Advances in Phenazines over the Past Decade: Review of Their Pharmacological Activities, Mechanisms of Action, Biosynthetic Pathways and Synthetic Strategies

Abstract

Phenazines are a large group of nitrogen-containing heterocycles, providing diverse chemical structures and various biological activities. Natural phenazines are mainly isolated from marine and terrestrial microorganisms. So far, more than 100 different natural compounds and over 6000 synthetic derivatives have been found and investigated. Many phenazines show great pharmacological activity in various fields, such as antimicrobial, antiparasitic, neuroprotective, insecticidal, anti-inflammatory and anticancer activity. Researchers continued to investigate these compounds and hope to develop them as medicines. Cimmino et al. published a significant review about anticancer activity of phenazines, containing articles from 2000 to 2011. Here, we mainly summarize articles from 2012 to 2021. According to sources of compounds, phenazines were categorized into natural phenazines and synthetic phenazine derivatives in this review. Their pharmacological activities, mechanisms of action, biosynthetic pathways and synthetic strategies were summarized. These may provide guidance for the investigation on phenazines in the future.

The Phenazine Scaffold Used as Cytotoxic Pharmacophore Applied in Bactericidal, Antiparasitic and Antitumor Agents

“…The phenazine N 5 ,N 10 -dioxide (PDO) derivatives (Figure 1) are a new generation of hybrid compounds that combine both N-oxide and DNA-π-stacking moieties. These PDO analogs applied as synthetic prodrugs are antitumor agents that selectively kill the hypoxic (anaerobic) cells commonly found in necrotic regions of solid tumors.…”

“…Phenazines have been extensively studied as natural products [1][2][3] with interesting biological effects (isolated as redox-active secondary metabolites primarily from Gram-negative Pseudomonas aeruginosa and Gram-positive Streptomyces bacteria or a few other genera from soil-derived actinomycetes, archaeal Methanosarcina species or marine habitats). [4][5][6] The role of phenazine natural pigments as antibiotics and antivirulence drugs was reviewed by Laursen et al, [7] Kerr, [8] Guttenberger et al, [5] Cimmino et al [9] and Yan et al [10] Natural phenazines helped scientists to guide the development of their synthetic analogs with tailored anti-infective properties with similar or even better pharmacological activity. [11][12][13] Synthetic phenazines with enhanced antiparasitic properties can improve the therapeutic activity of drugs applied in malaria treatments [14][15][16] or against the hepatitis C virus (HCV).…”

“…The role of phenazine natural pigments as antibiotics and anti‐virulence drugs was reviewed by Laursen et al ., [7] Kerr , [8] Guttenberger et al ., [5] Cimmino et al [9] . and Yan et al [10] . Natural phenazines helped scientists to guide the development of their synthetic analogs with tailored anti‐infective properties with similar or even better pharmacological activity [11–13] .…”

Synthesis of Nonsymmetrically Substituted 2,3-Dialkoxyphenazine Derivatives and Preliminary Examination of Their Cytotoxicity

“…Of the more than 6000 compounds reported to feature a phenazine system described in the literature, several hundreds have been reported to exhibit biological activity, such as antibacterial, antiparasitic, neuroprotective, insecticidal, anti-inflammatory, antifungal, and antitumor properties . The first known example of a phenazine-based natural product was pyocyanin (Figure , example A ), which is the characteristic blue pigment produced by Pseudomonas aeruginosa present on human skin, blue pus, and on certain other materials .…”

Biosynthetic Pathway Construction and Production Enhancement of 1-Hydroxyphenazine Derivatives in Pseudomonas chlororaphis H18

“…The biosynthesis of high-value chemicals from easily obtained renewable feedstock is a green, safe, and efficient method. So far, more than 180 natural phenazine derivatives have been isolated and over 6000 phenazine congeners have been synthesized. , Despite the phenazine core skeleton, only a few phenazine derivative biosynthetic pathways have been solved. − The biosynthesis or post-modification of many phenazines is still a mystery, and more phenazines with brilliant activities need to be explored.…”