Pharmacological and Predicted Activities of Natural Azo Compounds

This paper describes research on natural azo compounds isolated from fungi, plant, bacteria, and invertebrates. More than 120 biologically active diazene containing alkaloids demonstrate confirmed pharmacological activity, including antitumor, antimicrobial, and antibacterial effects. The structures, origin, and biological activities of azo compounds are reviewed. Utilizing the computer program PASS, some structure–activity relationship new activities are also predicted, pointing toward possible new applications of these compounds. This article emphasizes the role of natural azo compounds as an important source of drug prototypes and leads for drug discovery.

Using the structure-activity relationships (SAR) approach realized in the computer program PASS, some additional activities were also predicted, indicating possible new applications for these compounds. Keeping in mind that presented below data on biological activity of azo metabolites characterize only a small part of possible biological potential in these molecules, we tried to estimate their biological activity spectra by computer prediction.
For this purpose we used computer program PASS [19,20], which predicts more than 7000 pharmacological activities, mechanisms of action, mutagenicity, carcinogenicity, teratogenicity and embryotoxicity on the basis of structural formulae of compounds. PASS predictions are based on SAR analysis of the training set consisting of more than 900000 of drugs, drug-candidates and lead compounds. Algorithm of PASS predictions is described in detail in several publications [21][22][23][24]. Using MOL or SD files as an input for PASS program, user may get a list of probable biological activities for any drug-like molecule as an output. For each activity Pa and Pi values are calculated, which can be interpreted either as the probabilities of a molecule belonging to the classes of active and inactive compounds respectively, or as the probabilities of the first and second kind of errors in prediction. Although the majority of the known biological activities for respective azo compounds are associated with antineoplastic action, their number is less than 60% among the predicted focal activities. A computer analysis of the predicted biological activity spectra showed that 58 types of biological activity are predicted with Pa [ 70%, 199 with Pa [ 50%, 463 with Pa [ 30%, and 810 with Pa [ Pi. This paper emphasizes the role of natural azo dyes as important sources for drug discovery.

Azo Metabolites Derived from Actinomycetes and Fungal Species
Valanimycin (1), an azoxy antibiotic, was isolated from culture broths of Streptomyces viridifaciens MG456-hF10. It was active against both Gram-positive and Gram-negative bacteria, especially against E. coli BE1121, a DNA repair deficient mutant of E. coli K12. Valanimycin was toxic to in vitro cultures of cells of mouse leukemia L1210, P388/S, and P388/ADR, with IC 50 values of 0.8, 2.7, and 1.4 pg/mL, respectively. It prolonged the life span of mice inoculated with Ehrlich carcinoma or L1210 [25]. Valanimycin derivative (2) was found in culture broth of a S.
Three novel aromatic azoxy compounds, azoxymycins A (58), B (59), and C (60), have been isolated and identified from Streptomyces chattanoogensis L10, and their biosynthetic pathways have been reported [73]. Predicted activities see in Table 5 and the structures shown in Figs. 2 and 3.
Two vasodilators, designated WS-1228 A (triacsin C, 69) and B (triacsin D, 70), were discovered in the culture of Streptomyces aureofaciens [81,82]. Four years later, Omura and co-authors [83] reported two triacsins A (69) and B (70), inhibitors of acyl-CoA synthetase, which were isolated from the cultured broth of Streptomyces sp. The structurally related compounds WS-1228 A and B, known to be hypotensive vasodilators, were also found to inhibit acyl-CoA synthetase. The four compounds have N-hydroxytriazene moiety in their structures in common. The IC 50 values for triacsin A and WS-1228 A were 5.5 and 3.6 lg/mL, respectively. Triacsins A, B, C, and D, inhibitors of long chain acyl-CoA synthetase, possess different inhibitory potencies against the enzyme [84,85]. Acyl-CoA synthetase activity in the membrane fraction of Raji cells was also inhibited by triacsins, which display the same hierarchy of inhibitory potency as that against the enzyme from other sources, that is, the inhibitory potency of triacsin C (71) is greater than that triacsin A, followed by that of triacsin D (72), and is greater than or equal to that of triacsin B [85].

Concluding Remarks
Natural azo metabolites comprise a rare group of natural products. They are primarily present in fungi, plant, and microorganisms have also been detected in some invertebrates. Little information is known about the biological activities of these metabolites. Nevertheless, reported activities for these isolated compounds have shown strong anticancer, antibacterial, antiviral, and other activities. The widest spectra of biological activities are exhibited by isolated azo metabolites. Natural azo compounds have been shown to be promising candidates for the development of new drugs used for the treatment of several diseases.
Acknowledgements The work was partially supported (TAG and VVP) in the framework of the Russian State Academies of Sciences Fundamental Research Program for 2013-2020.

Compliance with Ethical Standards
Conflict of interest The authors declare no competing financial interest.
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