On the nature of folate derivatives in neurospora crassa and the effect of sulphanilamide

Summary The folic acid complex of Neurospora crassa has been separated by chromatography on DEAE-cellulose column and the nature of the individual derivatives ascertained from microbiological response. The functional groups of the polyglutamyl folates were ascertained.Major portion of Neurospora folates is composed of the polyglutamyl derivatives, as seen from the increase in activities for Streptococcus faecalis R, Pediococcus cerevisiae, and Lactobacillus casei after conjugase treatment.The presence of N¹⁰ and N⁵-formyl and N⁵-methyl tetrahydrofolic acid, N⁵-methyl diglutamyl tetrahydrofolic acid, two formylated derivatives of polyglutamates, and two N⁵-methyl polyglutamyl folates was ascertained in the folate complex of Neurospora crassa.Sulphanilamide growth inhibition results in the lowering of all the Neurospora folate derivatives.     

Biological activities and structure-activity relationship of substitution compounds of N-[2-(3-indolyl)ethyl]succinamic acid and N-[2-(1-naphthyl)ethyl]succinamic acid, derived from a new category of root-promoting substances, N-(phenethyl)succinamic acid analogs

In a previous study, it was demonstrated that N-(phenethyl)succinamic acid (PESA) derivatives form a new category of root-promoting substances which do not exhibit auxin-like activities, such as stem elongation and leaf epinasty (Soejima et al., 2000 [Plant Cell Physiol. 41s: 197]). In this study, N-[2-(3-indolyl)ethyl]succinamic acid (IESA) and N-[2-(1-naphthyl)ethyl]succinamic acid (NESA) were synthesized, and their biological activities were evaluated. In an adzuki root-promoting assay, IESA and NESA exhibited root-promoting activity equivalent to PESA. In adzuki stem elongation assays, elongation activity was not observed in the stem segments soaked in either an IESA or NESA aqueous solution, whereas the stem segments immersed in Indole-3-acetic acid (IAA) or 1-naphthylacetic acid (NAA) aqueous solution were clearly elongated. In an epinastic bending study, IAA and NAA exhibited leaf epinasty, whereas IESA and NESA did not, suggesting that the IESA and NESA derivatives belong to the same category of root-promoting substances as PESA derivatives and are different from auxin-like substances. In addition, eleven kinds of IESA derivatives and nineteen kinds of NESA derivatives were synthesized, and their root-promoting activities were measured. The activities of methyl ester derivatives were approximately three times higher than that of the acid compounds, with exceptions for some compounds. The partition coefficient (P) between 1-octanol and water for each IESA, NESA, and PESA derivative was measured in order to evaluate the hydrophobicity of their molecules and to determine their structure–activity relationship. The results indicate that the root-promoting activity of the acid compounds was significantly correlated with their hydrophobicity, whereas that of ester derivatives was not correlated.     

Synthesis of Some New Halogenated N-Thiazolyl Substituted 2-Mercapto Benzoic Acid Amides and Their Use as Possible Fungicides

One hundred and four acid amido compounds have been prepared by condensing 2-mercapto benzoic acid and its 5-bromo, 3, 5-dibromo and 3, 5-dichloro derivatives with 2-amino-4-substituted thiazoles and their 5-halogenated derivatives via the acid chloride. All these compounds have been tested against Helminthosporium. Four of the compounds were tested for their antibacterial, antihelminthic activities and also for their hypoglycemic activity.     

Cytotoxic Activities of Amino Acid‐Conjugate Derivatives of Abietane‐Type Diterpenoids against Human Cancer Cell Lines

Nine amino acid conjugate derivatives, each 2 – 10 and 12 – 20 , were prepared from abietic acid ( 1 ) and dehydroabietic acid ( 11 ), respectively, and they were evaluated for their cytotoxicities against four human cancer cell lines, i.e., leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK‐BR‐3). All compounds showed cytotoxicities against HL60 with IC₅₀ values in the range of 2.3–37.3 μM . In addition, most of the derivatives exhibited moderate cytotoxicities against the other cancer cell lines. Among the derivatives, methyl N‐[18‐oxoabieta‐8,11,13‐trien‐18‐yl]‐L ‐tyrosinate ( 19 ) exhibited potent cytotoxic activities against four cancer cell lines with IC₅₀ values of 2.3 (HL60), 7.1 (A549), 3.9 (AZ521), and 8.1 μM (SK‐BR‐3). Furthermore, all derivatives were shown to possess high selective cytotoxic activities for leukemia cells, since they exhibited only weak cytotoxicities against normal lymphocyte cell line RPMI1788.     

Hydroxycinnamates and their in vitro and in vivo antioxidant activities

Hydroxycinnamates are among the most widely distributed plant phenylpropanoids present in the free, conjugated-soluble and insoluble-bound forms. This review will focus on the occurrence, in vitro and in vivo antioxidant activities of ferulic, coumaric, caffeic and sinapic acids and their derivatives. Hydroxycinnamates are found in almost all food groups though they are abundant in cereals, legumes, oilseeds, fruits, vegetables and beverages and render antioxidant activity by scavenging hydroxyl radical, superoxide radical anion, several organic radicals, peroxyl radical, peroxinitrite and singlet oxygen, among others. Further, their antioxidant activity as chain breaking antioxidants and reducing agents is also notable. Ferulic acid and its derivatives such as ferulic acid ethyl ester, ferulic acid dehydrodimers, feruloyl glycosides and curcumin have demonstrated potent antioxidant activity in both in vitro and in vivo systems. Similarly, caffeic acid and some of its derivatives such as caffeic acid phenethyl ester, rosmarinic acid, and chlorogenic acid exhibit antioxidant activity. The highest antioxidant activity was observed for caffeic acid whereas p-coumaric acid had the least effect among major hydroxycinnamic acids. The importance of structural effects on the potency of antioxidant activity of hydroxycinnamates is discussed. While this review also shows the existence of substantial body of evidences for in vitro antioxidant activity of hydroxycinnamates, there is a clear gap for in vivo information, particularly for sinapic and p-coumaric acids and their derivatives. The role of grains, fruits, vegetables and red wine in disease risk reduction and health promotion could partly be attributed to their constituent hydroxycinnamates.     

Non-competitive antagonists for derivatives of p-aminobenzoic acid

Summary Shive's method of “inhibition analysis” was applied to the growth inhibition ofE. coli by some derivatives of p-aminobenzoic acid. In accordance with the findings ofWinkler andde Haan methionine, xanthine, serine, thymine, and valine were shown to be non-competitive antagonists of sulfanilamide forE. coli strain Bray β. It is highly probable that for this bacterium glycine should be added to this series. Methionine is the only non-competitive antagonist of the 2-chloro, 2-bromo, and 2-amino derivatives of P.A.B., provided their action is investigated at no higher concentrations than can be antagonised by P.A.B. The same complete series of non-competitive antagonists of sulfanilamide was shown to be active against the bacteriostatic action of the 2-methyl, 3-methyl, and 3-amino derivatives of P.A.B. The hypothesis is proposed that these derivatives are not competing directly with P.A.B. for an essential enzyme but that they are used by the bacterium in the formation of derivatives of pteroylglutamic acid; these may be competitive antagonists of co-enzymes, related to pteroylglutamic acid. There is some evidence in favour of this supposition. Further investigations are needed, however, before any judgment regarding its value can be given.     

Synthesis and Antiviral Activity of Hydrazides and Substituted Benzalhydrazides of Betulinic Acid and Its Derivatives

New nitrogen-containing derivatives of betulinic and betulonic acids, hydrazides and N"-benzalhydrazides, were synthesized. Their antiviral activities toward viruses of influenza A virus, herpes simplex type I virus, enterovirus ECHO6, and HIV-1 were studied in vitro. Betulinic acid 3-oxime was found to have the highest activity against the influenza virus. Betulonic acid, betulinic acid 4-chlorobenzalhydrazide, betulonic acid 3-oxime benzalhydrazide, and betulinic acid hydrazide inhibited the replication of herpes simplex type I virus. Betulinic acid hydrazide also showed antiviral activity toward HIV-1. All the derivatives of betulinic acid under study displayed a low antiviral activity toward enterovirus ECHO6.     

Detection of metal-chelating compounds from wood-rotting fungi Trametes versicolorand Wolfiporia cocos

For many years, the wood decay process by fungi was associated almost exclusively with production of lignocellulolytic enzymes. However, recent studies by electron microscopy have shown that fungal enzymes are too large to penetrate into the cell wall at an early stage of decay. Thus, the hypothesis that low molecular mass agents may initiate the breakdown of both cellulose and lignin was proposed. The purpose of this work was to detect low molecular mass compounds, with metal-chelating capability, from liquid cultures of two wood-rot fungi. The brown-rot fungus Wolfiporia cocos produced the highest chrome azurol S (CAS) reaction, simultaneously reducing the pH of the malt extract medium. In contrast, the white-rot fungus Trametes versicolor did not react with CAS and the pH remained approximately constant during the culture period. The presence of hydroxamate derivatives and oxalic acid was detected in extracts of low molecular mass of both fungi. Moreover, in W. cocos extracts, catecholate derivatives were also detected. Accumulation of oxalic acid was greater in W. cocos than in T. versicolor at the end of the culture period, and this might be responsible for the strong response from W. cocos in the CAS reaction.     

Pteroylpolyglutamates

Summary Reduced derivatives of the vitamin pteroylglutamic acid (folic acid) are essential coenzymes for the biosynthesis of purine nucleotides, methionine, thymidylate and for many other enzyme catalyzed reactions involving the transfer, oxidation and reduction of single carbon units. Pteroylglutamic acid is found in tissues in the form of poly--glutamyl derivatives of varying chain length. The present review covers the detection, distribution, synthesis, degradation, coenzyme function and inhibitory activities of pteroyl--glutamates. The biosynthesis and inhibitory activities of poly--glutamyl derivatives of methotrexate, an analog of pteroylglutamic acid having antitumor activity, are also considered. An hypothesis on the coenzymatic role of pteroylpoly--glutamates in the coordination of sequential enzymatic steps in the metabolism of single carbon units is presented.     

Quinic acid derivatives from Saussurea triangulata attenuates glutamate-induced neurotoxicity in primary cultured rat cortical cells

The leaves of Saussurea triangulata (Compositae) have been eaten with rice as a wrapping vegetable for preventing neuro-aging. However, the components responsible for the neuroprotective effects of S. triangulata still remain unidentified. In the process of investigating the neuroprotective activity of S. triangulata, we found that a methanol extract of S. triangulata exhibited significant protection against glutamate-induced toxicity in primary cultured rat cortical cells. Three quinic acid derivatives were isolated from the n-BuOH fraction of S. triangulata. Among these three quinic acid derivatives, methyl 5-caffeoylquinic acid (3) exhibited significant neuroprotective activities against glutamate-induced toxicity exhibiting cell viability of about 50%, at concentrations ranging from 0.1 μM to 10 μM. Therefore, the neuroprotective effect of S. triangulata might be due to the inhibition of glutamate-induced toxicity by the quinic acid derivatives from S. triangulata.     

Evaluation of new antimicrobial agents on Bacillus spp. strains: docking affinity and in vitro inhibition of glutamate-racemase

Three glutamic acid derivatives, two boron-containing and one imide-containing compound, were synthesized and tested for antimicrobial activity targeting glutamate-racemase. Antimicrobial effect was evaluated over Bacillus spp. Docking analysis shown that the test compounds bind near the active site of racemase isoforms, suggesting an allosteric effect. The boron derivatives had greater affinity than the imide derivative. In vitro assays shown good antimicrobial activity for the boron-containing compounds, and no effectiveness for the imide-containing compounds. The minimum inhibitory concentration of tetracycline, used as standard, was lower than that of the boron-containing derivatives. However, it seems that the boron-containing derivatives are more selective for bacteria. Experimental evidence suggests that the boron-containing derivatives act by inhibiting the racemase enzyme. Therefore, these test compounds probably impede the formation of the bacterial cell wall. Thus, the boron-containing glutamic acid derivatives should certainly be of interest for future studies as antimicrobial agents for Bacillus spp.     

Profiling and Elucidation of the Phenolic Compounds in the Aerial Parts of Gynura bicolor and G. divaricata Collected from Different Chinese Origins

Gynura bicolor and G. divaricata are not only known to be nutritive as cultured vegetables, but also beneficial as folk medicines in East Asia. As demonstrated by the current phytochemical knowledge, the genus Gynura is a promising source of phenolics with multiple medicinal activities. To expand this phytochemical knowledge, the phenolic secondary metabolites of G. bicolor and G. divaricata were studied. From the aerial parts of these two species, collected in five different Chinese locations, two fractions of phenolic compounds with different polarity were obtained by extraction and chromatographic separation. Using UPLC/MS/MS analysis, a total of 53 phenolics were either identified by comparison with respective reference compounds or tentatively characterized by their chromatographic behavior, UV‐absorption patterns, and MS fragmentations. Some naturally existing positional isomers of O‐caffeoylquinic acid, O‐p‐coumaroylquinic acid, O‐feruloylquinic acid, and dicaffeoylquinic acid as well as their methyl esters were qualitatively characterized by their specific fragmentation patterns in targeted MS/MS. In addition, the aerial parts of the two Gynura species contained kaempferol, quercetin oligoglycosides, and a variety of derivatives of benzoic acid, hydroxycinnamic acid, and caffeic acid. Furthermore, the distribution of phenolic compounds in the two species from different Chinese origins was discussed. Finally, an investigation of the total phenolic content and in vitro antioxidant activity of the various phenolic fractions was completed, to evaluate the potential of the extracts of these species for medicinal development. The free‐radical‐scavenging activities of the extracts derived from plants originating from Nanjing were proven to be higher than those of the other extracts, which correlated well with their total phenolic content.     

On the Nature of Nickel Compounds in Alyssum Bertolonii Desv.-II

Fifteen derivatives of 5-substituted tetronic acid (VII) and five derivatives of 3-acetyl-5-substituted phenyltetramic acid (III) were prepared and their biological activities were investigated. Among the compounds tested, 3-carboethoxy derivatives of tetronic acid showed a remarkable stimulating effect on the growth of rice roots, while the compounds which were removed the carboethoxy group from their 3-position displayed a strong inhibitory effect on the growth of rice roots and stalks. The fungicidal activity against Asp. niger and the effects on pupation and emergence of the housefly were also investigated as to the compounds synthesized.     

Phloroglucinol pathway in the strictly anaerobic Pelobacter acidigallici: fermentation of trihydroxybenzenes to acetate via triacetic acid

The strictly anaerobic, fermenting bacterium Pelobacter acidigallici degrades several trihydroxybenzene derivatives to stoichiometric amounts of acetate. We now report on the enzymatic activities in cell extracts which are responsible for the fermentative degradation of these aromatic compounds, and postulate a novel phloroglucinol pathway involving triacetic acid as an unusual metabolic intermediate. Gallate is decarboxylated to pyrogallol by a specific, Mg²⁺-dependent, soluble enzyme activity, followed by conversion of pyrogallol to phloroglucinol, involving an unusual intermolecular transhydroxylation described previously. Phloroglucinol is then reduced to dihydrophloroglucinol (5-hydroxy-1,3-cyclohexanedione) by an NADPH-dependent phloroglucinol reductase. Dihydrophloroglucinol is cleaved hydrolytically to 3-hydroxy-5-oxohexanoic acid, which is then oxidized to triacetic acid (3,5-dioxohexanoic acid) by a unique, NADP⁺-dependent dehydrogenase. Triacetic acid is activated by CoA transfer from acetyl-CoA, and then converted to 3 acetyl-CoA by two subsequent β-ketothiolase reactions. ATP is generated via phosphotransacetylase and acetate kinase.     

Cytotoxic and genotoxic effects of (R)- and (S)-ricinoleic acid derivatives

(R)-ricinoleic acid is the main component of castor oil from Ricinus communis L. Due to the presence of the hydroxyl group in homoallylic position and asymmetrically substituted carbon atom, it may undergo a number of chemical and biochemical transformations resulting in the products with some specific bioactivities. Conversion of (R)-ricinoleic acid into its (S)-enantiomer enables synthesis of both (R)- and (S)-ricinoleic acid derivatives and comparison of their biological activities. In the present research, (R)- and (S)-ricinoleic acid amides synthesized from methyl ricinoleates and ethanolamine or pyrrolidine as well as acetate derivatives of ethanolamine amides were studied to demonstrate their biological activities using HT29 cancer cells. Double staining of cells with fluorochromes (Hoechst 33258/propidium iodide) as well as 2,′7′-dichlorodihydrofluorescein (DCF) and comet assays were performed. Both the tested amides and acetates caused DNA damage and induced apoptotic and necrotic cell death. In the case of (R)- and (S)-enantiomers of one of the tested acetates, significant difference in the ability to induce DNA damage was observed, which showed the impact of the stereogenic center on the activities of these compounds.     

Inhibitory Activities of E–64 Derivatives on Papain

In order to investigate the active site of inhibition of E–64 against papain, the constituents of E-64 and their derivatives were synthesized and their activities on papain were assayed. It was consequently found trans-epoxysuccinic acid was essential for the activity. The difference of its optical activity gave no influence on the activity, but cis-form had no activity. Moreover, the structure-activity relationship of a series of the esters of trans-epoxysuccinic acid was also discussed. From these results, it was suggested that both epoxide and carbonyl group are important in the manifestation of the inhibitory action.     

Fukinolic acid and cimicifugic acids: a review

During the last decades, the research on the biological activities of extracts from Cimicifuga/Actaea species and Petasites japonicus as well as their active ingredients has been intensified. Besides terpenoids as dominant natural product group, hydroxycinnamic acid esters such as fukinolic acid and several cimicifugic acids have been isolated from Actaea and Petasites species and their chemical structures have been elucidated. Investigations on the biological properties of these hydroxycinnamic acid esters are currently undertaken and some compounds might be promising therapeutic tools. In this review, we have gathered information on the genera Actaea and Petasites, the occurrence of cimicifugic and fukinolic acids and some aspects of their biosynthesis. Furthermore, we have summarized the medicinal aspects of fukinolic acid and cimicifugic acids. In connection with the biological activities of these compounds, structural features of the hydroxycinnamic acid derivatives move into the focus. The position of the hydroxyl group at the aromatic rings and the introduction of an electron-donating moiety may be important for anti-inflammatory, antiviral, cytotoxic and vasoactive effects of these compounds.

     

Biological activity of bis-benzimidazole derivatives on DNA topoisomerase I and HeLa,MCF7 and A431 cells

Benzimidazoles of both natural and synthetic sources are the key components of many bio-active compounds. Several reports have shown antifungal, antiviral, H₂ receptor blocker and antitumor activities for benzimidazoles and their derivatives. In this study, we synthesized twelve bis-benzimidazole derivatives by selecting di(1H-benzo[d]imidazol-2-yl)methane as the main compound. The numbers of carbons at 2 positions of bis-benzimidazole derivatives were changed from 1 to 4, and derivatives were synthesized with methyl substitutions at 5- and/or 6- positions. The compounds were screened via in vitro plasmid superciol relaxation assays using mammalian DNA topoisomerase I and cytostatic assays were carried out against HeLa (cervix adenocarcinoma), MCF7 (breast adenocarcinoma) and A431 (skin epidermoid carcinoma) cells for selected derivatives. Our results suggest that the malonic acid derivatives of bis-benzimidazoles, namely, bis(5-methyl-1H-benzo[d]imidazol-2-yl)methane and bis(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)methane, were remarkably active compounds in interfering with DNA topoisomerase I and the former compound was also found to be cytotoxic against MCF7 and A431 cells. The inhibitory effects obtained with these derivatives are significant as these compounds can be potential sources of anticancer agents.     

Synthesis,antibacterial and antifungal activities of 3-(1,2,4-triazol-3-yl)-4-thiazolidinones

A new series of 3-(1,2,4-triazol-3-yl)-4-thiazolidinone derivatives has been synthesized by the reaction of Schiff bases of 3-amino-1,2,4-triazoles with mercaptoacetic acid and 2-mercaptopropionic acid. Their antibacterial and antifungal activities were evaluated against S. aureus, S. epidermidis, C. albicans and C. glabrata     

On the Manner of Cyclization of <Emphasis Type="Italic">N</Emphasis>-Acylated Aspartic and Glutamic Acid Derivatives

Abstract  

When synthesizing arylpiperazine library modified with N-acylated amino acid derivatives (e.g., cyclized aspartic acid, cyclized glutamic acid, proline) we wished to rapidly determine the way of cyclization of N-acylated glutamic acid derivatives. During concomitant cleavage and cyclization two alternative routes were possible—either formation of six-member imide (glutarimide) or five-member lactam. Application of MS/MS and ¹H NMR method allowed us to establish that cyclization of N-acylated glutamic acid derivatives preceded to lactams—N-acylated pyroglutamic acid derivatives.