Natural Products and Bioprospecting

, Volume 7, Issue 1, pp 151–169 | Cite as

Pharmacological and Predicted Activities of Natural Azo Compounds

  • Valery M. Dembitsky
  • Tatyana A. Gloriozova
  • Vladimir V. Poroikov
Open Access
Original Article

Abstract

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.

Keywords

Azo metabolites Alkaloids Fungi Plant Bacteria Sponges SAR 

1 Introduction

Natural azo compounds are diazene containing compounds. Also called diimine or diimide, these metabolites have an azo moiety (–N=N–) [1, 2, 3, 4]. The majority of natural diazene alkaloids have been isolated from microorganisms, plant parts (bark, berries, leaves, roots, and wood), fungi, fungal endophytes, lichenized ascomycetes and marine invertebrates [5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18].

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.

2 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 IC50 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. viridifaciens MG456-hF10 during biosynthesis of valanimycin (1) [26], and the elucidation of the structure was carried out on the more stable ammonia adduct (3) [27]. Predicted activities compounds (110) shown in Table 1 and structures shown in Fig. 1. α,β-Unsaturated azoxy-containing antibiotic LL-BH872α (4) was isolated from Streptomyces hinnulinis [28]. More recently, LL-BH872a, 2(Z)-OH (5) produced by Actinomadura sp., was isolated from the roots of Prunus armeniaca [27], and antibiotic LL-BH872a, 2(Z)-OH, 4′(Z)-OH (6), produced by Streptomyces misionensis [29].
Table 1

Confirmed and new biological activities of azo compounds (110) derived from actinomycetes

No.

Activity reviewed

Activities confirmed (Pa)

Additional predicted activities (Paa)

1

Antibiotic antineoplastic

Antineoplastic (0.985)

Antineoplastic antibiotic (0.848)

Phobic disorders treatment (0.819)

Hepatic disorders treatment (0.662)

2

Not studied

Antineoplastic (0.880)

Phobic disorders treatment (0.864)

Hepatic disorders treatment (0.852)

3

Not studied

Phobic disorders treatment (0.907)

Antiseborrheic (0.861)

Antineoplastic (0.862)

4

Antibiotic

Hepatic disorders treatment (0.872)

Antineoplastic (0.736)

Antieczematic (0.733)

5

Antibiotic

Antibacterial (0.507)

Hepatic disorders treatment (0.819)

Antiviral (arbovirus) (0.783)

Antineoplastic (0.746)

6

Antibiotic

Antibacterial (0.527)

Hepatic disorders treatment (0.765)

Antineoplastic (0.760)

Antifungal (0.653)

7

Antibiotic antifungal

Antifungal (0.640)

Hepatic disorders treatment (0.778)

Antineoplastic (0.763)

Antieczematic (0.717)

8

Antibiotic antifungal

Phobic disorders treatment (0.860)

Mucositis treatment (0.765)

Antiviral (arbovirus) (0.747)

9

Antifungal

Antifungal (0.658)

Hepatic disorders treatment (0.793)

Antiviral (arbovirus) (0.771)

Antineoplastic (0.779)

10

Antifungal

Antifungal (0.632)

Hepatic disorders treatment (0.819)

Antiviral (arbovirus) (0.783)

Antineoplastic (0.746)

aOnly activities with Pa > 0.5 are shown

Fig. 1

Biological active azo compounds derived from actinomycetes

Two antifungal antibiotics, maniwamycins A (7) and B (8), were isolated from the culture broth of Streptomyces prasinopilosus. Both antibiotics showed broad antifungal activities against Candida albicans IFM 40001, C. albicans N 508, C. albicans TIMM 0228, C. albicans TIMM 0237, Cryptococcus neoformans IFM 40038, Nannizzia otae JCM 1909, Trichophyton mentagrophytes IFM 40769, T. mentagrophytes IFM 40771, T. rubrum IFM 40768, and Staphylococcus aureus FDA 209P [30].

The microbial antifungal agent azoxybacilin (9) was isolated from the culture broth of Bacillus cereus NR2991. Azoxybacilin exhibits broad spectrum antifungal activity, especially against mycelial fungi, such as Aspergillus fumigatus and Trichophyton mentagrophytes [31, 32]. Azoxyalkene (10) is an unstable azoxy compound isolated from Actinomadura sp., an actinomycete growing in apricot roots. Preliminary biological assays revealed that exhibits weak antifungal activity against Rhodotorula sp. [27].

Elaiomycin (11) is an azoxy antibiotic that was first isolated from Streptomyces hepaticus and found to strongly inhibit the growth of Mycobacterium tuberculosis [33, 34, 35, 36]. Elaiomycins D-G (1215), antimicrobial and cytotoxic azoxides, were isolated from Streptomyces sp. HKI0708. Individual elaiomycins exhibit specific antimycobacterial, anti-Aspergillus, and cytotoxic activities, providing provisional data on SAR [37, 38]. Predicted activities compounds (1121) shown in Table 2 and the structures shown in Fig. 1. Elaiomycins K (16), L (17) and amide elaiomycin K (18), azoxy-type antibiotics, were detected in the culture filtrate extract of Streptomyces sp. Tü 6399. Both metabolites show weak antibacterial activity against Bacillus subtilis and Staphylococcus lentus as well as against the phytophathogenic Xanthomonas campestris [39].
Table 2

Confirmed and new biological activities of azo compounds (1121) derived from actinomycetes

No.

Activity reviewed

Activities confirmed (Pa)

Additional predicted activities (Paa)

11

Antibiotic anti-mycobacterial

Antibacterial (0.489)

Hepatic disorders treatment (0.733)

Antineoplastic (0.731)

Antieczematic (0.697)

12

Antibiotic antifungal cytotoxic

Antifungal (0.646)

Antineoplastic (0.738)

Hepatic disorders treatment (0.763)

Vasodilator, peripheral (0.738)

13

Antibiotic antifungal cytotoxic

Antifungal (0.639)

Vasodilator (0.722)

Antiinfective (0.684)

Vasodilator (0.637)

14

Antibiotic cytotoxic

Antineoplastic (0.549)

Phobic disorders treatment (0.769)

Antiviral (arbovirus) (0.688)

Natural killer cell stimulant (0.637)

15

Antibiotic cytotoxic

Antineoplastic (0.599)

Hepatic disorders treatment (0.604)

Vasodilator, peripheral (0.609)

16

Antibiotic antibacterial

Phobic disorders treatment (0.834)

Antiviral (arbovirus) (0.805)

Mucositis treatment (0.754)

17

Antibiotic antibacterial

Phobic disorders treatment (0.888)

Preneoplastic (0.779)

Mucositis treatment (0.756)

18

Antibiotic antibacterial

Phobic disorders treatment (0.837)

Mucositis treatment (0.734)

Natural killer cell stimulant (0.668)

19

Nematocide

Hepatic disorders treatment (0.849)

Phobic disorders treatment (0.672)

Antifungal (0.569)

20

Nematocide

Hepatic disorders treatment (0.849)

Phobic disorders treatment (0.672)

Antifungal (0.569)

21

Antibiotic antineoplastic

Antineoplastic (0.672)

Antiviral (arbovirus) (0.557)

aOnly activities with Pa > 0.5 are shown

Nematocidal antibiotics, jietacins A (19) and B (20), isolated from the culture broth of a Streptomyces sp. [40, 41], exhibited 10 times higher activities against the pine wood nematode Bursaphelenchus hgnicolus in comparison to avermectin Bla, which is known to have a potent activity against various nematodes and which is used as a nematocidal agent in the veterinary field [42, 43].

Hydrazides, geralcin C (21) was isolated from Streptomyces sp. LMA-545 together with geralcins A, B, D and E. Geralcin C has exhibited an IC50 of 0.8 μM against KB and HCT116 cancer cell lines. Furthermore, geralcin C inhibited the E. coli DnaG primase, a Gram-negative antimicrobial target, with an IC50 of 0.7 μM [44]. The antibiotic propanosine (K-76, 22), found in extracts of Micromonospora chalcea 671-AV2, has shown inhibitory activity against Valsa ceratosperma [45]. Predicted activities compounds (2239) shown in Table 3 and the structures shown in Figs. 1 and 2.
Table 3

Confirmed and new biological activities of azo compounds (2239) derived from actinomycetes

No.

Activity reviewed

Activities confirmed (Pa)

Additional predicted activities (Paa)

22

Antibiotic antifungal

Antineoplastic (0.845)

Phobic disorders treatment (0.775)

Antiviral (picornavirus) (0.735)

23

Antibiotic

Antineoplastic (0.781)

Phobic disorders treatment (0.750)

Antiviral (arbovirus) (0.565)

24

Antibacterial antineoplastic

Antineoplastic (0.923)

Antibacterial (0.613)

Antifungal (0.633)

Genital warts treatment (0.648)

Spasmolytic, urinary (0.605)

25

Antibacterial antineoplastic

Antineoplastic (0.927)

Antibacterial (0.573)

Spasmolytic, urinary (0.687)

Genital warts treatment (0.648)

Immunosuppressant (0.596)

26

Antibiotic antifungal

Antifungal (0.640)

Antibacterial (0.474)

Hepatic disorders treatment (0.778)

Antineoplastic (0.763)

Antieczematic (0.717)

27

Antibiotic antifungal

Antifungal (0.658)

Antibacterial (0.514)

Hepatic disorders treatment (0.793)

Antiviral (arbovirus) (0.771)

Antineoplastic (0.779)

28

Antineoplastic antibiotic cytotoxic ornithine decarboxylase inhibitor

Anti-Helicobacter pylori (0.995)

Kidney function stimulant (0.636)

Antieczematic (0.644)

Preneoplastic conditions treatment (0.590)

29

Antineoplastic antibiotic

Anti-Helicobacter pylori (0.994)

Preneoplastic conditions treatment (0.513)

30

Microtubule inhibitor

Anti-Helicobacter pylori (0.893)

Antieczematic (0.751)

Fibrinolytic (0.638)

31

Microtubule inhibitor

Anti-Helicobacter pylori (0.915)

Preneoplastic conditions treatment (0.670)

Kidney function stimulant (0.654)

32

Not studied

Antiseborrheic (0.793)

Antiinflammatory (0.780)

Hemostatic (0.668)

33

Nematocide

Antiseborrheic (0.793)

Antiinflammatory (0.780)

Hemostatic (0.668)

34

Nematocide

Anti-Helicobacter pylori (0.939)

Antiseborrheic (0.717)

Alopecia treatment (0.650)

35

Not studied

Antiinflammatory (0.714)

Phobic disorders treatment (0.682)

Preneoplastic conditions treatment (0.617)

36

Not studied

Anti-Helicobacter pylori (0.932)

Preneoplastic conditions treatment (0.605)

37

Nematocide cytotoxic

Anti-Helicobacter pylori (0.932)

Phobic disorders treatment (0.672)

Preneoplastic conditions treatment (0.568)

38

Not studied

Apoptosis agonist (0.935)

Antineoplastic (0.788)

Alopecia treatment (0.653)

39

Not studied

Apoptosis agonist (0.920)

Antineoplastic (0.724)

Antiviral (arbovirus) (0.622)

aOnly activities with Pa > 0.5 are shown

Fig. 2

Aromatic azo compounds derived from actinomycetes and fungal species

Another antibiotic, lyophyllin (23) was isolated from the mushroom Lyophyllum shimeji and showed inhibitory activity at a concentration of 50 μg/mL, inducing forebrain blisters within the cranial mesenchyme [46]. Two antibacterial and anti-tumoural agents, antibiotic DC1881A (24) and DC1881B (25) are produced by Streptomyces sp. DO-118 [47].

Two azoxy compounds, KA-7367A (26) and KA-7367B (27), which have antifungal activity, have been found in the culture broth of Streptomyces sp. (KC-7367, FERM BP-1277) [48]. Compound KA-7367A (26) showed antifungal activity against Candida albicans, Aspergilus fumigatus, Cryptococcus neoformans, Trichophyton mentagraphytes, and T. rubrum.

An antitumor antibiotic with a diazene N-oxide structure, calvatic acid (alvatic acid or calvatinic acid, 28), and a methyl derivative (29), are produced by the fungi Calvatia craniformis [49] and C. lilacina [50] and from puffball mushrooms Lycoperdon pyriforme [51]. Calvatic acid inhibited the growth of Gram-positive and Gram-negative bacteria at a concentration of 3–6 μg/mL [50] and showed cytotoxic activity by inhibiting cultured Yoshida sarcoma cell growth [49], and it also displayed carcinostatic activity against hepatoma and K562 leukemia cells [52]. Calvatic acid also showed antibacterial activity against the Gram-negative, microaerophilic bacterium Helicobacter pylori [53]. Two calvatic acid analogues (30 and 31) have demonstrated anti-microtubular properties [54].

Azoformamide (32), its (E)-form (33 and 35), and its azoxy derivatives (34 and 36) were isolated from the puffball Lycoperdon pyriforme [55, 56]. Extracts of the basidiomycete Lycoperdon pyriforme yielded 4-methoxy-benzene-1-azoformamide (33) and 4-methoxy-benzene-1-ONN-azoxyformamide (34), which possess nematicidal activity against the parasitic nematode Meloidogyne incognita. The chlorinated derivative (37) is less active towards nematodes, but more cytotoxic compared to (33 and 34) [57]. Two azoxyformamides (34 and 36) and two azoformamide derivatives (38 and 39) were isolated from the fruiting bodies of Calvatia craniiformis and Lycoperdon hiemale, respectively. Compounds (34) and (39) showed radicle growth inhibitory activities against lettuce seedlings, suggesting that the azoxy moiety contributes to the inhibitory activity. The plant growth inhibitory activities of (34, 36, and 39) against barnyard millet seedlings were also reported [58]. The red minor pigment deoxyrubroflavin (40, activity see in Table 4) was isolated from the pufball mushroom Calvatia rubro-flava [59]. The orange pigment rubroflavin (41) was found in the dried fruit bodies of North American puffball Calvatia rubro-flava and in C. craniformis [59, 60]. Oxyrubroflavin (42), craniformin (43), and cranformin (44) were isolated from C. rubro-flava [59, 60].
Table 4

Confirmed and new biological activities of azo compounds (4058) derived from actinomycetes and fungal species

No.

Activity reviewed

Activities confirmed (Pa)

Additional predicted activities (Paa)

40

Not studied

Antiinflammatory (0.957)

Antineoplastic (0.837)

Hemostatic (0.822)

41

Not studied

Hemostatic (0.962)

Antiinflammatory (0.956)

Antineoplastic (0.808)

42

Not studied

Antiinflammatory (0.964)

Hemostatic (0.952)

Antineoplastic (0.833)

43

Not studied

Antiinflammatory (0.953)

Antineoplastic (0.772)

Hemostatic (0.577)

44

Not studied

Antiinflammatory (0.961)

Antiarthritic (0.849)

Antineoplastic (0.781)

45

Insecticide

Antieczematic (0.732)

Kidney function stimulant (0.701)

Preneoplastic conditions (0.677)

46

Insecticide

Immunosuppressant (0.647)

Antieczematic (0.659)

Fibrinolytic (0.606)

47

Not studied

Preneoplastic (0.692)

Kidney function stimulant (0.631)

48

Not studied

Antimutagenic (0.758)

Spasmolytic, urinary (0.699)

Antineoplastic (0.660)

49

Not studied

Antiseborrheic (0.874)

Phobic disorders treatment (0.784)

Kidney function stimulant (0.752)

50

Not studied

Carminative (0.817)

Phobic disorders treatment (0.786)

Antiseborrheic (0.763)

51

Not studied

Antieczematic (0.843)

Phobic disorders treatment (0.832)

Kidney function stimulant (0.786)

52

Not studied

Phobic disorders treatment (0.840)

Fibrinolytic (0.720)

Preneoplastic conditions (0.703)

53

Not studied

Acaricide (0.821)

Phobic disorders treatment (0.782)

Antiseborrheic (0.773)

54

Not studied

Alopecia treatment (0.762)

Phobic disorders treatment (0.777)

Antiinflammatory, intestinal (0.699)

55

Not studied

Phobic disorders treatment (0.916)

Antiseborrheic (0.802)

Acaricide (0.726)

56

Not studied

Phobic disorders treatment (0.700)

Preneoplastic conditions treatment (0.606)

Immunosuppressant (0.612)

57

Not studied

Fibrinolytic (0.640)

Acaricide (0.636)

58

Not studied

Mucositis treatment (0.831)

Immunosuppressant (0.690)

aOnly activities with Pa > 0.5 are shown

Two strains of the insect pathogenic fungus Entomophthora virulenta were found to produce a mixture of 4,4′-azoxybenzene dicarboxylic acid (45) and 4,4′-hydroxymethyl azoxybenzene carboxylic acid, which showed insecticidal activity (46) [61, 62]. A formazane derivative (47) has been isolated from Agaricus silvicola [63]. The mutagenic alkaloid necatorin (48) has been isolated from the mushroom Lactarius necator [64, 65, 66]. Two azo dyes, 4,4′-dihydroxyazobenzene (49) and its methyl derivative (50), have been identified in the fresh sporophores of the mushroom Agaricus xanthodermus [67]. Several azo dyes are fungal toxins (5157) and are produced by entomogenous fungi, such as Beauveria bassiana, Beauveria brongniartii, Metarhizium anisopliae, and Verticillium lecanii [66, 68, 69, 70, 71, 72].

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.
Table 5

Confirmed and new biological activities of azo compounds (5977) derived from actinomycetes and fungal species

No.

Activity reviewed

Activities confirmed (Pa)

Additional predicted activities (Paa)

59

Not studied

Mucositis treatment (0.776)

Immunosuppressant (0.691)

60

Not studied

Antiviral (arbovirus)

(0.694)

Immunosuppressant (0.693)

Antipsoriatic (0.625)

61

Not studied

Genital warts treatment (0.726)

Antineoplastic (0.691)

62

Not studied

Genital warts treatment (0.726)

Antineoplastic (0.704)

Antiinflammatory (0.625)

63

Not studied

Genital warts treatment (0.726)

Antileukemic (0.567)

64

Not studied

Mucositis treatment (0.761)

Antiviral (arbovirus) (0.744)

65

Antibiotic antineoplastic

Antineoplastic (breast cancer) (0.552)

Alopecia treatment (0.641)

Vascular (periferal) disease treatment (0.592)

66

Not studied

Antineoplastic (0.868)

Antibacterial (0.678)

67

Antifungal

Antifungal (0.690)

Hepatic disorders treatment (0.994)

Hepatoprotectant (0.786)

Antiviral (arbovirus) (0.713)

68

Antifungal

Antifungal (0.662)

Hepatic disorders treatment (0.987)

Antineoplastic (0.738)

69

Vasodilator Acyl CoA synthetase inhibitor

Vasodilator (0.881)

Vasodilator, peripheral (0.599)

Antieczematic (0.830)

Spasmolytic (0.678)

70

Acyl CoA synthetase inhibitor

Vasodilator (0.759)

Spasmolytic (0.649)

Antineoplastic (0.668)

71

Acyl CoA synthetase inhibitor

Antieczematic (0.917)

Vasodilator (0.901)

Spasmolytic (0.706)

72

Acyl CoA synthetase inhibitor

Vasodilator (0.881)

Antieczematic (0.830)

Spasmolytic (0.678)

73

Antimicrobial antiviral antineoplastic

Antineoplastic (0.409)

Antiischemic, cerebral (0.752)

74

Antimicrobial antiviral antineoplastic

Antineoplastic (solid tumors) (0.618)

Antineoplastic (renal cancer) (0.408)

Genital warts treatment (0.656)

Cytostatic (0.562)

75

Antimicrobial antiviral antineoplastic

Antineoplastic (sarcoma) (0.482)

Gout treatment (0.865)

Genital warts treatment (0.648)

76

Antimicrobial antiviral antineoplastic

Guanyl-specific ribonuclease T1 inhibitor (0.709)

Genital warts treatment (0.531)

77

Antimicrobial antiviral antineoplastic

Antineoplastic (sarcoma) (0.469)

Anxiolytic (0.896)

Psychotropic (0.745)

Cognition disorders treatment (0.608)

aOnly activities with Pa > 0.5 are shown

Fig. 3

Miscellaneous azo compounds produced by actinomycetes and fungal species

Asterionellins A (61), B (62), and C (63), eight membered compounds with an azoxy-like moiety, have been isolated from Asterionella sp. [74, 75]. The unstable agaritine derivative (64) and a metabolite (65) were extracted from the fruit-bodies of mushroom Agaricus xanthoderma [76]. Glutamylazophenol (62) was also found in Agaricus sp. [77]. Compound (65) has exhibited strong antibiotic and anticancer activities [77, 78].

It is known that the anti-infective agent azamerone, a meroterpenoid, isolated from the saline culture of marine-derived Streptomyces sp. Azamerone displays weak in vitro cytotoxicity against mouse splenocite populations of T cells and macrophages. A biosynthetic precursor azo compound (66) of azamerone has also been found in the same Streptomyces sp. [79]. The Streptomyces sp. Ank75 produced two azoxy antibiotics, 67 and 68, and both compounds exhibited antifungal activity against Candida albicans and Mucor miehei [80].

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 IC50 values for triacsin A and WS-1228 A were 5.5 and 3.6 μg/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].

A novel metabolite, citreoazopyrone (73), was isolated from the mycelium of Penicillium citreo-viride. It inhibited the growth of hypocotyls of lettuce seedlings [86]. A family of antibiotics named fluviols, which includes compounds (74, 75), (76, 77), and pseudoiodinine (78), are pyrazolo-[4,3-e]as-triazine derivatives, which are produced by Pseudomonas fluorescens var. pseudoiodinum and Nostoc spongiaeforme. All of these isolated compounds showed antimicrobial, antiviral, and antitumour activities [87, 88, 89, 90]. Predicted activities compounds (7898) shown in Table 6 and the structures shown in Fig. 3. Schizocommunin (79) was isolated from a culture of the fungus Schizophyllum commune and exhibited strong cytotoxicity against murine lymphoma cells [91].
Table 6

Confirmed and new biological activities of azo compounds (7897) derived from actinomycetes and fungal species

No.

Activity reviewed

Activities confirmed (Pa)

Additional predicted activities (Paa)

78

Antimicrobial antiviral antineoplastic

Antineoplastic (sarcoma) (0.413)

Atherosclerosis treatment (0.924)

Genital warts treatment (0.600)

79

Cytotoxic antineoplastic

Antineoplastic (0.584)

Antineoplastic (liver cancer) (0.797)

Endothelial growth factor antagonist (0.885)

Angiogenesis inhibitor (0.632)

80

Not studied

Phobic disorders treatment (0.728)

Antineurotic (0.685)

81

Not studied

Antineurotic (0.694)

Phobic disorders treatment (0.648)

82

Not studied

Lysase stimulant (0.787)

Kidney function stimulant (0.518)

83

Not studied

Lysase stimulant (0.787)

Kidney function stimulant (0.518)

84

Interleukin 4 antagonist

Antiseborrheic (0.815)

Kidney function stimulant (0.721)

Phobic disorders treatment (0.749)

85

Antibacterial

Antineurotic (0.806)

Phobic disorders treatment (0.752)

86

Not studied

Not predicted: MolCharge: 1

87

Not studied

Not predicted: MolCharge: 1

88

Cytotoxic

Antineoplastic (0.666)

Antineoplastic (renal cancer) (0.614)

Pterin deaminase inhibitor (0.989)

Natural killer cell stimulant (0.587)

89

Cytotoxic antifungal

Antiallergic (0.765)

Cytostatic (0.712)

Erythropoiesis stimulant (0.692)

90

Antineoplastic antileukemic

Antineoplastic (0.749)

Antileukemic (0.622)

Genital warts treatment (0.936)

DNA synthesis inhibitor (0.825)

Cytostatic (0.701)

91

Antineoplastic antileukemic

Antineoplastic (0.752)

Antileukemic (0.634)

Antimetabolite (0.938)

DNA synthesis inhibitor (0.926)

Neuroprotector (0.910)

92

Antibiotic

Antineoplastic (sarcoma) (0.730)

93

Not studied

Antineoplastic(0.768)

Antibacterial (0.614)

Antifungal (0.592)

94

Antimicrobial antiviral antineoplastic

Glycopeptide-like antibiotic (0.627)

Antineoplastic(0.406)

Analgesic (0.637)

95

Antimicrobial antiviral antineoplastic

Glycopeptide-like Antibiotic (0.714)

Antineoplastic (0.519)

Antibacterial (0.409)

Analgesic (0.670)

96

Antimicrobial antiviral antineoplastic

Glycopeptide-like antibiotic (0.625)

Antineoplastic(0.443)

Analgesic (0.601)

97

Antimicrobial antiviral antineoplastic

Glycopeptide-like antibiotic (0.713)

Antineoplastic (0.547)

Antibacterial (0.424)

Analgesic (0.641)

aOnly activities with Pa > 0.5 are shown

3- and 4-methylcinnolines (80 and 81) were found in the volatile constituents of Hibiscus esculentus pods [92]. Azoxy compounds (82 and 83) were found in yeast extract [93]. The cinnoline derivatives (84) and 4849F (85) were isolated from a culture of Streptomyces sp. Compound (84) was shown to be an inhibitor of the IL-4 receptor, and alkaloid 4849F (85) has shown antibacterial activity [94]. Pyridazomycin (86), an antifungal antibiotic produced by Streptomyces violaceoniger sp. griseofuscus, inhibited the growth of Mucor hiemalis [95]. Pyridazomycin (86) and its analog (87), as chloride salts showed antimicrobial activity [96]. Compounds (88 or 89), also known as 8-azaguanine, is produced from guanine by Spteptomyces albus [97]. The cytotoxic effect of 8-azaguanine on the growth of carcinoma, sarcoma, osteogenic sarcoma, lymphosarcoma, and melanoma in animals was reported more than 65 years ago [98] (see Fig. 4).
Fig. 4

Biological active triazole derivatives, siderophores and octapeptides derived from actinomycetes and fungal species

Compound (89), also known as pathocidin, is an antifungal antibiotic that has been isolated from actinomycetes [99, 100] and inhibited the growth of many fungi, including Penicillium chrysogenum. 8-azaguanine-3N-β-d-ribofuranosyl (90) and 5′-phosphate-3N-β-d-ribofuranosyl (91) are known as natural metabolites and showed anticancer activity against L-1210 lymphoid leukemia and adenocarcinoma 755, among other activities [101]. A toxic red-tide dinoflagellate, Gymnodinium breve, produced the antibiotic 6-azidotetrazolo[5,1-a]phthalazine (92) [102].

The Burkholderia species secretes a variety of extracellular enzymes with proteolytic, lipolytic, and hemolytic activities. Several strains also secrete toxins, antibiotics, and siderophores [103]. The unusual dimeric siderophore, malleobactin D (93), was isolated from Burkholderia pseudomallei [104].

The amatoxins are a group of bicyclic octapeptides produced by some species of mushrooms belonging to the Agaricales: Amanita phalloides, A. ocreata, A. verna, A. bisporigera, Conocybe filaris, Galerina marginata, G. venenata, Lepiotia castanea, L. helveola, L. subincarnata, L. brunneoincarnata, L. brunneolilacea, and close relatives. Selected amatoxins showed toxicity to heat, the digestive tract, and strong inhibition of RNA polymerase II [105, 106, 107, 108]. Azo-amanitins (9497) are semi-natural compounds, and they showed antiviral, antimicrobial, and anticancer activities [109, 110, 111, 112]. Predicted activities compounds (8897) shown in Table 6 and the structures shown in Fig. 3.

3 Azo Metabolites Derived from Terrestrial and Marine Sources

The novel dimeric monoterpenoid indole alkaloid, geleganidine D (98), was isolated from the roots of flowering plant Gelsemium elegans. It showed moderate cytotoxic activity against MCF-7 and PC-12 cells [113]. Predicted activities compounds (98117) shown in Table 7 and the structures shown in Figs. 5 and 6.
Table 7

Confirmed and new biological activities of azo compounds (98117) derived from plants

No.

Activity reviewed

Activities confirmed (Pa)

Additional predicted activities (Paa)

98

Cytotoxic

Antineoplastic (0.730)

Antiprotozoal (plasmodium) (0.641)

Antiprotozoal (0.579)

99

Immunosuppressant

β-1,3-galactosyl-O-glycosyl-glycoprotein β-1,6-N-acetylglucosaminyl transferase inhibitor (0.954)

Antineoplastic (0.609)

100

Not studied

Neurodegenerative diseases treatment (0.920)

Antiparkinsonian (0.900)

Anxiolytic (0.796)

101

Not studied

Acaricide (0.721)

Antiviral (arbovirus) (0.681)

102

Not studied

Not predicted: MolCharge: 1

103

Not studied

Not predicted: MolCharge: 1

104

Not studied

Antiinfertility, female (0.940)

Antineoplastic(0.835)

Phobic disorders treatment (0.726)

105

Toxic carcinogenic mutagenic neurotoxic

Carcinogenic (0.975)

Toxic (0.932)

Neurotoxic (0.746)

Embryotoxic (0.957)

Teratogen (0.952)

Hepatotoxic (0.716)

106

Toxic carcinogenic mutagenic neurotoxic

Carcinogenic (0.975)

Toxic (0.932)

Eurotoxic (0.746)

Embryotoxic (0.957)

Teratogen (0.952)

Hepatotoxic (0.716)

107

Not studied

Antineoplastic (0.892)

Genital warts treatment (0.870)

Antiinfective (0.837)

108

Toxic carcinogenic mutagenic neurotoxic

Carcinogenic (0.964)

Toxic (0.943)

Neurotoxic (0.822)

Embryotoxic (0.960)

Teratogen (0.950)

Hematotoxic (0.695)

109

Not studied

Genital warts treatment (0.876)

Antineoplastic (0.866)

Vasoprotector (0.851)

110

Not studied

Antineoplastic (0.892)

Genital warts treatment (0.870)

Antiinfective (0.837)

111

Not studied

Antineoplastic (0.892)

Genital warts treatment (0.870)

Antiinfective (0.837)

112

Not studied

Antineoplastic (0.897)

Genital warts treatment (0.870)

Antiinfective (0.837)

113

Not studied

Antineoplastic (0.889)

Genital warts treatment (0.857)

Vasoprotector (0.828)

114

Not studied

Antineoplastic (0.889)

Genital warts treatment (0.857)

Vasoprotector (0.828)

115

Not studied

Antineoplastic (0.900)

Genital warts treatment (0.864)

Hepatic disorders treatment (0.791)

116

Not studied

Antineoplastic (0.889)

Genital warts treatment (0.857)

Vasoprotector (0.828)

117

Not studied

Antineoplastic (0.889)

Genital warts treatment (0.842)

Hepatic disorders treatment (0.810)

aOnly activities with Pa > 0.5 are shown

Fig. 5

Novel biological active azo compounds derived from plants

Fig. 6

Bioactive azoxy-glycosides derived from Cycadaceae plants and pyridine derivatives produced by marine sponge

Alkaloid brachystemidine G (99) was isolated from the roots of Brachystemma calycinum. This compound is a potent immunosuppressive agent, as demonstrated by its inhibition of mouse T and B-lymphocyte proliferation, with IC50 value of 5.6 μg/mL [114]. The 1,2,4-triazine derivative (100) was extracted from the seeds of the tropical flowering plant Butea monosperma [115]. It is known that the odor of this plant kills mosquitoes, the flowers are used as a dyeing color, and the gum, called kamarkas (Hindi), is used in food dishes [116]. Alkaloid (101) was isolated from the leaf extract of the flowering plant Aconnitum sungpanense [117].

Azoxy-glycosides have a common aglycone, methylazoxymethanol (MAM) and are found in Cycadaceae plants. To date, all of these glycosides that have been isolated have β-glycosidic linkages [118]. Methyl-azoxymethane (102), methylazoxy-methanol (MAM, 103), methylazoxymethanol acetate (104), and cycasin (105 and 106) metabolites were extracted from the seeds and roots of cycad plants Cycadaceae, Stangeriaceae, and Zamiaceae [16, 118, 119, 120, 121, 122, 123], which are conifers common to the tropics and subtropics. MAM (103) was shown to induce a variety of tumors, primarily liver and renal cell carcinomas [124]. Cycasins (105 and 106) and macrozamin (107) are very toxic azoxyglycosides of Cycadales.

Azoxy-glycosides may have played an important ecological role as antiherbivore defenses. Cycasin, which together with macrozamin represent the major azoxy-glycosides occurring in cycads, has been reported to elicit responses similar to those that have been observed during carcinogenicity, mutagenicity, and neurotoxicity assays. The first isolation of a glycoside, neocycasin A (108), was reported [125]. More recently, a range of neocycasin compounds, including neocycasin B, C, D, E, F, G, H, I, and J (109117), were isolated from different plants [126, 127, 128, 129, 130, 131, 132, 133].

The first identified cytotoxic bis-3-alkylpyridine alkaloid containing an azoxy moiety, pyrinadine A (118), was isolated from an Okinawan marine sponge Cribrochalina sp. [134]. Additional cytotoxic bis-3-alkylpyridine alkaloids, pyrinadines B, C, D, E, F, G, and H (119125) were isolated from the same Okinawan marine sponge. Pyrinodemins showed cytotoxicity against P388 murine leukemia cells [135, 136]. Predicted activities compounds (118125) shown in Table 8 and the structures shown in Fig. 6.
Table 8

Confirmed and new biological activities of azo compounds (118125) derived from marine sponge

No.

Activity reviewed

Activities confirmed (Pa)

Additional predicted activities (Paa)

118

Cytotoxic

Antineoplastic (0.776)

Antieczematic (0.693)

Antiinflammatory (0.646)

119

Cytotoxic

Antineoplastic (0.747)

Cardiovascular analeptic (0.567)

Fibrinolytic (0.538)

120

Cytotoxic

Antineoplastic (0.747)

Cardiovascular analeptic (0.567)

Fibrinolytic (0.538)

121

Cytotoxic

Antineoplastic (0.771)

Antieczematic (0.671)

Antiinflammatory (0.645)

122

Cytotoxic

Antineoplastic (0.771)

Antieczematic (0.671)

Antiinflammatory (0.645)

123

Cytotoxic

Antineoplastic (0.771)

Antieczematic (0.671)

Antiinflammatory (0.645)

124

Cytotoxic

Antineoplastic (0.771)

Antieczematic (0.671)

Antiinflammatory (0.645)

125

Cytotoxic

Antineoplastic (0.776)

Antieczematic (0.693)

Antiinflammatory (0.646)

aOnly activities with Pa > 0.5 are shown

4 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.

Notes

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.

References

  1. 1.
    H.E. Bigelow, Chem. Rev. 9, 117–167 (1931)CrossRefGoogle Scholar
  2. 2.
    T.A. La Rue, Lloydia 40, 307–321 (1977)Google Scholar
  3. 3.
    C.C. Nawrat, C.J. Moody, Nat. Prod. Rep. 28, 1426–1444 (2011)PubMedCrossRefGoogle Scholar
  4. 4.
    L.M. Blair, J.J. Sperry, Nat. Prod. 76, 794–812 (2013)CrossRefGoogle Scholar
  5. 5.
    V.M. Dembitsky, Phytomedicine 21, 1559–1581 (2014)PubMedCrossRefGoogle Scholar
  6. 6.
    V.M. Dembitsky, J. Nat. Med. (Tokyo) 62, 1–33 (2008)CrossRefGoogle Scholar
  7. 7.
    V.M. Dembitsky, Eur. J. Med. Chem. 43, 223–251 (2008)PubMedCrossRefGoogle Scholar
  8. 8.
    F.M.D. Ismail, D.O. Levitsky, V.M. Dembitsky, Eur. J. Med. Chem. 44, 3373–3387 (2009)PubMedCrossRefGoogle Scholar
  9. 9.
    D.M. Pereira, P. Valentão, P.B. Andrade, Dyes Pigm. 111, 124–134 (2014)CrossRefGoogle Scholar
  10. 10.
    A.B. Soliev, K. Hosokawa, K. Enomoto, Evid. Based Complement. Altern. Med. 670349 (2011). doi: 10.1155/2011/670349
  11. 11.
    V.M. Dembitsky, T. Řezanka, Folia Microbiol. 50, 363–391 (2005)CrossRefGoogle Scholar
  12. 12.
    V.M. Dembitsky, Chem. Biodivers. 1, 673–781 (2004)PubMedCrossRefGoogle Scholar
  13. 13.
    A. Sergeiko, V.V. Poroikov, L.O. Hanuš, V.M. Dembitsky, Open Med. Chem. J. 2, 26–37 (2008)PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    A. Torres, M. Hochberg, I. Pergament, R. Smoum, V. Niddam, V.M. Dembitsky, Eur. J. Biochem. 271, 780–784 (2004)PubMedCrossRefGoogle Scholar
  15. 15.
    M. Wainwright, Biotech. Histochem. 85, 341–354 (2010)PubMedCrossRefGoogle Scholar
  16. 16.
    A.M. Bode, Z. Dong, Cancer Prev. Res. (Phila.) 8, 1–8 (2015)CrossRefGoogle Scholar
  17. 17.
    A.S. Shawali, N.A. Samy, J. Adv. Res. 6, 241–254 (2015)PubMedCrossRefGoogle Scholar
  18. 18.
    V.M. Dembitsky, Tetrahedron 59, 4701–4720 (2003)CrossRefGoogle Scholar
  19. 19.
    D.A. Filimonov, A.A. Lagunin, T.A. Gloriozova, A.V. Rudik, Chem. Heterocycl. Compd. 50, 444–457 (2014)CrossRefGoogle Scholar
  20. 20.
    V.V. Poroikov, D.A. Filimonov, Y.V. Borodina, A.A. Lagunin, J. Chem. Inf. Comput. Sci. 40, 1349–1355 (2000)PubMedCrossRefGoogle Scholar
  21. 21.
    V.M. Dembitsky, T. Gloriozova, V.V. Poroikov, Mini Rev. Med. Chem. 5, 319–336 (2005)PubMedCrossRefGoogle Scholar
  22. 22.
    V.M. Dembitsky, T. Gloriozova, V.V. Poroikov, Mini Rev. Med. Chem. 7, 571–589 (2007)PubMedCrossRefGoogle Scholar
  23. 23.
    V.M. Dembitsky, T. Gloriozova, V.V. Poroikov, Phytomedicine 22, 183–202 (2015)PubMedCrossRefGoogle Scholar
  24. 24.
    D.O. Levitsky, T.A. Gloriozova, V.V. Poroikov, V.M. Dembitsky, Mathews J. Pharm. Sci. 1, 003 (2016)Google Scholar
  25. 25.
    M. Yamato, H. Iinuma, H. Naganawa, Y. Yamagishi, M. Hamada, T. Masuda, H. Umezawa, V. Abe, M. Hori, J. Antibiot. 39, 184–191 (1986)PubMedCrossRefGoogle Scholar
  26. 26.
    Y. Ma, R.J. Parry, Microbiology 146, 345–352 (2000)PubMedCrossRefGoogle Scholar
  27. 27.
    G. Bianchi, D. Dallavalle, L. Merlini, G. Nasini, S. Quaroni, Planta Med. 69, 574–576 (2003)PubMedCrossRefGoogle Scholar
  28. 28.
    W.J. McGahren, M.P. Kunstmann, J. Am. Chem. Soc. 91, 2808–2810 (1969)PubMedCrossRefGoogle Scholar
  29. 29.
    W.J. McGahren, M.P. Kunstmann, J. Am. Chem. Soc. 92, 1587–1590 (1970)PubMedCrossRefGoogle Scholar
  30. 30.
    M. Nakayama, Y. Takahashi, H. Itoh, K. Kamiya, M. Shiratsuchi, G. Otani, J. Antibiot. 42, 1535–1540 (1989)PubMedCrossRefGoogle Scholar
  31. 31.
    M. Fujiu, S. Sawairi, H. Shimada, H. Takaya, Y. Aoki, T. Okuda, K. Yokose, J. Antibiot. 47, 833–835 (1994)PubMedCrossRefGoogle Scholar
  32. 32.
    Y. Aoki, M. Kondoh, M. Nakamura, T. Fujii, T. Yamazaki, H. Shimada, M. Arisawa, J. Antibiot. 47, 909–916 (1994)PubMedCrossRefGoogle Scholar
  33. 33.
    T.H. Haskell, A. Ryder, Q.R. Bartz, Antibiot. Chemother. (Northfield) 4, 141–144 (1954)Google Scholar
  34. 34.
    J. Ehrlich, L.E. Anderson, G.L. Coffey, W.H. Feldman, Antibiot. Chemother. (Northfield) 4, 338–342 (1954)Google Scholar
  35. 35.
    L.E. Anderson, J. Ehrlich, S.H. Sun, P.R. Burkholder, Antibiot. Chemother. (Northfield) 6, 100–115 (1956)Google Scholar
  36. 36.
    K. Ohkuma, G. Nakamura, S. Yamashita, J. Antibiot. 10, 224–225 (1957)PubMedGoogle Scholar
  37. 37.
    L. Ding, B.S. Ndejouong, A. Maier, H.H. Fiebig, C. Hertweck, J. Nat. Prod. 75, 1729–1734 (2012)PubMedCrossRefGoogle Scholar
  38. 38.
    N. Manderscheid, S.E. Helaly, A. Kulik, J. Wiese, J. Antibiot. 66, 85–88 (2013)PubMedCrossRefGoogle Scholar
  39. 39.
    S. Omura, K. Otoguro, N. Imamura, H. Kuga, J. Antibiot. 40, 623–629 (1987)PubMedCrossRefGoogle Scholar
  40. 40.
    N. Imamura, H. Kuga, K. Otoguro, H. Tanaka, S. Omura, J. Antibiot. 42, 156–158 (1989)PubMedCrossRefGoogle Scholar
  41. 41.
    K. Tsuzuki, F.S. Yan, K. Otoguro, S. Omura, J. Antibiot. 44, 774–784 (1991)PubMedCrossRefGoogle Scholar
  42. 42.
    J.R. Egerton, D.A. Ostlind, L.S. Blair, C.H. Eary, Antimicrob. Agents Chemother. 15, 372–378 (1979)PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    A. Sugawara, M. Kubo, T. Nakashima, T. Hirose, Tetrahedron 71, 2149–2157 (2015)CrossRefGoogle Scholar
  44. 44.
    G. Le Goff, M.T. Martin, B.I. Iorga, E. Adelin, J. Nat. Prod. 76, 142–149 (2013)PubMedCrossRefGoogle Scholar
  45. 45.
    Y. Abe, J.I. Kadokura, A. Shimazu, H. Seto, N. Otake, Agric. Biol. Chem. 47, 2703–2705 (1983)Google Scholar
  46. 46.
    W.Y. Chan, T.B. Ng, J.S. Lam, J.H. Wong, Appl. Microbiol. Biotechnol. 85, 985–993 (2010)PubMedCrossRefGoogle Scholar
  47. 47.
    H. Nakano, M. Hara, T. Katsuyama, Y. Uozaki, K. Gomi, U.S. Chem. Abstr. 119, 158353 (1993)Google Scholar
  48. 48.
    M. Nakaynma, H. Ito, I. Watanabe, M. Shiratsuchi, US Patent 4,981,954 (1991)Google Scholar
  49. 49.
    H. Umezawa, T. Takeuchi, H. Iinuma, M. Ito, M. Ishizuka, J. Antibiot. 28, 87–90 (1975)PubMedCrossRefGoogle Scholar
  50. 50.
    R. Calvino, R. Fruttero, A. Gasco, A. Miglietta, L. Gabriel, J. Antibiot. 39, 864–868 (1986)PubMedCrossRefGoogle Scholar
  51. 51.
    A. Gasco, A. Serafino, V. Mortarinin, E. Menziani, Tetrahedron Lett. 38, 3431–3432 (1974)CrossRefGoogle Scholar
  52. 52.
    O. Brossa, E. Gadoni, A. Olivero, M. Seccia, A. Miglietta, L. Gabriel, E. Gravela, Res. Commun. Chem. Pathol. Pharmacol. 70, 143–153 (1990)PubMedGoogle Scholar
  53. 53.
    D. Boschi, C. Cena, R. Fruttero, M.I. Brenciaglia, Pharmazie 56, 670–672 (2001)PubMedGoogle Scholar
  54. 54.
    A. Miglietta, E. Gadoni, M. Buffa, A. Olivero, L. Gabriel, Eur. J. Drug Metab. Pharm. 20, 249–254 (1995)CrossRefGoogle Scholar
  55. 55.
    T. Okuda, N. Nakayama, A. Fujiwara, Nippon Kingakukai Kaiho 23, 225–234 (1982)Google Scholar
  56. 56.
    T. Okuda, A. Fujiwara, Nippon Kingakkai Kaiho 23, 235–239 (1984)Google Scholar
  57. 57.
    B. Köpcke, A.A.H. Mayer, O. Sterner, Nat. Prod. Lett. 13, 41–46 (1999)CrossRefGoogle Scholar
  58. 58.
    T. Kamo, M. Kashiwabara, K. Tanaka, S. Ando, H. Shibata, M. Hirota, Nat. Prod. Res. 20, 507–510 (2006)PubMedCrossRefGoogle Scholar
  59. 59.
    Y. Takaishi, Y. Murakami, M. Uda, T. Ohashi, N. Hamamura, Phytochemistry 45, 997–1001 (1997)CrossRefGoogle Scholar
  60. 60.
    F. Burkhard, A. Siegbert, W. Steglich, J. Fleischhauer, Eur. J. Org. Chem. 16, 3097–3104 (2001)Google Scholar
  61. 61.
    N. Claydon, J. Invertebr. Pathol. 32, 319–324 (1978)CrossRefGoogle Scholar
  62. 62.
    D.W. Roberts, in Microbia Control of Pests and Plant Diseases 1970–1980, ed. by H.D. Burges (Academic Press, New York, 1981), pp. 441–464Google Scholar
  63. 63.
    W. Steglich, in Biologically Active Molecules (1989), pp. 1–8Google Scholar
  64. 64.
    T. Suortti, Food Chem. Toxicol. 22, 579–581 (1984)PubMedCrossRefGoogle Scholar
  65. 65.
    T. Suortti, A. von Wright, J. Chromatogr. 255, 529–532 (1983)PubMedCrossRefGoogle Scholar
  66. 66.
    S. Yannai, Dictionary of food compounds with CD-ROM: Additives, flavors, and ingredients (Chapman & Hall/CRC, Boca Raton, 2004)Google Scholar
  67. 67.
    M. Gill, R.J. Strauch, Z. Naturforsch. C 39, 1027–1029 (1984)PubMedGoogle Scholar
  68. 68.
    A.T. Gillespie, N. Claydon, Pesticide Sci. 27, 203–215 (1989)CrossRefGoogle Scholar
  69. 69.
    M.J. Bidochka, G.G. Khachatourians, J. Insect. Pathol. 58, 106–117 (1991)CrossRefGoogle Scholar
  70. 70.
    G.G. Khachatourians, Biochemistry and molecular biology of entomopathogenic fungi, in The Mycota VI. Human and Animal Relationships, ed. by D.H. Howard, J.D. Miller (Springer, Berlin, 1996), pp. 331–363CrossRefGoogle Scholar
  71. 71.
    D.N. Pegler, Mushrooms and Toadstools (Mitchell Beazley, London, 1983)Google Scholar
  72. 72.
    C. Dickinson, J. Lucas, The Encyclopedia of Mushrooms (G. P. Putnam’s Sons, New York, 1979)Google Scholar
  73. 73.
    Y.Y. Guo, H. Li, Z.X. Zhou, X.M. Mao, Org. Lett. 17, 6114–6117 (2015)PubMedCrossRefGoogle Scholar
  74. 74.
    R. Wang, The investigation of biologically active secondary metabolites produced by diatoms. Ph.D. Dissertation, University of Rhode Island (1992)Google Scholar
  75. 75.
    Y. Shimizu, Chem. Rev. 93, 1685–1698 (1993)CrossRefGoogle Scholar
  76. 76.
    B. Levenberg, J. Biol. Chem. 239, 2267–2274 (1964)PubMedGoogle Scholar
  77. 77.
    S. Hilbig, T. Andries, W. Steglich, T. Anke, Angew. Chem. 97, 1063–1069 (1985)CrossRefGoogle Scholar
  78. 78.
    K. Dornberger, W. Ihn, W. Schade, D. Tresselt, A. Zureck, L. Radics, Tetrahedron Lett. 27, 559–566 (1986)CrossRefGoogle Scholar
  79. 79.
    J.Y. Cho, H.C. Kwon, P.G. Williams, P.R. Jensen, W. Fenical, Org. Lett. 8, 2471–2474 (2006)PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    M. Bahi, Bandamycin as new antifungal agent and further secondary metabolites from terrestrial and marine microorganisms. Ph.D. Dissertation, Göttingen (2012)Google Scholar
  81. 81.
    K. Yoshida, M. Okamoto, K. Umehara, M. Iwami, J. Antibiot. 35, 151–156 (1982)PubMedCrossRefGoogle Scholar
  82. 82.
    H. Tanaka, K. Yoshida, Y. Itoh, H. Imanaka, J. Antibiot. 35, 157–163 (1982)PubMedCrossRefGoogle Scholar
  83. 83.
    S. Omura, H. Tomoda, Q.M. Xu, Y. Takahashi, Y. Iwai, J. Antibiot. 39, 1211–1218 (1986)PubMedCrossRefGoogle Scholar
  84. 84.
    H. Tomoda, K. Igarashi, S. Omura, Biochim. Biophys. Acta 921, 595–598 (1987)PubMedCrossRefGoogle Scholar
  85. 85.
    H. Ui, A. Ishiyama, H. Sekiguchi, M. Namatame, A. Nishihara, Y. Takahashi, K. Shiomi, K. Otoguro, S. Omura, J. Antibiot. 60, 220–222 (2007)PubMedCrossRefGoogle Scholar
  86. 86.
    S. Kosemura, S. Yamamura, Tetrahedron Lett. 38, 3025–3026 (1997)CrossRefGoogle Scholar
  87. 87.
    V.V. Smirnov, E.A. Kiprianova, A.D. Garagulya, S.E. Esipov, S.A. Dovjenko, FEMS Microbiol. Lett. 153, 357–361 (1997)PubMedCrossRefGoogle Scholar
  88. 88.
    H.J. Lindner, G. Schaden, Chem. Ber. 105, 1949–1955 (1972)PubMedCrossRefGoogle Scholar
  89. 89.
    K. Hirata, H. Nakagami, J. Takashina, T. Mahmud, M. Kobayashi, Heterocycles 43, 1513–1519 (1996)CrossRefGoogle Scholar
  90. 90.
    M. Mojzych, J. Chem. Soc. Pak. 33, 698–702 (2011)Google Scholar
  91. 91.
    T. Hosoe, K. Nozawa, N. Kawahara, K. Fukushima, Mycopathologia 146, 9–12 (1999)PubMedCrossRefGoogle Scholar
  92. 92.
    J.M. Ames, G. MacLeod, Phytochemistry 29, 1201–1207 (1990)CrossRefGoogle Scholar
  93. 93.
    P.W. Brian, Bot. Rev. 17, 357–430 (1951)CrossRefGoogle Scholar
  94. 94.
    K. Wang, L. Guo, Y. Zou, Y. Li, J. Wu, J. Antibiot. 60, 325–327 (2007)PubMedCrossRefGoogle Scholar
  95. 95.
    R. Grote, Y. Chen, A. Zeeck, J. Antibiot. 41, 595–601 (1988)PubMedCrossRefGoogle Scholar
  96. 96.
    H. Bockholt, J.M. Beale, J. Rohr, Angew. Chem. 106, 1733–1735 (1994)CrossRefGoogle Scholar
  97. 97.
    K. Hirasawa, K. Isono, J. Antibiot. 31, 628–629 (1978)PubMedCrossRefGoogle Scholar
  98. 98.
    K. Susugiura, G.H. Hitchings, L.F. Cavalieri, C.C. Stock, Cancer Res. 10, 178–185 (1950)Google Scholar
  99. 99.
    K. Anzai, J. Nagatsu, S. Suzuki, J. Antibiot. 14, 340–342 (1961)PubMedGoogle Scholar
  100. 100.
    K. Anzai, S. Suzuki, J. Antibiot. 14, 253 (1961)PubMedGoogle Scholar
  101. 101.
    A. Stachelska-Wierzchowska, J. Wierzchowski, A. Bzowska, B. Wielgus-Kutrowska, B Mol. 21, 44–49 (2016)Google Scholar
  102. 102.
    M.B. Hossain, D. van der Helm, Acta Crystallogr. 41C, 1199–1202 (1985)Google Scholar
  103. 103.
    V. Ludovic, M.C. Groleau, V. Dekimpe, E. Deziel, Prod. J. Microbiol. Biotechnol. 17, 1407–1429 (2007)Google Scholar
  104. 104.
    J. Franke, K. Ishida, M. Ishida-Ito, C. Hertweck, Angew. Chem. Int. Ed. 52, 8271–8275 (2013)CrossRefGoogle Scholar
  105. 105.
    T. Wieland, H. Faulstich, C.R.C. Crit, Rev. Biochem. 5, 185–260 (1978)Google Scholar
  106. 106.
    F. Enjalbert, S. Rapiorm, J. Nouguier-Soulém, S. Guillon, N. Amouroux, C. Cabot, J. Toxicol. Clin. Toxicol. 40, 715–757 (2002)PubMedCrossRefGoogle Scholar
  107. 107.
    C. Karlson-Stiber, H. Persson, Toxicon 42, 339–349 (2003)PubMedCrossRefGoogle Scholar
  108. 108.
    J. Garcia, V.M. Costa, A. Carvalho, P. Baptista, P.G. de Pinho, M. de Lourdes Bastos, F. Carvalho, Food Chem. Toxicol. 86, 41–55 (2015)PubMedCrossRefGoogle Scholar
  109. 109.
    E. Falck-Pedersen, P.W. Morris, D.L. Venton, Int. J. Peptide Protein Res. 21, 431–439 (1983)CrossRefGoogle Scholar
  110. 110.
    E.S. Falck-Pedersen, Synthesis and characterization of 7′-azo-γ-amatoxins. Ph.D. Dissertation, University of Illinois. University Microfilms International, Ann Arbor, Michigan (1981)Google Scholar
  111. 111.
    V.M. Dembitsky, A.A.A. Al Quntar, M. Srebnik, Chem. Rev. 111, 209–237 (2011)PubMedCrossRefGoogle Scholar
  112. 112.
    T. Wieland, Peptides of Poisonous Amanita Mushrooms (Springer, Berlin, 1986)CrossRefGoogle Scholar
  113. 113.
    W. Zhang, X.J. Huang, S.-Y. Zhang, D.-M. Zhang, R.-W. Jiang, J.-Y. Hu, X.-Q. Zhang, L. Wang, W.-C. Ye, J. Nat. Prod. 78, 2036–2044 (2015)PubMedCrossRefGoogle Scholar
  114. 114.
    Q. Lu, L. Zhang, G.-R. He, H.-X. Liang, G.-H. Du, Y.-X. Cheng, Chem. Biodivers. 4, 2948–2952 (2007)PubMedCrossRefGoogle Scholar
  115. 115.
    M. Porwal, B.K. Mehta, D.N. Gupta, Nat. Acad. Sci. Lett. 2, 81–84 (1988)Google Scholar
  116. 116.
    F. Rana, M. Avijit, Int. J. Res. Pham. Chem. 2, 1035–1039 (2012)Google Scholar
  117. 117.
    X. Wang, Z. Lib, B. Yanga, Fitoterapia 75, 789–791 (2004)PubMedCrossRefGoogle Scholar
  118. 118.
    P. Spencer, R.C. Fry, G.E. Kisby, Front. Genet. 3, 192–194 (2012)PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    G.L. Laqueur, M. Spatz, Cancer Res. 28, 2262–2267 (1968)PubMedGoogle Scholar
  120. 120.
    R.W. Morgan, G.R. Hoffmann, Mutat. Res. 114, 19–58 (1983)PubMedCrossRefGoogle Scholar
  121. 121.
    D. Schneider, M. Wink, F. Sporer, P. Lounibos, Naturwis-senschaften 89, 281–294 (2002)CrossRefGoogle Scholar
  122. 122.
    A. Prado, J. Ledezma, L. Cubilla-Rios, J.C. Bede, D.M. Windsor, J. Chem. Ecol. 37, 736–740 (2011)PubMedCrossRefGoogle Scholar
  123. 123.
    S.F. Dossaji, Totins in certain indigenous Kenya plants. Ph.D. Thesis, University of Nairobi (1971)Google Scholar
  124. 124.
    T. Tanaka, H. Kohno, M. Murakami, R. Shimada, S. Kagami, Oncol. Rep. 7, 501–508 (2000)PubMedGoogle Scholar
  125. 125.
    K. Nishida, A. Kobayashi, T. Nagahama, T. Numata, Bull. Agric. Chem. Soc. Jpn. 23, 460–464 (1959)Google Scholar
  126. 126.
    T. Nagahama, T. Numata, K. Nishida, K. Agric, Chem. Soc. Jpn. 23, 556–559 (1959)Google Scholar
  127. 127.
    S.S. Chang, Y.L. Chan, M.L. Wu, J.F. Deng, T. Chiu, J. Toxicol. Clin. Toxicol. 42, 49–54 (2004)PubMedCrossRefGoogle Scholar
  128. 128.
    F. Yagi, K. Tadera, Biochim. Biophys. Acta 1289, 315–321 (1996)PubMedCrossRefGoogle Scholar
  129. 129.
    D.-F. Hwang, T.-Y. Chen, Ref. Modul. Food Sci. 326–330 (2016)Google Scholar
  130. 130.
    W.W. Wells, M.G. Yang, W. Bolzer, O. Mickelsen, Anal. Biochem. 25, 325–329 (1968)PubMedCrossRefGoogle Scholar
  131. 131.
    A. Moretti, S. Sabato, G. Siniscalco, Phytochemistry 20, 1415–1416 (1981)CrossRefGoogle Scholar
  132. 132.
    P. Lindblad, K. Tadera, F. Yagi, Environ. Exp. Bot. 30, 429–434 (1990)CrossRefGoogle Scholar
  133. 133.
    J.E. Poulton, ACS Symp. Ser. 533, 170–190 (1993)CrossRefGoogle Scholar
  134. 134.
    Y. Kariya, T. Kubota, J. Fromont, J. Kobayashi, Tetrahedron Lett. 47, 997–998 (2006)CrossRefGoogle Scholar
  135. 135.
    Y. Kariya, T. Kubota, J. Fromont, J. Kobayashi, Bioorg. Med. Chem. 14, 8415–8419 (2006)PubMedCrossRefGoogle Scholar
  136. 136.
    T. Kubota, K. Kura, J. Fromont, J. Kobayashi, Tetrahedron 69, 96–100 (2013)CrossRefGoogle Scholar

Copyright information

© The Author(s) 2017

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Valery M. Dembitsky
    • 1
  • Tatyana A. Gloriozova
    • 2
  • Vladimir V. Poroikov
    • 2
  1. 1.National Scientific Center of Marine BiologyVladivostokRussia
  2. 2.Institute of Biomedical ChemistryMoscowRussia

Personalised recommendations