Research Progress of Phenazine-1-carboxylic Acid and Its Analogue

doi:10.6023/cjoc201904023

Abstract

Phenazine-1-carboxylic acid (PCA) as a natural product widely exists in microbial metabolites of Pseudomonads and Streptomycetes, which displays potent inhibitory activities against plant pathogens, and has medical antibacterial and antitumor effects, and so on. In this review, the biosynthesis and chemosynthesis of phenazine-1-carboxylic acid are summarized. At the same time, the diverse biological evaluations of its biosynthetic and chemosynthetic analogues are summarized, which could provide reference for the study of structural modifications and biological activities of these analogues.

Key words: phenazine-1-carboxylic acid, analogues, research progress

Cite this article

Zhu Xiang, Wu Qinglai, Li Junkai. Research Progress of Phenazine-1-carboxylic Acid and Its Analogue[J]. Chinese Journal of Organic Chemistry, 2019, 39(10): 2744-2758.

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Fig. & Tab. 31

Figure 1. Chemical structure of phenazine-1-carboxylic acid

Figure 2. Biosynthesis of phenazine-1-carboxylic scid and phenazine-1,6-dicarboxylic acid

Figure 3. Biosynthesis of derivatives of phenazine

Scheme 1. Reaction of o-aminobenzoic acid with nitrobenzene

Scheme 2. Reaction of o-phenylenediamine with 1-methyl-2,3- dihydroxy cyclohexene

Scheme 3. Reaction of 2,3-diaminobenzoic acid with 1,2-cyclo- hexanedione

Scheme 4. Reaction of 3-methylbenzene-1,2-diamine with pyrocatechol

Scheme 5. Reaction of phenazine-1-methyl with NBS to phenazine-1-carboxylic acid

Scheme 6. Synthesis of phenazine-1-carboxylic acid from 3- nitroaniline

Scheme 7. Cu-catalyzed Jourdan-Ullmann reaction of 2-bromo- 3-nitrobenzoic acid with aniline

Scheme 8. Pd-catalyzed ullmann-coupling of o-bromonitro- benzene with aniline

Scheme 9. Reaction of Benzoxepine-4-carboxylates with benzene-1,2-diamine

Scheme 10. Synthesis of phenazines from dibenzodiazepines

Compd.	R¹	R²	R³	R⁴	R⁵	R⁶	R⁷	R⁸
1	OH	H	H	H	H	H	H	H
2	NH₂	H	H	H	H	H	H	H
3	NHNH₂	H	H	H	H	H	H	H
4	OH	OH	H	H	H	H	H	H
5	OH	H	H	OH	H	H	H	H
6	OH	H	H	H	OH	H	H	H
7	OH	H	H	H	H	H	H	OH
8	OH	OH	OH	H	H	H	H	H
9	OH	OH	H	H	OH	H	H	H
10	OH	OH	H	H	H	H	H	OH
11	OH	OH	OH	OH	H	H	H	H
12	OH	H	H	H	COOH	H	H	H
13	OH	OH	OH	H	COOH	H	H	H
14	OCH₃	H	H	H	COOCH₃	OH	H	H
15	OCH₃	H	H	OH	COOCH₃		H	H
16	OCH₃	H	H	OH	COOCH₃		H	OH
17	OH	OCH₃	H	H	H		H	H

Table 1. Simple derivatives of PCA produced by pseudomona s

Compd.	R¹	R²	R³	R⁴	R⁵	R⁶	R⁷	R⁸
20	OH	H	OH	H	OH	H	H	H
21	OH	H	H	H	CH₂OH	H	H	OH
22	OH	H	H	H	CH₃	H	H	OCH₃
23	OH	H	H	H	COOCH₃	H	H	H
24	OH	OH	H	H	COOCH₃	H	H	H
25	OCH₃	H	H	H		H	H	H
26	OCH₃	H	H	H	OCH₃	H	H	H

Table 2. Simple derivatives of PCA produced by Streptomyces

Scheme 11. Synthesis of phenazine-1-carboxamides 52

Scheme 12. Synthesis of phenazine-1-carboxamides 53

Scheme 13. Synthesis of bis(phenazine-1-carboxamides) 54

Scheme 14. Synthesis of benzo[a]-phenazine-6-carboxamides 55

Scheme 15. Synthesis of phenazine-1-carboxamides 63

Scheme 16. Synthesis of aminophenazine-1- carboxylates 64 and 65

Scheme 17. Synthesis of phenazine-1-carboxamides 66

Scheme 18. Synthesis of Phenazine-1-carboxylic acid derivatives based on the modification of PCA carboxyl group

Scheme 19. Synthesis of phenazine-1-carboxylic acid diacylhydrazine derivatives

Scheme 20. Synthesis of phenazine-1-carboxylic acid diacylhydrazine derivatives

Scheme 21. Synthesis of phenazine-1-carboxylic acid diamide derivatives

Scheme 22. Synthesis of phenazine-1-carboxylic acid 1,3,4- oxadiazol-2-yl thioether derivatives of phenazine-1-carboxylic acid

Scheme 23. Phenazine-1-carboxylic acid-hydroxybenzoic acid ester derivatives

Scheme 24. Synthesis of phenazine-1-carboxylic-piperazine derivatives

Compd.	EC₅₀/(μmol?L^–1)
Compd.	Rhizoctonia solani	Alternaria solani	Fusarium oxysporu	Fusarium graminearum	Pyricularia oryzac Cavgra
86a	24.6±0.8	42.9±2.1	73.7±1.6	73.8±2.2	34.2±3.3
PCA	33.2±2.3	81.5±4.3	186.5±1.2	176.4±2.1	37.3±1.9

Table 3. Fungicidal activities of 86a and PCA against five pathogenic fungi in vitro

Scheme 25. Synthesis of phenazine-1-carboxylic-L-alanine conjugates

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