exhibit the most positive E1/2 values within each class. Reversible first wave reductions were observed for iodinin, iodinin copper complex, 1,6-dimethoxyphenazine-5-oxide, 1,6-dimethoxyphenazine, quinoxaline-1,4-dioxide, 2-methylquinoxaline-1,4-oxide and 2,3-diphenylquinoxaline-1,4-dioxide. The results are correlated with structure. Some relationships exist between reduction potential and reported antimicrobial activity. A possible mechanism of drug action is addressed.

Anti-Bacterial Agents↗
PubMed1986

Phenazine methosulfate induces a neurally-mediated contraction of the guinea-pig ileum.

Phenazine methosulfate (PMS) and related phenazines are widely used in biochemistry and histochemistry and act as anti-bacterial agents, however, there is little information on their pharmacological actions. In the present paper the guinea-pig ileum was used as a model for studying the effects of PMS on nerve cells. PMS was found to contract intestinal muscle. This action appeared to be mediated by the activation of muscarinic receptors since it was blocked by atropine. Neostigmine potentiated the response to PMS. The nerve blocker tetrodotoxin prevented the effect of PMS and it is concluded that PMS causes the release of acetylcholine from nerve elements. The action of PMS on nerves is not mediated by nicotinic receptors. Receptors for serotonin, substance P or cholecystokinin also appear not to be involved. Of all the phenazines tested PMS was found to be the most potent and reversible.

Acetylcholine↗
PubMed1984

Inhibition by superoxide dismutase and catalase of the damage of isolated Leishmania mexicana amazonensis by phenazine methosulfate.

Phenazine methosulfate, a cationic electron carrier, inhibits the extracellular growth of promastigotes and the conversion of amastigotes into promastigote forms of Leishmania mexicana amazonensis. Growth inhibition and damage of extracellular parasites by PMS was counteracted by superoxide dismutase, a scavenger of the superoxide anion (O2-), and to a lesser extent, by catalase, a scavenger of hydrogen peroxide (H2O2). Inactivated dismutase and catalase were ineffective. Thus, damage of isolated L.m. amazonensis by phenazine methosulfate, involves the participation of O2- and H2O2. The role of the oxygen metabolites in the toxicity of phenazine methosulfate remains unknown. That O2- can damage the parasites is supported by the finding that superoxide dismutase also protected promastigotes from damage induced by oxygen intermediates generated by a xanthine-xanthine oxidase system. Killing of the parasites by crystal violet, a triphenylmethane, or basic blue 24, a phenothiazine, was not inhibited by superoxide dismutase.

Animals↗
PubMed2005

Novel synthetic isoquinolino[5,4-ab]phenazines: inhibition toward topoisomerase I, antitumor and DNA photo-cleaving activities.

The novel DNA interactive isoquinolino[5,4-ab]phenazine derivatives were designed and synthesized. Their inhibitory abilities toward topoisomerase I, antitumor activities and DNA photo-cleaving abilities were examined. The substituents at peri sites of two phenazine N atoms played very important roles for all these biological activities. At a concentration of 100 microM, all these phenazine derivatives (but A2 and A6) exhibited an inhibitory activity toward topoisomerase I. A6 had efficient antitumor activities against both human lung cancer cell (A549) and murine leukemia cell (P388). A1, A5, and A6 exhibited antitumor activities selectively against P388. A2 was the most efficient DNA photocleaver, which had converted supercoiled DNA from form I to form II at <1 microM. Under anaerobic conditions, the electron transfer mechanism mainly contributed to DNA photo-induced cleavage, while under aerobic conditions, superoxide anion was also involved in this process.

Antineoplastic Agents↗
PubMed1993

Pseudomonas fluorescens var. aluphilia--the influence of Al3+ on the growth rate and formation of phenazines.

The thin-layer chromatographic characterization of phenazine derivatives formed by a subspecies of Pseudomonas fluorescens under iron deficiency conditions in the presence of Al3+ showed that regarding type and quantity they were relatively different from phenazines generated on the basis of Be(2+)-containing culture media or containing neither Be2+ ions nor Al3+ ions. A comparison has shown that bacterial synthesis of phenazine derivatives is stimulated more by Be2+ ions than by Al3+ ions.

Aluminum↗
PubMedDate not supplied

Sequence-recognition and cleavage of DNA by a netropsin-phenazine-di-N-oxide conjugate.

We report the synthesis, DNA-binding and cleaving properties, and cytotoxic activities of R-128, a hybrid molecule in which a bis-pyrrolecarboxamide-amidine element related to the antibiotic netropsin is covalently tethered to a phenazine-di-N-oxide chromophore. The affinity and mode of interaction of the conjugate with DNA were investigated by a combination of absorption spectroscopy, circular dichroism, and electric linear dichroism. This hybrid molecule binds to AT-rich sequences of DNA via a bimodal process involving minor groove binding of the netropsin moiety and intercalation of the phenazine moiety. The bidentate mode of binding was evidenced by linear dichroism using calf thymus DNA and poly(dA-dT).(dA-dT). In contrast, the drug fails to bind to poly(dG-dC).poly(dG-dC), because of the obstructive effect of the guanine 2-amino group exposed in the minor groove of this polynucleotide. DNase I footprinting studies indicated that the conjugate interacts preferentially with AT-rich sequences, but the cleavage of DNA in the presence of a reducing agent can occur at different sequences not restricted to the AT sites. The main cleavage sites were detected with a periodicity of about 10 base pairs corresponding to approximately one turn of the double helix. This suggests that the cleavage may be dictated by the structure of the double helix rather than the primary nucleotide sequence. The conjugate which is moderately toxic to cancer cells complements the tool box of reagents which can be utilized to produce DNA strand scission. The DNA cleaving properties of R-128 entreat further exploration into the use of phenazine-di-N-oxides as tools for investigating DNA structure.

Animals↗
PubMed2003

Structure and mechanism of Pseudomonas aeruginosa PhzD, an isochorismatase from the phenazine biosynthetic pathway.

PhzD from Pseudomonas aeruginosa is an isochorismatase involved in phenazine biosynthesis. Phenazines are antimicrobial compounds that provide Pseudomonas with a competitive advantage in certain environments and may be partly responsible for the persistence of Pseudomonas infections. In vivo, PhzD catalyzes the hydrolysis of the vinyl ether functional group of 2-amino-2-deoxyisochorismate, yielding pyruvate and trans-2,3-dihydro-3-hydroxyanthranilic acid, which is then utilized in the phenazine biosynthetic pathway. PhzD also catalyzes hydrolysis of the related vinyl ethers isochorismate, chorismate, and 4-amino-4-deoxychorismate. Here we report the 1.5 A crystal structure of native PhzD, and the 1.6 A structure of the inactive D38A variant in complex with isochorismate. The structures reveal that isochorismate binds to the PhzD active site in a trans-diaxial conformation, and superposition of the structures indicates that the methylene pyruvyl carbon of isochorismate is adjacent to the side chain carboxylate of aspartate 38. The proximity of aspartate 38 to isochorismate and the complete loss of activity resulting from the conversion of aspartate 38 to alanine suggest a mechanism in which the carboxylate acts as a general acid to protonate the substrate, yielding a carbocation/oxocarbonium ion that is then rapidly hydrated to form a hemiketal intermediate, which then decomposes spontaneously to products. The structure of PhzD is remarkably similar to other structures from a subfamily of alpha/beta-hydrolase enzymes that includes pyrazinamidase and N-carbamoylsarcosine amidohydrolase. However, PhzD catalyzes unrelated chemistry and lacks a nucleophilic cysteine found in its close structural relatives. The vinyl ether hydrolysis catalyzed by PhzD represents yet another example of the catalytic diversity seen in the alpha/beta-hydrolase family, whose members are also known to hydrolyze amides, phosphates, phosphonates, epoxides, and C-X bonds.

Catalytic Domain↗
PubMed1987

Potential antitumor agents. 51. Synthesis and antitumor activity of substituted phenazine-1-carboxamides.

In a further investigation of electron-deficient DNA-intercalating ligands as antitumor drugs, a series of substituted N-[2-(dimethylamino)ethyl]phenazine-1-carboxamides have been synthesized and evaluated. Fluorine-directed ring closure of N-phenyl-3-nitroanthranilic acids provided a new, unequivocal synthesis of several of the required phenazine-1-carboxylic acids, and the corresponding carboxamides were prepared and evaluated against L1210 leukemia in vitro and against P388 leukemia and Lewis lung carcinoma in vivo. Substitution on the phenazine ring was broadly tolerated, and the cytotoxicity of the resulting compounds correlated positively with the electron-withdrawing power of the substituent group. The positional effects of substituents were even more evident, with 9-substituted compounds being the most active. One derivative, N-[2-(dimethylamino)ethyl]-9-methoxyphenazine-1-carboxamide, had activity against Lewis lung carcinoma in mice equal to that of the best DNA-intercalating agents yet described, being capable of effecting a high-proportion cure of the advanced disease.

Amides↗
PubMed2000

Bis(phenazine-1-carboxamides): structure-activity relationships for a new class of dual topoisomerase I/II-directed anticancer drugs.

Ring-substituted bis(phenazine-1-carboxamides), linked by a -(CH(2))(3)NMe(CH(2))(3)- chain, were prepared from the corresponding substituted phenazine-1-carboxylic acids by reaction of the intermediate imidazolides with bis(3-aminopropyl)methylamine. The compounds were evaluated for growth inhibitory activity in a panel of tumor cell lines, including P388 leukemia, Lewis lung carcinoma, and wild-type (JL(C)) and mutant (JL(A) and JL(D)) forms of human Jurkat leukemia. The latter mutant lines are resistant to topoisomerase (topo) II targeted agents because of lower levels of the enzyme. Analogues with small, lipophilic substituents (e.g., Me, Cl) at the 9-position were the most potent inhibitors, superior to the corresponding dimeric bis(acridine-4-carboxamides) (bis-DACA analogues). Several of the compounds were preferentially (up to 2-fold) more cytotoxic toward the mutant Jurkat lines than the wild-type. To test whether this selectivity was related to topoisomerase action, the most potent of the compounds (9-methyl) was evaluated in a cell-free system. It poisoned topo I at drug concentrations of 0.25 and 0.5 microM and inhibited the catalytic activity of both topo I and topo II at concentrations of 1 and 5 microM, respectively. Results from the NCI human tumor cell line panel showed the compounds had preferential activity toward colon tumor lines (on average 9.5-fold more active in the HT29 line than in the cell line panel as a whole). Several analogues produced significant growth delays in the relatively refractory subcutaneous colon 38 tumor model in vivo. In particular, the 9-methyl compound was substantially more potent in this tumor model than the clinical dual topo I/II poison DACA (total dose 90 versus 400 mg/kg) with comparable activity. The bis(phenazine-1-carboxamides) are a new and interesting class of dual topo I/II-directed anticancer drugs.

Amides↗
PubMed2005

Photoexcitation in Cu(I) and Re(I) complexes containing substituted dipyrido[3,2-a:2',3'-c]phenazine: a spectroscopic and density functional theoretical study.

Copper(I) and rhenium(I) complexes [Cu(PPh(3))(2)(dppz-11-COOEt)]BF(4), [Cu(PPh(3))(2)(dppz-11-Br)]BF(4), [Re(CO)(3)Cl(dppz-11-COOEt)] and [Re(CO)(3)Cl(dppz-11-Br)] (dppz-11-COOEt = dipyrido-[3,2a:2',3'c]phenazine-11-carboxylic ethyl ester, dppz-11-Br = 11-bromo-dipyrido[3,2a:2',3'c]-phenazine) have been studied using Raman, resonance Raman, and transient resonance Raman (TR(2)) spectroscopy, in conjunction with computational chemistry. DFT (B3LYP) frequency calculations with a 6-31G(d) basis set for the ligands and copper(I) centers and an effective core potential (LANL2DZ) for rhenium in the rhenium(I) complexes show close agreement with the experimental nonresonance Raman spectra. Modes that are phenazine-based, phenanthroline-based, and delocalized across the entire ligand structure were identified. The nature of the absorbing chromophores at 356 nm for ligands and complexes was established using resonance Raman spectroscopy in concert with vibrational assignments from calculations. This analysis reveals that the dominant chromophore for the complexes measured at 356 nm is ligand-centered (LC), except for [Re(CO)(3)Cl(dppz-11-Br)], which appears to have additional chromophores at this wavelength. Calculations on the reduced complexes, undertaken to model the metal-to-ligand charge transfer (MLCT) excited state, show that the reducing electron occupies a ligand MO that is delocalized across the ligand structure. Resonance Raman spectra (lambda(exc) = 514.5 nm) of the reduced rhenium complexes show a similar spectral pattern to that observed in [Re(CO)(3)Cl(dppz)](*-); the measured bands are therefore attributed to ligand radical anion modes. These bands lie at 1583-1593 cm(-1) for [Re(CO)(3)Cl(dppz-11-COOEt)] and 1611 cm(-1) for [Re(CO)(3)Cl(dppz-11-Br)]. The thermally equilibrated excited states are examined using nanosecond-TR(2) spectroscopy (lambda(exc) = 354.7 nm). The TR(2) spectra of the ligands provide spectral signatures for the (3)LC state. A band at 1382 cm(-1) is identified as a marker for the (3)LC states of both ligands. TR(2) spectra of the copper and rhenium complexes of dppz-11-Br show this (3)LC band, but it is not prominent in the spectra of [Cu(PPh(3))(2)(dppz-11-COOEt)](+) and [Re(CO)(3)Cl(dppz-11-COOEt)]. Calculations suggest that the lowest triplet states of both of the rhenium(I) complexes and [Cu(PPh(3))(2)(dppz-11-Br)](+) are metal-to-ligand charge transfer in nature, but the lowest triplet state of [Cu(PPh(3))(2)(dppz-11-COOEt)](+) appears to be LC in character.

Copper↗
PubMed2001

Tetramethylpiperidine-substituted phenazines inhibit the proliferation of intrinsically multidrug resistant carcinoma cell lines.

The effects of nine new tetramethylpiperidine (TMP)-substituted phenazines on the growth of a human esophageal cancer cell line (WHCO3), two human hepatocellular carcinoma cell lines (PLC and HepG2) and three human colon cancer cell lines (CaCo2, COLO 320DM and HT29) were compared to those of clofazimine, B669 and five standard chemotherapeutic agents. The three most active TMP-substituted phenazines against these cell lines were B3962, B4126 and B4125 with mean IC50 values for all the cancer cell lines tested of 0.36, 0.47 and 0.48 microg/ml respectively. B3962 and B4126, but not B4125 were also the most active against a semi-continuous human fibroblast culture (MRC5). The compound with the highest tumor specificity relative to the fibroblast culture, was B4125. Importantly, there was minimal variation in sensitivity of the different cell lines, including a multidrug resistant cell line (COLO 320DM) expressing high levels of P-glycoprotein, to the TMP-substituted phenazines. This was not the case with the standard chemotherapeutic agents. The efficacy of compounds such as B4125 against a broad spectrum of multidrug resistant cancer cell lines, together with their relatively high tumor specificity, suggests that these agents may be useful in the treatment of intrinsically resistant cancers such as colon and liver cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Root colonization by phenazine-1-carboxamide-producing bacterium Pseudomonas chlororaphis PCL1391 is essential for biocontrol of tomato foot and root rot.

The phenazine-1-carboxamide-producing bacterium Pseudomonas chlororaphis PCL1391 controls tomato foot and root rot caused by Fusarium oxysporum f. sp. radicislycopersici. To test whether root colonization is required for biocontrol, mutants impaired in the known colonization traits motility, prototrophy for amino acids, or production of the site-specific recombinase, Sss/XerC were tested for their root tip colonization and biocontrol abilities. Upon tomato seedling inoculation, colonization mutants of strain PCL1391 were impaired in root tip colonization in a gnotobiotic sand system and in potting soil. In addition, all mutants were impaired in their ability to control tomato foot and root rot, despite the fact that they produce wild-type levels of phenazine-1-carboxamide, the antifungal metabolite previously shown to be required for biocontrol. These results show, for what we believe to be the first time, that root colonization plays a crucial role in biocontrol, presumably by providing a delivery system for antifungal metabolites. The ability to colonize and produce phenazine-1-carboxamide is essential for control of F. oxysporum f. sp. radicis-lycopersici. Furthermore, there is a notable overlap of traits identified as being important for colonization of the rhizosphere and animal tissues.

Amino Acid Sequence↗
PubMed2001

Introduction of the phzH gene of Pseudomonas chlororaphis PCL1391 extends the range of biocontrol ability of phenazine-1-carboxylic acid-producing Pseudomonas spp. strains.

Pseudomonas chlororaphis PCL1391 controls tomato foot and root rot caused by Fusarium oxysporum f. sp. radicis-lycopersici. Its biocontrol activity is mediated by the production of phenazine-1-carboxamide (PCN). In contrast, the take-all biocontrol strains P. fluorescens 2-79 and P. aureofaciens 30-84, which produce phenazine-1-carboxylic acid (PCA), do not control this disease. To determine the role of the amide group in biocontrol, the PCN biosynthetic genes of strain PCL1391 were identified and characterized. Downstream of phzA through phzG, the novel phenazine biosynthetic gene phzH was identified and shown to be required for the presence of the 1-carboxamide group of PCN because a phzH mutant of strain PCL1391 accumulated PCA. The deduced PhzH protein shows homology with asparagine synthetases that belong to the class II glutamine amidotransferases, indicating that the conversion of PCA to PCN occurs via a transamidase reaction catalyzed by PhzH. Mutation of phzH caused loss of biocontrol activity, showing that the 1-carboxamide group of PCN is crucial for control of tomato foot and root rot. PCN production and biocontrol activity of the mutant were restored by complementing the phzH gene in trans. Moreover, transfer of phzH under control of the tac promoter to the PCA-producing biocontrol strains P. fluorescens 2-79 and P. aureofaciens 30-84 enabled these strains to produce PCN instead of PCA and suppress tomato foot and root rot. Thus, we have shown, for what we believe is the first time, that the introduction of a single gene can efficiently extend the range of the biocontrol ability of bacterial strains.

Amino Acid Sequence↗
PubMed2006

Hydrogen bonding in two solid phases of phenazine-chloranilic acid (1/1) determined at 170 and 93 K.

The crystal structures in two solid phases, i.e. phase II stable between 146 and 253 K and phase IV below 136 K, of the title compound [phenazine-chloranilic acid (1/1), C12H8N2.C6H2Cl2O4, in phase II, and phenazinium hydrogen chloranilate, C12H9N2+.C6HCl2O4-, in phase IV], have been determined. Both phases crystallize in P2(1), and each structure was refined as an inversion twin. In phase II, the phenazine and chloranilic acid molecules are arranged alternately through two kinds of O-H...N hydrogen bonds. In phase IV, salt formation occurs by donation of one H atom from the chloranilic acid molecule to the phenazine molecule; the resulting monocation and monoanion are linked by N-H...O and O-H...N hydrogen bonds.

Benzoquinones↗
PubMed1988

Structure-activity relationships of selected phenazines against Mycobacterium leprae in vitro.

Structure-activity relationships of phenazines against Mycobacterium leprae were investigated by using an in vitro radiorespirometric assay. In general, activity in ascending order was observed in compounds containing no chlorine atoms, a monochlorinated phenazine nucleus, and chlorines in the para positions of both the anilino and phenyl rings. The most active compounds contained a 2,2,6,6-tetramethylpiperidine substitution at the imino nitrogen. Most of these chlorinated phenazines were considerably more active in vitro than clofazimine (B663).

Clofazimine↗
PubMed2006

Rhizobium etli USDA9032 engineered to produce a phenazine antibiotic inhibits the growth of fungal pathogens but is impaired in symbiotic performance.

Phenazine production was engineered in Rhizobium etli USDA9032 by the introduction of the phz locus of Pseudomonas chlororaphis O6. Phenazine-producing R. etli was able to inhibit the growth of Botrytis cinerea and Fusarium oxysporum in vitro. Black bean inoculated with phenazine-producing R. etli produced brownish Fix(-) nodules.

Anti-Bacterial Agents↗