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PubMed1980

Effect of chemical modification and fragmentation on antigenic determinants of internal protein p30 and surface glycoprotein gp70 of type C retroviruses.

The effects of protein modification on the antigenic determinants of p30 and gp70 of type C retroviruses were investigated by using solid-phase competition radioimmunoassays. Proteins were modified by reduction with 2-mercaptoethanol and subsequent carboxymethylation of SH groups with iodoacetamide or by amidination of alpha and epsilon amino groups with methylacetimidate. The type-specific determinants of gp70 were found to be conformational in nature, as they were destroyed by these chemical modifications. Group- and interspecies-specific determinants of gp70 antigens, however, appear to be sequential and do not involve residues susceptible to these chemical reagents. Conformation-dependent type-specific determinants of p30 were affected only by methylacetimidate. Group- and interspecies-specific determinants of p30 are similar to those of gp70 in that they also appear to be sequential antigenic sites. Therefore, the broadly reactive group- and interspecies-specific determinants of gp70 and p30 can be followed into small peptides. Accordingly, a cyanogen bromide cleavage fragment derived from the carboxyl-terminal one-third of Rauscher leukemia virus p30 was found to carry group-specific determinants but no detectable interspecies-specific determinants. In contrast, a peptide obtained by limited trypsin cleavage of p30, which was derived from the NH(2)-terminal region of the protein, contained at least one of the interspecies determinants shared with feline leukemia virus p27.

AKR murine leukemia virus↗
PubMed1982

The cross-linking of tubulin with imidoesters.

Tubulin was reacted with a monofunctional imidoester, ethyl acetimidate, and three bifunctional imidoesters ranging in extension from 5 to 10 A. Extensive cross-linking was found to occur with the three bifunctional reagents resulting in the formation of dimers, trimers, tetramers, pentamers, and hexamers. In addition, a similar cross-linking patterns was observed with the monofunctional reagent. This type of cross-linking is rarely seen when proteins are reacted with imidoesters. Given that the cross-linking span of ethyl acetimidate is only 3 A it is reasonable to infer that there are nucleophilic groups in close proximity within the tubulin dimer. Amidinated tubulin is still capable of assembling into microtubules.

Amino Acids↗
PubMed1990

Phospholipid asymmetry in the plasma membrane of malaria infected erythrocytes.

The transbilayer distribution of glycerophospholipids in the plasma membrane of Plasmodium knowlesi infected erythrocytes was studied by using lysine-116-epsilon-N-palmitoyl amidinated pancreatic phospholipase A2. As a consequence of its superior membrane penetrating capacities, this modified enzyme rapidly degrades its substrates in the outer membrane leaflet of intact erythrocytes, a property that makes the enzyme an excellent tool to study the malaria parasitized red cell. The modified phospholipase A2 caused a nonlytic hydrolysis of up to 12-15% of the phosphatidylethanolamine and none of the phosphatidylserine in the red cell membrane, irrespective of whether the cells harboured trophozoite and schizont stages of parasites or no parasites at all. The absence of phosphatidylserine at the exterior surface of Plasmodium infected erythrocytes was confirmed by applying the prothrombinase assay on Plasmodium falciparum infected human erythrocytes. Consequently, the results from these and previous studies indicate that the plasma membrane of Plasmodium infected erythrocytes exhibit a normal transbilayer phospholipid asymmetry.

Animals↗
PubMed2004

Characterization of the choline carrier of Plasmodium falciparum: a route for the selective delivery of novel antimalarial drugs.

New drugs are urgently needed to combat the growing problem of drug resistance in Plasmodium falciparum malaria. The infected erythrocyte is a multicompartmental system, and its transporters are of interest as drug targets in their own right and as potential routes for the delivery of antimalarial drugs. Choline is an important nutrient that penetrates infected erythrocyte membranes through the endogenous carrier and through parasite-induced permeability pathways, but nothing is known about its transport into the intracellular parasite. Here we present the first characterization of choline transport across the parasite membrane. Transport exhibits Michaelis-Menten kinetics with an apparent K(m) of 25.0 +/- 3.5 muM for choline. The carrier is inhibitor-sensitive, temperature-dependent, and Na(+)-independent, and it is driven by the proton-motive force. Highly active bis-amidine and bis-quaternary ammonium compounds are also known to penetrate the host erythrocyte membrane through parasite-induced permeability pathways. Here, we demonstrate that the parasite choline transporter mediates the delivery of these compounds to the intracellular parasite. Thus, the induced permeability pathways in the host erythrocyte membrane and the parasite choline transporter described here form a cooperative transport system that shows great promise for the selective targeting of new agents for the chemotherapy of malaria.

Animals↗
PubMed2006

Uncharged isocoumarin-based inhibitors of urokinase-type plasminogen activator.

BACKGROUND: Urokinase-type plasminogen activator (uPA) plays a major role in extracellular proteolytic events associated with tumor cell growth, migration and angiogenesis. Consequently, uPA is an attractive target for the development of small molecule active site inhibitors. Most of the recent drug development programs aimed at nonpeptidic inhibitors targeted at uPA have focused on arginino mimetics containing amidine or guanidine functional groups attached to aromatic or heterocyclic scaffolds. There is a general problem of limited bioavailability of these charged inhibitors. In the present study, uPA inhibitors were designed on an isocoumarin scaffold containing uncharged substituents. RESULTS: 4-Chloro-3-alkoxyisocoumarins were synthesized in which the 3-alkoxy group contained a terminal bromine; these were compared with similar inhibitors that contained a charged terminal functional group. Additional variations included functional groups attached to the seven position of the isocoumarin scaffold. N- [3-(3-Bromopropoxy)-4-chloro-1-oxo-1H-isochromen-7-yl]benzamide was identified as an uncharged lead inhibitor of uPA, Ki = 0.034 microM. Molecular modeling of human uPA with these uncharged inhibitors suggests that the bromine occupies the same position as positively charged arginino mimetic groups. CONCLUSION: This study demonstrates that potent uncharged inhibitors of uPA can be developed based upon the isocoumarin scaffold. A tethered bromine in the three position and an aromatic group in the seven position are important contributors to binding. Although the aim was to develop compounds that act as mechanism-based inactivators, these inhibitors are competitive reversible inhibitors.

Journal Article↗
PubMed2002

Structure-activity relationships (SAR) of [D-Arg(2)]dermorphin(1-4) analogues, N(alpha)-amidino-Tyr-D-Arg-Phe-X.

In investigating the development of compounds with potent analgesic effects after oral administration, 74 C-terminal analogues (N(alpha)-amidino-Tyr-D-Arg-Phe-X), based on the structure of N(alpha)-amidino-Tyr-D-Arg-Phe-Me beta Ala-OH (ADAMB), were synthesized. Their analgesic activity was evaluated using the mouse-tail pressure test after both subcutaneous and oral administration, and the structure-activity relationships (SAR) were examined in detail. The results clearly indicated that compounds containing beta-amino acid without a side chain at the X position are preferable for expression of potent analgesic activity, and that the free carboxyl group is superior in its analgesic activity to that of the esterified or amidated carboxy group at the C-terminal. In addition, N-methylation of the amide bond at the 4th position contributed to improved analgesic activity. These results indicated that the strong and long-lasting analgesic effect of ADAMB is expressed by the synergistic effects of N(alpha)-amidination, the N-methylation of the amide bond at the 4th position and the carbon chain length (beta-Ala) of the residue at the 4th position, and that this is the most suitable structure.

Administration, Oral↗
PubMed2003

Synthesis and evaluation of guanidine-containing Schiff base copper(II), zinc(II), and iron(III) chelates as trypsin inhibitors.

3-Formyl-4-hydroxyphenylguanidine hydrochloride and its Schiff base copper(II), zinc(II), and iron(III) chelates were synthesized and their inhibitory activity against bovine beta-trypsin were determined. Syntheses of Schiff base metal chelates were carried out from 3-formyl-4-hydroxyphenylguanidine, various L-amino acids, and divalent metal acetate. Their structures were established on the basis of spectroscopic evidence and elemental analysis. The inhibitory activity of these chelates against bovine beta-trypsin was determined. The guanidine-containing copper(II) and zinc(II) chelates behaved as potent competitive inhibitors of trypsin. However, similar inhibitory activity was not observed for guanidine-containing iron(III) chelates. The inhibition constants (K(i) values, ca. 10(-5) M) of guanidine-containing Schiff base copper(II) and zinc(II) chelates were slightly lower than those (ca. 10(-6) M) of the corresponding amidine-containing Schiff base chelates with regard to bovine trypsin.

Amino Acids↗
PubMed2006

Effective preparation of cycloheptimidazol-4-one compounds.

Effective preparation of cycloheptimidazol-4-ones was developed. The reactions of 2-tosyloxytropone (5) with amidines (6) carried out under simple conditions such as aq. NaOH in toluene at 35 degrees C afforded the corresponding cycloheptimidazol-4-ones (3) in low yield. However, by adding tetra-n-butylammonium bromide (n-Bu(4)NBr) to this reaction system, the yield was improved dramatically. The reaction conditions were screened in detail.

Catalysis↗
PubMed2006

Use of fourier transform infrared spectroscopy to follow the heterocumulene aided thermal dehydration of phthalic and naphthalic acids.

Fourier transform infrared (FT-IR) spectroscopy has been successfully employed to follow the formation of phthalic anhydride and 1,8-naphthalic anhydride on heating their corresponding acids. The effects of three heterocumulenes, cyanamide, dicyandiamide, and sodium cyanate, on the temperature of formation of the anhydrides were also investigated using this method. It was found that the carbodiimides cyanamide and dicyandiamide dramatically lowered the temperature at which thermal dehydration of the acid led to anhydride formation. It was noted that cyanamide had a stronger catalytic effect than dicyandiamide, presumably due to the electron-withdrawing effect of the amidine group. Sodium cyanate was also found to promote the thermal dehydration of the acids to form the corresponding anhydrides. Under more severe conditions, phthalic acid anhydride formed is seen to react further, leading to the formation of phthalimide. The discrepancy between the products obtained with cyanamide and sodium cyanate leads to the conclusion that, unlike earlier claims, imide formation is not due to the reaction of the anhydride with the urea formed but with sodium cyanate itself. However, only the phthalic anhydride five-membered ring system is sufficiently reactive towards the CNO- nucleophile to form the imide; the six-membered 1,8-naphthalic anhydride system does not react in this way.

Journal Article↗
PubMed1979

Ethyl bromoacetimidate, a NH2-specific heterobifunctional reagent. Model reactions with ribonuclease.

Ethyl bromoacetimidate was designed as a potential reagent for cross-linking protein NH2 groups with a vicinal nucleophile. The chemical properties of this compound were studied by model reactions with small molecules. Ethyl bromoacetimidate amidinates lysine residues in ribonuclease at pH 9. In a second step, at lower pH values, one of the bromoacetamidino groups bound to the enzyme alkylates a proximal histidine residue. This substitution is pH-dependent with a sharp optimum at 5.6, the same as was earlier observed for alkylation of histidine-119: histidine-12 by halogenoacetates and halogenoacetamides. A common mechanism is suggested for all these types of alkylation. Ethyl bromoacetimidate thus appears as a short-distance crosslinker which can be used, for example, to explore chemically the microenvironment of an essential lysine residue of an enzyme within the active site.

Acetamides↗
PubMed1980

Syntheses and hypoglycemic activities of ethyl esters and various amides of omega-guanidino fatty acids with medium chain length.

The omega-guanidino fatty acids C6-C12 were prepared by amidination of the corresponding omega-amino acids. omega-Amino acids C7-C10 which are not available commercially, were obtained by use of Hofmann degradation of the next higher dicarboxylic monoamid monoethyl esters. For use in biological tests, the omega-guanidino fatty acids were converted into ethyl esters, dimethylamides, sometimes also into methyl- or diethylamides. In isolated fat cells these compounds inhibit glucose oxidation. The inhibition increases with increasing chain length. For example, glucose oxidation (control 100%) is diminished by the dimethylamides of 9-guanidinononanoic acid to 70%, of 10-guanidinodecanoic acid to 62%, of 11-guanidinoundecanoic acid to 17% and of 12-guanidinododecanoic acid to 12%. The same compounds -- except the ethyl esters--depress the blood glucose levels in mice after intraperitoneal injection. Blood glucose levels between 30 and 10 mg/100 ml are reached and convulsions are observed. In the mice fall test, ca. 15-30 min post inj., the mice fall down; the blood glucose values of the fallen mice are hypoglycemic. The toxicity of the compounds examined is remarkably high; lethal dose per mouse (20 g) is 3-5 mg for the dimethylamides. It is obvious that a relationship exists between the inhibition of glucose oxidation in adipocytes and the depression of blood glucose level. The stronger the inhibition, the stronger the blood glucose lowering effect.

Adipose Tissue↗
PubMed1980

Insulin-like partial effects of agmatine derivatives in adipocytes.

In previous investigations, we described insulin-like effects of agmatine [(4-aminobutyl)guanidine] in vitro. In the present work we have examined whether these effects of agmatine can be enhanced by variation in chain length (C3 and C5 forms) and by alkylation. Propyl, butyl, pentyl, hexyl, octyl, isobutyl and isopentyl groups were introduced into C4- and C5-agmatine by hydrogenation of the corresponding azomethines. Alkylation of C3-agmatine was carried out by addition of alkylamines to acrylonitrile, followed by hydrogenation and amidination. For the biological assays, isolated fat cells from rat epididymic adipose tissue were used. N4-Butyl- and N4-pentyl-C4-agmatines lead to a two-fold, N4-hexyl-C4-agmatine to a three-fold enhancement of glucose oxidation in adipocytes. Alkylated C4- and C5-agmatines induce a three-fold increase in lipogenesis compared to agmatine. Alkylation of C3-agmatine does not increase its potency in this test. In our test system, insulin decreases adrenalin-induced lipolysis to 40% of the control value (100%). Agmatine and alkylated C4-agmatines yield very similar values (37% and 27-44% respectively). The alkylated C3-agmatines also exert strongly antilipolytic effects (25-35%), while the effects of the alkylated C5-agmatines are weaker. The synthesized agmatine derivatives were injected intraperitoneally into mice. Tolerable doses do not cause any significant reduction in blood glucose levels.

Adipose Tissue↗
PubMed1980

Regeneration of full enzymatic activity by reoxidation of reduced pancreatic phospholipase A2.

Reduction of porcine pancreatic phospholipase A2 with 2-mercaptoethanol in the presence of 6M guanidinium hydrocholoride or 8M urea resulted in the complete disruption of all seven disulfide bridges and the concomitant loss of all enzymatic activity. Through aerobic oxidation of the reduced protein at pH 8.0 in the presence of 5 mM cysteine and 0.9M guanidinium hydrochloride up to 90% of the specific activity of the native enzyme was restored. After purification of the reoxidized phospholipase A2 by Sephadex G-75 gel filtration and chromatography on CM-cellulose pure phospholipase A2 was obtained in 80% yield. This purified reoxidized phospholipase A2 was found to be indistinguishable from the native enzyme as judged by its enzymatic activity, lipid and Ca2+ binding properties. Similar results were obtained using S-sulfonated phospholipase A2, prophospholipase A2 or Nepsilon-amidinated phospholipase A2. For the latter two proteins reoxidation was slower than that of the reduced phospholipase A2.

Animals↗
PubMed1981

Semisynthesis of human proinsulin, I. Preparation of arginyl-A-chain cyclic bis-disulfide.

The semisynthesis of Arg-A-(SS)2 is described by the following chemical and enzymatic procedures: 1) A-(SSO theta 3)4 was acylated with arginine N-carboxyanhydride by the known method. Arg-A-(SSO theta 3)4 was purified, reduced and oxidized to Arg-A(SS)2. When A(SS)2 was acylated under identical conditions a gel-like product was obtained which could be purified after oxidative sulfitolysis. This was then converted to Arg-A-(SS)2 as described above. Both the pathways gave the desired product in 20-25% yield. 2) Boc-Orn(Msc) was quantitatively attached to A-(SS)2 by the mixed anhydride method, the Msc group was then removed and the ensuing N delta-free amino function was amidinated. Traces of unconverted Orn derivative (less than 6%) were still present. 3) Boc-Arg(HBr) was attached to A-(SS)2 by the mixed anhydride method and Arg-A(SS)2 was isolated after removal of the Boc group in 25% yield. 4) Boc-Arg(DHCH) was attached to A-(SS)2 by the mixed anhydride method. DHCH and Boc groups were removed in two steps and Arg-A-(SS)2 was isolated in 29% yield. 5) Boc-Arg was condensed with A-(SS)2 by trypsin-catalyzed synthesis. The removal of Boc group and purification yielded the desired product in 40-42% yield. This procedure was the most efficient and proceeded stereospecifically.

Arginine↗
PubMed1986

Covalent fixation of NAD+ to dehydrogenases and properties of the modified enzymes.

Starting from 6-chloropurine riboside and NAD+, different reactive analogues of NAD+ have been obtained by introducing diazoniumaryl or aromatic imidoester groups via flexible spacers into the nonfunctional adenine moiety of the coenzyme. The analogues react with different amino-acid residues of dehydrogenases and form stable amidine or azobridges, respectively. After the formation of a ternary complex by the coenzyme, the enzyme and a pseudosubstrate, the reactive spacer is anchored in the vicinity of the active site. Thus, the coenzyme remains covalently attached to the protein even after decomposition of the complex. On addition of substrates the covalently bound coenzyme is converted to the dihydro-form. In enzymatic tests the modified dehydrogenases show 80-90% of the specific activity of the native enzymes, but they need remarkably higher concentrations of free NAD+ to achieve these values. The dihydro-coenzymes can be reoxidized by oxidizing agents like phenazine methosulfate or by a second enzyme system. Various systems for coenzyme regeneration were investigated; the modified enzymes were lactate dehydrogenase from pig heart and alcohol dehydrogenase from horse liver; the auxiliary enzymes were alcohol dehydrogenase from yeast and liver, lactate dehydrogenase from pig heart, glutamate dehydrogenase and alanine dehydrogenase. Lactate dehydrogenase from heart muscle is inhibited by pyruvate. With alanine dehydrogenase as the auxiliary enzyme, the coenzyme is regenerated and the reaction product, pyruvate, is removed. This system succeeds to convert lactate quantitatively to L-alanine. The thermostability of the binary enzyme systems indicates an interaction of covalently bound coenzymes with both dehydrogenases; both binding sites seem to compete for the coenzyme. The comparison of dehydrogenases with different degrees of modifications shows that product formation mainly depends on the amount of incorporated coenzyme.

Alanine Dehydrogenase↗
PubMed1994

Insecticides and acaricides: resistance and environmental impact.

Insecticides continue to be the primary means of control for ectoparasites on livestock. Intensive use of these materials has led to resistance to organochlorines, organophosphates and pyrethroids among populations of Haematobia irritans irritans, H. irritans exigua and Lucilia cuprina. Similarly, use of acaricides has led to resistance in one-host Boophilus ticks to all currently-used organophosphate-carbamates, synthetic pyrethroids and amidines. Resistance in multi-host ticks is less widespread. New chemicals are available for the control of resistant ectoparasites, but there are concerns over resistance and residues problems, which prompt the authors to discuss new pest management strategies. Environmental concerns are raised regarding the use of pesticides on livestock.

Animals↗
PubMed2005

Dual molecules as new antimalarials.

A new antimalarial pharmacological approach based on inhibition of the plasmodial phospholipid metabolism has been developed. The drugs mimic choline structure and inhibit de novo phosphatidylcholine biosynthesis. Three generations of compounds were rationally designed. Bisquaternary ammonium salts showed powerful antimalarial activity, with IC(50) in the nanomolar range. To remedy their low per os absorption, bioisosteric analogues (bis-amidines) were designed and exhibited similar powerful activities. Finally, the third generation compounds are bis-thiazolium salts and their non-ionic precursors: prodrugs, which in vivo can lead to thiazolium drugs after enzymatic transformation. The compounds are equally effective against multiresistant Plasmodium falciparum malaria. These molecules exert a very rapid cytotoxic effect against malarial parasites in the very low nanomolar range and are active in vivo against P. vinckei-infected mice, with ED(50) lower than 0.2 mg/kg. They are able to cure highly infected mice and, retain full activity after a single injection. They also retain full activity against P. falciparum and P. cynomolgi in primate models with no recrudescence and at lower doses. Compounds are accumulated in P.falciparum-infected erythrocyte, which ensures their potency and specificity. Recently, we discovered that compounds also interact with malarial pigment enhancing the antimalarial effect. It is quite likely that they are dual molecules, exerting their antimalarial activity via two simultaneous toxic effects on the intracellular intraerythrocytic parasites. The current leader compounds are accessible in few steps from commercial products. These crystalline molecules present a remarkable biological activity and low toxicity which is promising for the development of a new antimalarial drug.

Animals↗
PubMed1993

Insulin does not induce the hydrolysis of a glycosyl phosphatidylinositol in rat fetal hepatocytes.

An inositol phosphoglycan that is the polar head group of a glycosyl phosphatidylinositol has been considered as a putative mediator of insulin action. To gain insight into the functions of this hormone during development, the relationships between insulin, insulin receptors, glycosyl phosphatidylinositol, and inositol phosphoglycan were studied. Glycosyl phosphatidylinositol was isolated and characterized in fetal liver as early as day 15 of intrauterine life. In isolated hepatocytes from fetal and adult rats labeled with [3H]glucosamine, [3H]galactose, or [3H]myo-inositol, these molecules were incorporated into glycosyl phosphatidylinositol. In hepatocytes labeled with [3H]glucosamine and then allowed to react with [1-14C]IAI, the [3H]glycosyl phosphatidylinositol was purified as the 14C-labeled amidinated lipid. Glycosyl phosphatidylinositol molecules from fetal and adult cells were sensitive to hydrolysis by a phosphatidylinositol-specific phospholipase C from B. cereus. The product of this hydrolysis inhibits the activity of a cAMP-dependent protein kinase, whereas this effect was abolished by nitrous acid deamination. In isolated hepatocytes from adult animals, an inverse correlation between extracellular insulin and the number of insulin receptors and the cellular content of glycosyl phosphatidylinositol was observed. However, in fetal hepatocytes insulin failed to reduce the glycosyl-phosphatidylinositol content when labeled either with [1-14C]isethionyl acetimidate or [3H]glucosamine, whereas insulin-like growth factor I produced a significant hydrolysis of glycosyl phosphatidylinositol. Fetal and adult hepatocytes were incubated with insulin or inositol phosphoglycan after which glycogen phosphorylase activities were determined. Inositol phosphoglycan mimicked the action of insulin on both forms of the enzyme from adult hepatocytes, whereas in fetal cells insulin did not change, and purified inositol phosphoglycan reduced the activities of glycogen phosphorylase. These findings suggest a dissociation between insulin receptor occupancy and the expected hormonal effects in fetal hepatocytes. This could be related to alterations at a postreceptor level.

Animals↗