Medicinal applications of heavy-metal compounds

A brief summary of the key role for certain heavy-metal compounds in medicine is discussed, with a special focus on very recent findings in the following four topics: platinum anti-tumor compounds (novel mononuclear compounds, dinuclear compounds and trinuclear compounds with promising activity); ruthenium anti-tumor compounds (the first clinical trial for a Ru compound has begun); gadolinium NMR-imaging compounds (association with biomacromolecules is now possible); technetium compounds (the use of organometallic precursors opens a plethora of new species and enables the labeling of, for example, neurotransmitter molecules).     

Effect of Glucose on the Interaction of Hydrophobic Compounds with the Alanine Receptor Field of Bacillus subtilis Spores during Initiation of Germination

Glucose interfered with the inhibitory action of hydrophobic compounds, such as n-octanol, diphenylamine and 2-tert-butylphenol, during L-alanine-initiated germination of Bacillus subtilis spores. The action of glucose on the action of the hydrophobic compounds was not competitive, and the binding affinity of glucose was not essentially affected by the hydrophobic compounds, indicating the presence of separate binding sites for glucose and the hydrophobic compounds. The binding affinity of D-alanine, a competitive inhibitor of L-alanine, was not affected by the hydrophobic compounds, indicating separate binding sites for D-alanine and the hydrophobic compounds. A possible arrangement of the binding sites for glucose and for the hydrophobic compounds in relation to those for L- and D-alanine on the spores is discussed.     

Detection of organic compounds on Mars]

McKay et al. detected polycyclic aromatic hydrocarbons (PAHs) in Martian meteorite ALH 84001 by two-step laser mass spectrometry. From the presence of PAHs, together with other results, they concluded that there were past life of Mars. On the other hands, no organisms nor organic compounds were detected in Martian regolith in Viking experiments in 1976. In order to obtain solid evidence for organisms or bioorganic compounds compounds on Mars, further analyses of Martian samples are required. There may be four classes of organic compounds on Mars, which are (i) organic compounds abiotically formed from primitive Mars atmosphere, (ii) Organic compounds delivered out of Mars, (iii) Organic compounds biotically formed by Mars organisms, and (iv) Organic compounds abiotically formed from the present Mars atmosphere. Possible organic compounds on Mars and analytical methods for them are discussed.     

Phytodegradation of organic compounds

The phytodegradation of organic compounds can take place inside the plant or within the rhizosphere of the plant. Many different compounds and classes of compounds can be removed from the environment by this method, including solvents in groundwater, petroleum and aromatic compounds in soils, and volatile compounds in the air. Although still a relatively new area of research, there are many laboratories studying the underlying science necessary for a wide range of applications for plant-based remediation of organic contaminants.     

Effect of water and temperature stress on the content of active constituents of Hypericum brasiliense Choisy.

Hypericum brasiliense is a medicinal herb containing several compounds with important pharmacological activity. In this study, we investigated the effects of water stress (waterlogging and drought) and temperature (low and high, constant and alternate) on the content of betulinic acid and phenolic compounds (quercetin, rutin, 1,5-dihydroxyxanthone, isouliginosin B) in this species. In general, the water stress increased the levels of all of the compounds analyzed, particularly some of the phenolic compounds. On the other hand, the responses to alternating temperatures varied according to the compound. The results for plants kept in growth chambers indicated that low light intensity might have influenced the levels of the compounds. There was also a reallocation of carbon, with water-stressed plants showing a reduction in growth while the levels of the compounds increased. In the temperature treatments, such an increase was evident only for the phenolic compounds.     

An exploration of the binding site of aldolase using N-(omega-hydroxyalkyl) glycolamidobisphosphoric esters

N-(omega-Hydroxyalkyl)glycolamidobisphosphoric esters (P-O-CH2-CO-NH-(CH2)n -O-P), which are analogues of the aldolase (D-fructose-1,6-bisphosphate D-glyceraldehyde-3-phosphate-lyase, EC 4.1.2.13) substrate fructose 1,6-bisphosphate, were synthesized and used for probing its active site. These phosphate compounds competitively inhibited aldolase activity. The Ki value was lowest when the maximum distance between the phosphorus atoms of the bisphosphate was brought close to that of fructose 1,6-bisphosphate. The inhibitor constants, Ki, were compared to those of alkanediol monoglycolate bisphosphoric esters and alkanediol bisphosphate compounds, which were reported previously by Ogata et al. The values of Ki for the bisphosphate compounds containing an amide group, the amide bisphosphate compounds, were smaller than those for the bisphosphate compounds containing an ester group, the ester bisphosphate compounds, and those for alkanediol bisphosphates were the largest for the same distance between phosphorus atoms in these bisphosphates. The difference spectra of aldolase caused by binding of a saturating concentration of N-(omega-hydroxypropyl)glycolamidobisphosphoric ester resembled that of butanediol monoglycolate bisphosphoric ester. However, the effects of the amide bisphosphate compounds on the absorption spectrum of aldolase were smaller than those of the ester bisphosphate compounds for the same distance between phosphorus atoms in these bisphosphate compounds. These results suggest that the synthesized phosphate compounds bind to aldolase at the active site and the -CO-NH- group of the compounds might be held more tightly than the -CO-O- group by hydrogen bonds, presumably with the amino acid residues in the active site, such as Lys-146 or -229 and Asp-33 or Glu-187. On the other hand, the -CO-O- group might be more effective in changing the environment of the Trp-147 residue in the active site of this enzyme.     

Structural specificity of aromatic compounds with special reference to mutagenic activity in Salmonella typhimurium--a series of chloro- or fluoro-nitrobenzene derivatives

The mutagenicity of 21 chloro- or fluoronitrobenzene compounds and 9 chloro- or fluorobenzene compounds in Salmonella typhimurium (strains TA98, TA1538, TA1537, TA100 and TA1535) was examined. The tests were carried out under the conditions of absence and presence of liver microsomal activation. 15 nitro-group compounds had mutagenic activity; above all, compounds of fluoronitrobenzene were mutagenic for both types of strain. On the other hand, chloronitrobenzene compounds were mutagenic for base-pair substitution strains only. Mutagenic activity was exhibited by all compounds having a chloro or fluoro substituent at the para and ortho position in the nitrobenzene nucleus. All compounds without a nitro substituent showed no mutagenic activity.     

Prophage induction and mutagenicity of a series of anti-tumour platinum(II) and platinum(IV) co-ordination complexes

11 platinum compounds with nitrogen donor ligands, previously tested for anti-tumour activity, were studied for induction of prophage lambda and for mutagenicity in the Ames assay, with various strains of Salmonella. The compounds included cis and trans isomers of Pt(II) and Pt(IV) complexes and were tested with and without metabolic activation. All the cis compounds elicited prophage induction, whereas the trans compounds were inactive. Mutagenicity was found only in strains containing the R factor, indicating that SOS-type repair processes are required for the conversion of initial DNA lesions into mutations. Mutation induction was also influenced by the excision-repair process. The 2 trans compounds were not, or only slightly, mutagenic; all other compounds were mutagenic in at least one strain, exhibiting a 2-20-fold increase over the spontaneous background level. Addition of liver homogenate had no significant effect on the number of mutants. One compound induced exclusively frameshift mutations. The other mutagenic compounds induced frameshift mutations as well as base-pair substitutions. 7 compounds were more mutagenic for the repair-proficient than for the repair-deficient strains; only one showed the opposite effect. This suggests that for mutagenicity testing of platinum compounds, repair-proficient strains are more sensitive indicators. The differences in response of the various strains are more sensitive indicators. The differences in response of the various strains toward the compounds suggest the formation of different DNA lesions and/or a selective action of repair processes on these lesions. In general, a good qualitative correlation was observed between prophage-inducing capacity, mutagenicity in bacterial and mammalian cells and anti-tumour activity.     

Biosensor analysis of drug-target interactions: direct and competitive binding assays for investigation of interactions between thrombin and thrombin inhibitors

The sensitivity of BIACORE technology is sufficient for detection and characterization of binding events involving low-molecular-weight compounds and their immobilized protein targets. The technology requires no labeling and provides information on the stability of the compound/target complex with a single injection of the compound. This is useful for qualifying hits obtained in a primary screen and in lead optimization. Although immobilized targets can be reused, the surface may slowly deteriorate, solvent effects can distort binding levels during injection of compounds, and some compounds may exhibit broad protein selectivity rather than target specificity. A reliable direct binding assay for compounds binding to immobilized thrombin using a combination of two reference surfaces, a dextran surface for subtraction and calibration of solvent effects and a protein surface for identification of compounds that tend to bind proteins, has been developed. Eleven compounds with known binding specificity to thrombin and 159 additional compounds were investigated. All compounds with known binding specificity were identified at 1 and 10 microM concentration. One additional compound was scored as positive. The direct binding assay compared favorably with two competitive assay formats, a surface competitive assay and a inhibitor in solution assay, that were examined in parallel.     

Antibacterial components of honey

The antibacterial activity of honey has been known since the 19th century. Recently, the potent activity of honey against antibiotic-resistant bacteria has further increased the interest for application of honey, but incomplete knowledge of the antibacterial activity is a major obstacle for clinical applicability. The high sugar concentration, hydrogen peroxide, and the low pH are well-known antibacterial factors in honey and more recently, methylglyoxal and the antimicrobial peptide bee defensin-1 were identified as important antibacterial compounds in honey. The antibacterial activity of honey is highly complex due to the involvement of multiple compounds and due to the large variation in the concentrations of these compounds among honeys. The current review will elaborate on the antibacterial compounds in honey. We discuss the activity of the individual compounds, their contribution to the complex antibacterial activity of honey, a novel approach to identify additional honey antibacterial compounds, and the implications of the novel developments for standardization of honey for medical applications.     

Differentiation of the drug-binding sites of calmodulin

Calmodulin contains several binding sites for hydrophobic compounds. The apparent specificity of various 'calmodulin antagonists' for these sites was investigated. The Ki values for the inhibition of calmodulin-activated cyclic-nucleotide phosphodiesterase and myosin light-chain kinase was determined. In addition, the Kd values of the same compounds for binding to calmodulin were measured. The compounds could be separated into four groups. Group I and II compounds inhibited competitively the activation of the phosphodiesterase and myosin light-chain kinase by calmodulin. Group I compounds inhibited the activation of the phosphodiesterase and myosin light-chain kinase at identical concentrations. In contrast, group II compounds inhibited the activation of the phosphodiesterase at 5-10-fold lower concentrations than that of myosin light-chain kinase. Group III compounds inhibited the activation of these enzymes by an uncompetitive mechanism. Group IV compounds inhibited the activation of the phosphodiesterase with Ki values above 10 microM and did not affect the activation of myosin light-chain kinase. Binding of [3H]bepridil to calmodulin under equilibrium conditions yielded one high-affinity site (apparent Kd 0.4 microM) and four low affinity sites (apparent Kd 44 microM). Group I compounds interfered with the binding of bepridil to the high and low-affinity sites in a competitive manner. Group II compounds interfered in a non-competitive manner with the high-affinity site and apparently competed only with one of the low-affinity sites. Group III compounds did not compete with any of the bepridil-binding sites. Nimodipine, a group III compound, bound to one site on calmodulin with a Kd value of 1.1 microM. Other dihydropyridines competed with [3H]nimodipine for this site. The group I and II compounds, trifluoperazine and prenylamine, did not affect the binding of [3H]nimodipine. These data show that 'calmodulin antagonists' can be differentiated into at least three distinct groups. Kinetic and binding data suggest that the three groups bind to at least three different sites on calmodulin. Selective occupation of these sites may inhibit specifically the activation of distinct enzymes.     

The anti-malarial activity of bivalent imidazolium salts

A series of compounds containing bivalent imidazolium rings and one triazolium analog were synthesized and evaluated for their ability to inhibit the replication of Plasmodium falciparum cultures. The activity and selectivity of the compounds for P. falciparum cultures were found to depend on the presence of electron-deficient rings that were spaced an appropriate distance apart. The activity of the compounds was not critically dependent on the nature of the linker between the electron-deficient rings, an observation that suggests that the rings were responsible for the primary interaction with the molecular target of the compounds in the parasite. The bivalent imidazolium and triazolium compounds disrupted the process whereby merozoites gain entry into erythrocytes, however, they did not appear to prevent merozoites from forming. The compounds were also found to be active in a murine Plasmodium berghei infection, a result consistent with the compounds specifically interacting with a parasite component that is required for replication and is conserved between two Plasmodium species.     

四吡咯化合物生物合成研究进展

四吡咯化合物是存在于生物体中一类具有重要功能的化合物,已经广泛应用于农业、食品和医药等领域.由于化学合成法的烦琐流程和高昂成本以及动植物提取法存在品质不均一等缺点,大幅度限制了其工业化生产与相关应用.近年来,合成生物学的快速发展为微生物利用可再生生物质资源高效合成四吡咯化合物提供了新的技术手段.针对四吡咯化合物生物合成...     

Antimutagenic compounds and their possible mechanisms of action

Mutagenicity refers to the induction of permanent changes in the DNA sequence of an organism, which may result in a heritable change in the characteristics of living systems. Antimutagenic agents are able to counteract the effects of mutagens. This group of agents includes both natural and synthetic compounds. Based on their mechanism of action among antimutagens, several classes of compounds may be distinguished. These are compounds with antioxidant activity; compounds that inhibit the activation of mutagens; blocking agents; as well as compounds characterized with several modes of action. It was reported previously that several antitumor compounds act through the antimutagenic mechanism. Hence, searching for antimutagenic compounds represents a rapidly expanding field of cancer research. It may be observed that, in recent years, many publications were focused on the screening of both natural and synthetic compounds for their beneficial muta/antimutagenicity profile. Thus, the present review attempts to give a brief outline on substances presenting antimutagenic potency and their possible mechanism of action. Additionally, in the present paper, a screening strategy for mutagenicity testing was presented and the characteristics of the most widely used antimutagenicity assays were described.     

The recent progress of isoxazole in medicinal chemistry

Isoxazole compounds exhibit a wide spectrum of targets and broad biological activities. Developing compounds with heterocycle rings has been one of the trends. The integration of isoxazole ring can offer improved physical-chemical properties. Because of the unique profiles, isoxazole ring becomes a popular moiety in compounds design. In this review article, the major focus has been paid to the applications of isoxazole compounds in treating multiple diseases, including anticancer, antimicrobial, anti-inflammatory, etc. Strategies for compounds design for preclinical, clinical, and FDA approved drugs were discussed. Also, the emphasis has been addressed to the future perspectives and trend for the application.     

Synthesis and pharmacological evaluation of a novel series of 3-aryl-2-(2-substituted-4-methylthiazole-5-yl)thiazolidin-4-one as possible anti-inflammatory and antimicrobial agents

A new series of 3-aryl-2-(2-aryl/benzyl-4-methylthiazole-5-yl)thiazolidin-4-one was synthesized by condensation of 2-aryl/benzyl-4-methylthiazole-5-carbaldehyde, aromatic amines and thioglycolic acid in toluene. All the synthesized compounds are characterized by IR, NMR and elemental or mass analysis. Sixteen out of the newly synthesized compounds were screened for in vivo anti-inflammatory activity using carrageenan-induced rat paw edema method. Some of the synthesized compounds exhibited good anti-inflammatory activity compared with indomethacin. The synthesized compounds were also evaluated for their in vitro antimicrobial activity. Some of the compounds showed mild antibacterial activity while most of the compounds showed good antifungal activity.     

Effects of membrane partitioning and other physical chemical properties on the apparent potency of "membrane active" compounds evaluated using red blood cell lysis assays

The membrane-destabilizing properties of Amphotericin B and Zwittergent were used as benchmark compounds for examining in detail their membrane-altering effects in a series of human red blood cell lysis assays. The procedures included examining dose responses and the effects of different cell concentrations on potency in rbc lysis assays. In order to enhance detection of subtle membrane effects, we also used a range of NaCl concentrations to osmotically stress the rbc's. Using the benchmark compounds, a set of conditions was developed for examination of subtle membrane effects that may be applied to series of compounds with suspected membrane-perturbation activity. A group of experiments was defined that allow detection of the most important membrane-modifying behaviors among a diverse group of compounds. From an initial screen of bacterial growth inhibition over 150 compounds were examined for membrane-altering properties using the limited experimental protocols developed from the benchmark compounds. Several dose-response patterns were observed as useful for classifying compounds based on their tendency to alter membrane integrity and to partition into the lipids of membranes, as well as their propensity to form aggregates or precipitates. The methods may prove generally useful for distinguishing compounds whose primary activity is membrane destabilization from more interesting and useful pharmacological mechanisms of action.     

Screening of Plasmodium falciparum iron superoxide dismutase inhibitors and accuracy of the SOD-assays

In vitro evaluation of a chemical library of synthetic compounds using two consecutive assays has led to the discovery of fifteen compounds which have the ability to inhibit recombinant Plasmodium falciparum iron superoxide dismutase (PfSOD), suggested as a highly selective target for design of antiparasitic drugs. A large number of compounds were in fact excluded, because they were found to significantly interfere with the components of the assays, thus outlining the drawbacks relative to the use of standard SOD-assays for the research of compounds targeting SODs. The best of the selected compounds showed significant antimalarial activities against two strains of P. falciparum, including a strain moderately resistant to chloroquine.     

Review of organic matter in the Orgueil meteorite

The Orgueil meteorite is a carbonaceous chondrite containing about 3.1% carbon, 5.5% sulfur and 19.9% water. Virtually all of the carbon is present as organic carbon although only about 20% is soluble in common organic solvents; the remainder is in the form of a highly substituted, irregular and aromatic polymer. Detailed methods of analysis have been improved in the past ten years sufficient for the detection of individual compounds in most of the following classes of organic compounds: hydrocarbons, oxygen-, sulfur- and nitrogen-containing organic compounds, optically active species, isotopes, bacteria and organized elements. Ten series of homologous compounds have been observed in the aliphatic hydrocarbons.In the 1950's, when interest was renewed in the Orgueil meteorite, the analytical capabilities may have given a bias toward biogenic agencies for the formation of the organic matter found in the meteorites. Some of the key biochemical compounds for extraterrestrial life are present. There is doubt, however, that these particular compounds are truly indigenous. The possibility that the indigenous organic compounds in the meteorite are present as a result of abiogenic syntheses in the cosmos is becoming more generally accepted.