Structure-activity relationships among mycotoxins

Relationships between structural features and biological effects of mycotoxins are reviewed. Structure-activity relationships are characterized at the molecular, subcellular, cellular, or supracellular level. Major chemical and physicochemical factors responsible for bioactivity of mycotoxins are stressed. A variety of chemical families of mycotoxins are then discussed from the point of view of structure-activity relationships. The structurally related families comprise small lactones, macrocyclic lactones, isocoumarin derivatives, aflatoxins and related compounds trichothecenes, anthraquinones, indole-derived tremorgens and selected amino acid-derived mycotoxins such as sporidesmins and cyclosporines. Biological effects of mycotoxins include acute and chronic toxicity, antimicrobial activity, mutagenicity and genotoxicity, carcinogenicity and biochemical modes of action.     

Relation between the chemical structure and mutagenic activity of derivatives of the herbicide toluin

Different mutagenic activities of 13 methoxy- and ethoxy-derivatives of the herbicide toluin are shown. Relationship of these activities with chemical structure is analysed. It was found out that mutagenic activity of the compound depends on its chemical structure. The higher degree of mutagenicity of analogues having-ortho-positions, as compared with the derivatives of toluin with -para- and -meta-positions was established.     

Mutagenicity of azo dyes: structure-activity relationships.

Azo dyes are extensively used in textile, printing, leather, paper making, drug and food industries. Following oral exposure, azo dyes are metabolized to aromatic amines by intestinal microflora or liver azoreductases. Aromatic amines are further metabolized to genotoxic compounds by mammalian microsomal enzymes. Many of these aromatic amines are mutagenic in the Ames Salmonella/microsomal assay system. The chemical structure of many mutagenic azo dyes was reviewed, and we found that the biologically active dyes are mainly limited to those compounds containing p-phenylenediamine and benzidine moieties. It was found that for the phenylenediamine moiety, methylation or substitution of a nitro group for an amino group does not decrease mutagenicity. However, sulfonation, carboxylation, deamination, or substitution of an ethyl alcohol or an acetyl group for the hydrogen in the amino groups leads to a decrease in the mutagenic activity. For the benzidine moiety, methylation, methoxylation, halogenation or substitution of an acetyl group for hydrogen in the amino group does not affect mutagenicity, but complexation with copper ions diminishes mutagenicity. The mutagenicity of benzidine or its derivatives is also decreased when in the form of a hydrochloride salt with only one exception. Mutagenicity of azo dyes can, therefore, be predicted by these structure-activity relationships.     

Relative efficiencies of a series of square-planar plantinum(II) compounds on Salmonella mutagenesis.

Twelve Pt(II) compounds have been tested for mutagenicity on Salmonella typhimurium (strain TA 100). Very high mutagenic activities were found for the cis derivatives. A correlation is suggested between these results and a formerly described model of chemical reactivity towards DNA, according to which cis derivatives from intra-strand chelates with guanine. A smaller activity was found with monodentate complexes with DNA.     

Quantitative "structure-antimicrobial activity" relations of the new azole derivatives

New azole derivatives are synthesized and examined with the purpose of searching antimicrobic drugs and of determining the quantitative structure--activity relationships. Their antifungal and antibacterial activity is fixed. Certain regularities of the relationships between the chemical structure of compounds and their activity are determined by the Free-Wilson model. The influence of aryl and alkyl radicals in 1.2 and 5 positions of azoles on antimicrobial properties is discussed. Prospects for the further studies of this group of chemicals are shown.     

Auspicious role of the steroidal heterocyclic derivatives as a platform for anti-cancer drugs

Steroids are polycyclic compounds that have a wide range of biological activities. They are bio-synthesized from cholesterol through a series of enzyme-mediated transformations, so they are highly lipophilic and readily enter most cells to interact with intracellular receptors, making them ideal vehicles for targeting a broad array of pathologies. New curative agents for cancers have been developed from several steroidal derivatives. Some biologically important properties of modified steroids are dependent on structural features of the steroid moiety and their side chains. Therefore, chemical derivatization of steroids provides a way to modify their function, and many structure–activity relationships have been confirmed by such synthetic modifications. Several studies demonstrate that steroidal heterocyclic derivatives can be effective in the prevention and treatment of many types of hormone-dependent cancers. The present review is a concise report on steroidal heterocyclic derivatives, with special emphasis on steroid heterocyclic derivatives with 5 membered rings or six-membered rings having interesting therapeutic potential as enzyme inhibitors and cytotoxic drugs to be used as candidates for anti-cancer drug development.     

Antifungal properties of new series of quinoline derivatives

The series of quinoline derivatives were prepared. The synthetic approach, analytical, and spectroscopic data of all synthesized compounds are presented. All the prepared derivatives were analyzed using the reversed-phase high performance liquid chromatography (RP-HPLC) method for the lipophilicity measurement. In the present study, the correlation between RP-HPLC retention parameter log K (the logarithm of capacity factor K) and various calculated log P data is shown. The relationships between the lipophilicity and the chemical structure of the studied compounds are discussed as well. The prepared compounds were tested for their in vitro antifungal activity. 2-[(3-Hydroxyphenylimino)methyl]quinolin-8-ol (8), 2-[(4-hydroxyphenylimino)methyl]quinolin-8-ol (9) and 2-[(2,5-dichloro-4-nitrophenylamino)methoxymethyl]quinolin-8-ol (10) showed in vitro antifungal activity comparable to or higher than that of the standard fluconazole. Structure-activity relationships among the chemical structure, the physical properties, and the biological activities of the evaluated compounds are discussed in the article.     

Mutagenicity of nitro- and amino-substituted phenazines in Salmonella typhimurium

The nitro- and amino-substituted phenazines were synthesized and assayed for their mutagenicity in Salmonella typhimurium strains TA98 and TA98NR. Of 7 tested nitrophenazines, 4 were mutagenic in the absence of a microsomal metabolic activation system (S9 mix) and were more mutagenic in TA98 than in TA98NR. The order of mutagenicity of nitrophenazines in TA98 is 1.7- less than 2- less than 2.8- less than 2.7-substituted phenazine. Of 7 tested amino derivatives, 4 exhibited mutagenic activity with S9 mix in TA98. 1-Nitro-, 1-amino, 1.6-dinitro-, 1.9-dinitro-, 1.6-diamino- and 1.9-diamino-phenazine were not mutagenic. As regards the relationship between mutagenic potency and chemical structure of the phenazines, the results suggested that structural requirements favoring mutagenic activity were the presence of substituents at the 2 and/or 7 position. Furthermore, 2.7-disubstituted phenazines were extremely mutagenic, 2.7-dinitrophenazine and 2.7-diaminophenazine induced 36,450 and 12,110 rev./nmole, respectively. In the preliminary study, 2.7-diaminophenazine was identified by gas chromatography/mass spectrometry from the reaction mixture of m-phenylenediamine and hydrogen peroxide.     

Structure-activity relationships of the azide metabolite, azidoalanine, in S. typhimurium

Azide is metabolized to the proximate mutagen, L-azidoalanine in bacterial systems. While this novel mutagenic metabolite plays a key role in azide mutagenesis, the biochemistry of this role is unknown. The chemical synthesis of authentic racemic azidoalanine and several derivatives thereof allowed the exploration of structure-activity relationships with this unique mutagen. We found that whereas azide, azidoalanine and azidoalanine tert.-butyl ester were of comparable mutagenic potency, derivatives which lack the free amino group, such as azidopropionic acid and amino-blocked azidoalanine, were orders of magnitude less active. These findings demonstrate that the free amino group is essential for significant activity, while the carboxyl group may be less important. This conclusion together with the finding that DL-azidoalanine is a less potent mutagen than azide itself, suggests that the metabolite, while necessary for azide mutagenicity, may not be the ultimate mutagenic species. Instead, the data are consistent with the hypothesis that azidoalanine requires further bioactivation.     

Mutagenicity of K-region epoxides of polycyclic aromatic compounds: Structure-activity relationship

The mutagenicity of several K-region arene oxides waas tested in histidine-dependent mutants of Salmonella typhimurium. Benzo(a)pyrene-4,5-oxide and pyrene-4,5-oxide as well as some substituted phenanthrene oxides were mutagenic in strains TA 1538 and TA 98 which detect frame-shift mutagens.Structure-activity relationships are discussed from the standpoint of chemical reactivity. The absence of direct correlation between electrophilic reactivity and mutagenicity may suggest that primilarily physical properties, such as relative position of the epoxide group and molecular shape of arene oxides, are important for the emergence of mutagenicity of arene oxides.     

The mutagenic action of nitroimidazoles. IV. A comparison of the mutagenic action of several nitroimidazoles and some imidazoles.

The mutagenic action of 51 imidazoles was investigated. The fluctuation test of Luria and Delbrück was used, with Klebsiella pneumoniae as test organism. 8 compounds, including 5 with a weak mutagenic action in the fluctuation test, were also investigated by the Ames test in which Salmonella typhimurium TA100 was used. Of the 51 imidazoles examined, 33 were nitroimidazoles. 31 of the latter appeared to be mutagenic, whereas out of the 18 other imidazoles without a nitro group only 2 were mutagenic. Several of the substances tested for mutagenicity showed an antimicrobial activity. No direct relationship between antimicrobial action, growth inhibition and mutagenicity was established. With methyl-nitroimidazoles a relationship was found between the chemical structure and mutagenic action. However, when the nitroimidazoles had a more complex chemical structure, a relationship between this structure and mutagenicity could not be established.     

An experimental study of the amides of aromatic carboxylic acids as radiosensitizing agents]

In experiments with mice a study was made of the radiosensitizing efficacy of 10 aromatic carbonic acid amides, benzene, naphthalene, pyridine and quinoline derivatives. It has been found, for this group of substances, that there is a direct correlation between the ability of the substance to reduce the splenic endocolonies production and the inhibitory activity with regard to poly(ADP-ribose) polymerase of thymocyte nuclei. Within the group of substances under study, new agents are found and described and new relationships are revealed between their chemical structure and biological activity.     

Structure-based methods for predicting mutagenicity and carcinogenicity: are we there yet?

There is a great deal of current interest in the use of commercial, automated programs for the prediction of mutagenicity and carcinogenicity based on chemical structure. However, the goal of accurate and reliable toxicity prediction for any chemical, based solely on structural information remains elusive. The toxicity prediction challenge is global in its objective, but limited in its solution, to within local domains of chemicals acting according to similar mechanisms of action in the biological system; to predict, we must be able to generalize based on chemical structure, but the biology fundamentally limits our ability to do so. Available commercial systems for mutagenicity and/or carcinogenicity prediction differ in their specifics, yet most fall in two major categories: (1) automated approaches that rely on the use of statistics for extracting correlations between structure and activity; and (2) knowledge-based expert systems that rely on a set of programmed rules distilled from available knowledge and human expert judgement. These two categories of approaches differ in the ways that they represent, process, and generalize chemical-biological activity information. An application of four commercial systems (TOPKAT, CASE/MULTI-CASE, DEREK, and OncoLogic) to mutagenicity and carcinogenicity prediction for a particular class of chemicals—the haloacetic acids (HAs)—is presented to highlight these differences. Some discussion is devoted to the issue of gauging the relative performance of commercial prediction systems, as well as to the role of prospective prediction exercises in this effort. And finally, an alternative approach that stops short of delivering a prediction to a user, involving structure-searching and data base exploration, is briefly considered.     

Mutagenicity of aryl propylene and butylene oxides with salmonella

10 aryl propylene oxides and 6 aryl butylene oxides were synthesized. Dose-mutagenicity relationships were studied for these compounds and for 1,2-epoxybutane, using both the preincubation and plate incorporation Ames tests with Salmonella typhimurium strains TA100 and TA1535. Structure-mutagenicity relationships were further examined by concurrent testing at single doses with the plate incorporation assay in strain TA100. In both series of compounds, mutagenicity showed very correlation to chemical reactivity, molar volume and partition values. However, all compounds were mutagenic in at least one system with the propylene oxides being more mutagenic than the corresponding butylene oxide derivatives. The naphthyl derivatives in each series were the most mutagenic.     

Development of a toxicity test to be coupled to the Ames Salmonella assay and the method of constriction of the required strains

A 'toxicity' test protocol is described here to be used for determining the bactericidal effect of the chemicals which are tested for their mutagenic activity by the Ames method. Two sets of strains, isogenic with the Ames tester strains except for their his character, are constructed. One set is the his+ derivatives of the tester strains which are used for measuring the survival of the inoculum cells after exposure to the chemical. The other set is the stable his- derivatives of the tester strains which are used for simulating the background growth in the Ames mutagenicity plate test. The per cent survival of the his+ cells in the inoculum in the presence of the 'filler cells' is used as a measure of the toxic effect of the chemical.     

Classification according to chemical structure, mutagenicity to Salmonella and level of carcinogenicity of a further 42 chemicals tested for carcinogenicity by the U.S. National Toxicology Program

This paper is an extension and update of an earlier review published in this journal (Ashby and Tennant, 1988). A summary of the rodent carcinogenicity bioassay data on a further 42 chemicals tested by the U.S. National Toxicology Program (NTP) is presented. An evaluation of each chemical for structural alerts to DNA-reactivity is also provided, together with a summary of its mutagenicity to Salmonella. The 42 chemicals were numbered and evaluated as an extension of the earlier analysis of 222 NTP chemicals. The activity patterns and conclusions derived from the earlier study remain unchanged for the larger group of 264 chemicals. Based on the extended database of 264 NTP chemicals, the sensitivity of the Salmonella assay for rodent carcinogens is 58% and the specificity for the non-carcinogens is 73%. A total of 32 chemicals were defined as equivocal for carcinogenicity and, of these, 11 (34%) are mutagenic to Salmonella. An evaluation is made of instances where predictions of carcinogenicity, based on structural alerts, disagree with the Salmonella mutagenicity result (12% of the database). The majority of the disagreements are for structural alerts on non-mutagens, and that places these alerts as a sensitive primary screen with a specificity lower than that of the Salmonella assay. That analysis indicates some need for assays complementary to the Salmonella test when screening for potential genotoxic carcinogens. It also reveals that the correlation between structural alerts and mutagenicity to Salmonella is probably greater than 90%. Chemicals predicted to show Michael-type alkylating activity (i.e., CH2 = CHX; where X = an electron-withdrawing group, e.g. acrylamide) have been confirmed as a structural alert, and the halomethanes (624 are possible) have been classified as structurally-alerting. To this end an extended carcinogen-alert model structure is presented. Among the 138 NTP carcinogens now reviewed, 45 (33%) are non-mutagenic to Salmonella and possess a chemical structure that does not alert to DNA-reactivity. These carcinogens therefore either illustrate the need for complementary genetic screening tests to the Salmonella assay, or they represent the group of non-genotoxic carcinogens referred to most specifically by Weisburger and Williams (1981); the latter concept is favoured.     

Amaryllidaceae isocarbostyril alkaloids and their derivatives as promising antitumor agents

This review covers the isolation, total synthesis, biologic activity, and more particularly the in vitro and in vivo antitumor activities of naturally occurring isocarbostyril alkaloids from the Amaryllidaceae family. Starting from these natural products, new derivatives have been synthesized to explore structure-activity relationships within the chemical class and to obtain potential candidates for preclinical development. This approach appears to be capable of providing novel promising anticancer agents.     

Biological activity of usnic acid and its derivatives: Part 1. Activity against unicellular organisms

Usnic acid (UA) is a commercially available lichen metabolite. Its biological activity is diverse. Its broad occurrence in various lichen species, simple isolation procedure, and high optical purity of the isolated product make it promising as a base for developing novel pharmaceuticals. To date, scientific progress has made it possible to expand the scope of applications of UA and comprehend the biological mechanisms mediating its action. This review of the biological activity of UA and its derivatives summarizes publications of the recent decade. New data on the mechanisms of UA action on living organisms are discussed, and ways to modify its biological activity by altering its chemical structure and to control its bioavailability are considered. Special attention is paid to prospects of using semisynthetic UA derivatives as pharmacological agents. Data on the influence of the enantiopurity of UA on its biological activity are analyzed. The first part of the review is dedicated to UA biosynthesis and the biological action of UA and its derivatives on unicellular organisms.     

Heteroaryl urea inhibitors of fatty acid amide hydrolase: Structure–mutagenicity relationships for arylamine metabolites

The structure–activity relationships for a series of heteroaryl urea inhibitors of fatty acid amide hydrolase (FAAH) are described. Members of this class of inhibitors have been shown to inactivate FAAH by covalent modification of an active site serine with subsequent release of an aromatic amine from the urea electrophile. Systematic Ames II testing guided the optimization of urea substituents by defining the structure–mutagenicity relationships for the released aromatic amine metabolites. Potent FAAH inhibitors were identified having heteroaryl amine leaving groups that were non-mutagenic in the Ames II assay.