Phenazine antibiotics

L. S. Thoma.show and D. M. Weller, Role of phenazine antibiotic from Pseudomonas fluorescens in biological control of Gaeumannomyces graminis var. tritici. Journal of Bacteriology 770 3499 (1988). 

As part of a screening program for bioactive compounds from endosym-biontic microorganisms, Zeeck et al. successfully isolated a group of new, structurally related phenazine antibiotics, the so called endophenazines A (74), B (75), C (76), and D (77) from the arthropod-associated endosymbiont Strepto-... 

This type of reaction is usually promoted by applied pressure and some of the examples have been reviewed by us [87]. The Menschutkin reaction of the phenazine 137 with the allyl bromide 138 occurs only in poor yield with elimination of HBr from 138, whereas at 1.2 GPa and rt the reaction constitutes a total synthesis of phenazinomycin (139), a rare type of phenazine antibiotic, albeit only in 20% yield (Scheme 38) [88]. 

Tsujibo, H., Sato, T, Inui, M., Yamamoto, H., Inamorai, Y. Intracellular accumulation of phenazine antibiotics produced by an alkahphilic actinomycete. I. Taxonomy, isolation and identification of the phenazine anhbiotics. Bio/C/ieni. 1988,52(2), 301-306. 

Ring substituents show enhanced reactivity towards nucleophilic substitution, relative to the unoxidized systems, with substituents a to the fV-oxide showing greater reactivity than those in the /3-position. In the case of quinoxalines and phenazines the degree of labilization of a given substituent is dependent on whether the intermediate addition complex is stabilized by mesomeric interactions and this is easily predicted from valence bond considerations. 2-Chloropyrazine 1-oxide is readily converted into 2-hydroxypyrazine 1-oxide (l-hydroxy-2(l//)-pyrazinone) (55) on treatment with dilute aqueous sodium hydroxide (63G339), whereas both 2,3-dichloropyrazine and 3-chloropyrazine 1-oxide are stable under these conditions. This reaction is of particular importance in the preparation of pyrazine-based hydroxamic acids which have antibiotic properties. 

The best-studied system producing antibiotics in the rhizosphere are fluorescent pseudomonads, producing up to seven different compounds, as summarized in Fig. 9 2-hydroxyphenazine-l-carboxylate, phenazine-l-carboxylate, 2-hydroxy-phenazine, pyrrolnitrin, pyocyanine, 2.4-diacetylphloroglucinol. and pyoluteorin (48). Nine genes have been identified in the synthesis of phenazine-1-carboxylic... 

Pusecker, K., Laatsch, H., Helmke, E., and Weyland, H., Dihydrophencomycin methyl ester, a new phenazine derivative from a marine Streptomycete, J. Antibiot., 50, 479, 1997. 

Shikimic acid (144), or a close relative, has been deduced to be the source of a C7N unit (shown with heavy bonding) common to the antibiotics mitomycin (147)128 129 and rifamycin S (148) 129-131 a similar unit is also apparent in strep-tovaricin D (149). Shikimic acid is a proven precursor for bacterial phenazines which are arguably constructed from two related C7N units132 (for further research on these metabolites, see below). 

Antibiotics such as pyoluteorin, pyrrolnitrin, phenazine-l-carboxylate, and 2,4-diacetylphloroglucinol are produced in the spermosphere and rhizosphere and play an important role in suppression of soil-borne plant pathogens. Suppression in a number of cases studied correlates with the production in the soil of the antibiotics. 

Until now, several types of polycyclic aromatic nitrogen heterocycles have been known. In fact, heterocyclic synthesis plays an important role in modern life. Among the nitrogen heterocycles, quinoxaline and phenazine derivatives have attracted great interest because of their wide application in organic and medicinal chemistry. Many phenazine compounds are found in nature and are produced by bacteria. Quinoxalines are the fundamental components of several pharmacological active compounds and some antibiotics such as levomycin, echinomycin, and actinomycin (Bailly et al, 1999 Dell et al, 1975). 

Phenazine natural products are isolated as secondary metabolites primarily from Pseudomonas, Strep-tomyces, and a few other genera from soil or marine habitats. The biological properties of this class of natural products include antibiotic, antitumor, antimalaria, and antiparasitic activities. The role of phenazine pigments as antibiotics and virulence factors has been briefly reviewed recently, and the biochemistry of phenazine production was reviewed in 1986.8... 

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