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Nine N-(4-substituted amino-4-oxobutyryl)-N-substituted glycines expected to have inhibitory activity on angiotensin-converting enzyme were synthesized. All of the title compounds and their t-butyl esters were unreported in the literature. In preliminary test in rats, compounds V2, V6 and V7 showed marked hypotensive activity.
This paper reports the synthesis of nine N-(4-carbethoxy-4-substituted butyryl)-N-substituted glycines and their corresponding t-butyl esters. The former were expected to have inhibitory activity of angiotensin-converting enzyme. All of the compounds mentioned above were unreported in the literature. In preliminary test in rats, compounds VII7 and VII9 showed marked hypotensive activity.
A series of tripeptides possessing trifluoromethyl or aryl ketone residues at P1 were prepared and evaluated both in vitro and in vivo as potential inhibitors of human leukocyte elastase (HLE). Tripeptides containing non naturally occurring N-substituted glycine residues at the P2-position have been demonstrated to be potent in vitro inhibitors of HLE, with IC50 values in the submicromolar range. Sterically demanding substituents on the P2-nitrogen have no detrimental effect on in vitro potency. The inhibition process presumably acts via hemiketal formation with the active site Ser195 of HLE, and is facilitated by the strongly electron withdrawing trifluoromethyl functionality. Deletion of the amino acid at the P3-subsite region affords inactive compounds. Valine is the preferred residue at the P1-position, whereas the corresponding glycine, alanine, alpha,alpha-dimethylglycine, or phenylalanine analogues are all inactive. The compounds described herein all confer a high degree of in vitro specificity when tested against representative cysteine, aspartyl, metallo, and other serine proteases. One of the most potent in vitro inhibitors is (3RS)-N-[4-[[[(4-chlorophenyl)sulfonyl]amino]carbonyl]phenyl] oxomethyl]-L-valyl-N-(2,3-dihydro-1H-inden-2-yl)glycine N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]amide (20i; BI-RA-260) (IC50 = 0.084 microM). Compound 20i was also tested in hamsters in an elastase-induced pulmonary hemorrhage (EPH) model. In this model, intratracheal (it.) administration of 20i, 5 min prior to HLE challenge, effectively inhibited hemorrhage in a dose-dependent manner with an ED50 of 4.8 micrograms. The inhibitor 20i, 20 micrograms administered it. 24, 48, and 72 h prior to HLE challenge, exhibits significant inhibition against hemorrhage at all time points (97%, 64% and 49%, respectively). In a 21-day chronic model of emphysema in hamsters, 200 micrograms of HLE administered it. caused an elastase-induced emphysema in the lungs which can be quantitated histologically utilizing image analysis. In this assay, 20i significantly inhibited pulmonary lesions associated with septal destruction and increased alveolar spaces, when dosed at 20 micrograms it. 5 min prior to challenge with HLE.
Peptoids, oligomers of N-substituted glycines, are described as a motif for the generation of chemically diverse libraries of novel molecules. Ramachandran-type plots were calculated and indicate a greater diversity of conformational states available for peptoids than for peptides. The monomers incorporate t-butyl-based side-chain and 9-fluorenylmethoxy-carbonyl alpha-amine protection. The controlled oligomerization of the peptoid monomers was performed manually and robotically with in situ activation by either benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate or bromotris(pyrrolidino)phosphonium hexaflurophosphate. Other steps were identical to peptide synthesis using alpha-(9-fluorenylmethoxycarbonyl)amino acids. A total of 15 monomers and 10 oligomers (peptoids) are described. Preliminary data are presented on the stability of a representative oligopeptoid to enzymatic hydrolysis. Peptoid versions of peptide ligands of three biological systems (bovine pancreatic alpha-amylase, hepatitis A virus 3C proteinase, and human immunodeficiency virus transactivator-responsive element RNA) were found with affinities comparable to those of the corresponding peptides. The potential use of libraries of these compounds in receptor- or enzyme-based assays is discussed.
Several tripeptide trifluoromethyl ketones containing non-naturally occurring N-substituted glycine residues at the P2-position are effective human leukocyte elastase (HLE) inhibitors in vitro and possess IC50 values in the submicromolar range. Deletion of the amino acid at the P3-subsite region affords inactive compounds. The trifluoromethyl ketone derivative of valine is the preferred residue at the P1-position; whereas, the corresponding glycine or alpha, alpha-dimethyl glycine analogs result in inactive compounds.
Radioprotective effects of vitamin complexes were shown. Author issued the possible mechanisms of the phenomena.
The guinea pigs were administrated vit. A (400 i.u.), vit. B2 (1 mg) or vit. B15 (5 mg). On the 9-th day of the experiment part of them was infected with 5000 invasive eggs of Ascaris suum. The invasion lasted 6 days and was controlled by lungs and kidney weight, and number of larvae in the lungs. The activity of amylase was determined by saccharogenic method in both organs. In the lungs of infected animals the activity of alpha-amylase was about 3 times lower than in the control. The infection of guinea pigs which were given vitamins did not cause change of enzyme's activity. In the kidney directive tendency was the same, but the differences were smaller. The infection resulted in an increase of relative mass of lungs. This index and number of larvae was considerable smaller in guinea pigs with vitamins A and B15 administration. Any testing agent did not cause change of relative weight of kidney.
Oxygen uptake (OU) and cell viability (CV) of isolated rat hepatocytes as a part of the indexes of hepatopathy were determined following treatment with DADA, the active principle of pangamic acid. DADA increased OU at high concentrations, but not at low ones. However, CV became higher as the concentration became lower. DADA led to no remarkable toxicity when used alone. When the mixture of DADA and calcium gluconate was tested, DADA showed no palliative action; nor did it when combined with other hepatotoxins such as trapidil, rifampicin, hexobarbital, thiopental sodium, and Citanest-octapressin.
The effect of pH buffers and related compounds on the conductance of an outwardly rectifying anion channel has been studied using the patch-clamp technique. Single-channel current-voltage relationships were determined in solutions buffered by trace amounts of bicarbonate and in solutions containing N-substituted taurines (HEPES, MES, BES, TES) and glycines (glycylglycine, bicine and tricine), Tris and bis-Tris at millimolar concentrations. HEPES (pK alpha = 7.55) reduced the conductance of the channel when present on either side of the membrane. Significant inhibition was observed with 0.6 mM HEPES on the cytoplasmic side (HEPESi) and this effect increased with [HEPESi] so that conductance at the reversal potential was diminished approximately 25% with 10 mM HEPEsi and approximately 70% at very high [HEPESi]. HEPESi block was relieved by applying positive voltage but positive currents were not consistent with a Woodhull-type blocking scheme in that calculated dissociation constants and electrical distances depended on HEPES concentration. Results obtained by varying total HEPESi concentration at constant [HEPES-] and vice versa suggest both the anionic and zwitterionic (protonated) forms of HEPES inhibit. Structure-activity studies with related compounds indicate the sulfonate group and heterocyclic aliphatic groups are both required for inhibition from the cytoplasmic side. TES (pK alpha = 7.54), substituted glycine buffers (pK alpha = 8.1-8.4) and bis-Tris (pK alpha = 6.46) had no measurable effect on conductance and appear suitable for use with this channel.
1. We describe the use of benzyloxycarbonylmethionine and ethoxycarbonylmethionine for the selective protection of the amino groups of glycine-A1 and lysine-B29 of pig insulin. We have used the Edman method to remove residues from the N-terminal and of the B-chain of the N(A1)N(B29)-di-protected derivatives. The benzyloxycarbonyl group shows slight but noticeable lability in the acid-cleavage step, but the ethoxycarbonyl group remained intact even after five cycles of degradation. 2. We have prepared the following truncated forms of insulin via the di(ethoxycarbonylmethionyl) derivative: des-Phe(B1)-insulin;des-(Phe(B1)-Val(B2))-insulin; des-(Phe(B1)-Val(B2)-Asn(B3))-insulin;des- (Phe(B1)-Val(B2)-Asn(B3)-Gln(B4))-insulin; des-(Phe(B1)-Val(B2)-Asn(B3) -Gln(B4)-His(B5))-insulin. 3. Insulin was re-synthesized from the di-protected des-Phe(B1)-insulin by reaction with an active ester of t-butoxycarbonyl-l-phenylalanine. The product after deprotection crystallized, and the immunoreactivity of the crystalline material was identical with that of the native protein. 4. We have prepared the following analogues of insulin in a similar manner: [l-Ala(B1)]insulin; [l-Val(B1)]insulin; [l-Tyr(B1)]insulin; [m-F-l-Phe(B1)]insulin; [o-F-l-Phe(B1)]-insulin; [o-F-l-Phe(B2)]des-Phe(B1)-insulin. All had between 34 and 62% of the activity of insulin in the fat-cell test. 5. We have also investigated the use of the benzyol, toluene-p-sulphonyl, p-nitrobenzyloxycarbonyl and 2,4-dinitrophenyl groups for the N-protection of the methionine active esters. Each should have had some particular advantage over the benzyloxycarbonyl and ethoxycarbonyl groups, but all proved in practice to have disadvantages that more than outweighed anything in their favour.
According to recent experimental data the renal transport of amino acids (AA) is characterized as follows. 1. Kinetics: Several reabsorption systems remove AA from the tubular fluid by active transport with Michaelis-Menten type kinetics. Passive diffusion does play only a relatively small role in reabsorption, but determines the pump leak steady state concentration at the end of the tubule. 2. Stereospecificity: Except for aspartate the naturally occurring L-analogs show a much larger affinity to the transport "carriers" than the D-isomers do. 3. Specificity: Separate transport mechanisms exist for a) the "acidic" AA (Glu and Asp); b) the "dibasic" AA (Arg, Lys, Orn); c) cystine/cystine; d) the "imino" acids (Pro, OH-Pro and other N-substituted AA); e) the beta- and gamma-AA (beta-Ala, GABA, Taurine); f) all other "neutral" AA. For the group (d) and maybe also for (b) and glycine additional low capacity/high affinity systems exist. 4. Localization: Except for glycine and taurine under normal conditions more than 80% of the filtered load are reabsorbed within the first third of the proximal tubule. At an elevated load the rest of the proximal tubule (including pars recta) but not the distal nephron is included into the reabsorptive process. AA are also taken up from the peritubular blood. 5. Energy sources: At least the main part of AA uptake at the brushborder membrane is dependent from a transmembranal Na+-gradient which in turn is established by the ATP driven Na+-pumps at the basolateral side of the cell (Secondary active transport or co-transport of AA). 6. Biochemistry: The biochemical nature of the AA-"carriers" is unknown. The recent hypothesis than a "gamma-glutamyl cycle" plays a major role in this context has been disproved to great extent. 7. Peptides: Oligopeptides (Angiotensin, Gluthathion) filtered at the glomerulum are hydrolyzed by brushborder peptidases within the tubule lumen. The splitting products, the free constituent amino acids, are reabsorbed subsequently by their respective transport systems.
An affinity adsorbent for trypsin [EC 3.4.21.4] (GGA Sepharose) was prepared. Glycylglycyl-L-arginine (GGA) was synthesized by a simple procedure and was immobilized on agarose gel. This adsorbent proved to have essentially the same characteristics as AP Sepharose, which is an affinity adsorbent containing tryptic peptides of protamine (1). GGS Sepharose was specific for native trypsin and had a stronger affinity at lower pH's (6-5) than at the optimum pH of trypsin action (8.2). It also proved to be suitable for analytical experiments because of its relatively weak affinity. By comparison of the elution profiles of trypsin from GGA Sepharose under various conditions, the nature of the interaction of trypsin with the adsorbent could be studied. It was found that alpha- and beta-trypsin could be distinguished. In the presence of arginine and N-substitute arginines, the elution of trypsin was accelerated. From the extents of the accelerating effects, the affinities of these compouunds could be compared.
Vinylogous hydroxamic acids (3-(N-hydroxy-N-alkylamino)-2-propen-1-ones, VHA) were prepared as antiinflammatory agents. The synthesis, chemical properties, and in vitro biological activities of these relatively unexplored compounds are described. The VHAs were prepared by condensation of the appropriate N-substituted hydroxylamine with any of the three reagents: a 1,3-dicarbonyl compound (method A); a vinylogous amide (method B); or an alkynone (method C). The VHAs exist as one or more tautomers in solution with the relative proportions of each being dependent upon the structure of the VHA, solvent, and pH. VHAs undergo some of the typical reactions of hydroxamic acids as well as those of vinylogous amides. VHAs are active as inhibitors of 5-lipoxygenase and of IL-1 biosynthesis in vitro, which do not inhibit other enzymes of the arachidonic acid cascade. They have been shown by ESR studies to bring about inhibition of soybean type 1 15-lipoxygenase by reduction of the active site iron.
The typical plant sterols (sitosterol, stigmasterol and campesterol) were compared with respect to their ability to regulate membrane fluidity of soybean phosphatidylcholine (PC) vesicles. Fluidity changes were monitored by the steady-state fluorescence anisotropy with 1,6-diphenyl-1,3,5-hexatriene as a probe and assigned to a measure of the acyl chain orientational order. Sitosterol and campesterol appear to be the most suitable sterols in ordering the acyl chains of soybean lecithin bilayers, even more efficient than cholesterol, the standard of reference for sterol effects on membranes, suggesting that they play a significant role in the regulation of plant membrane properties. Stigmasterol is shown to be much less active. Cycloartenol, a biosynthetic precursor of plant sterols, increases the acyl chain order with the same efficiency as cholesterol. We also investigated the effects of two unusual sterols, 24-methylpollinastanol and 14 alpha,24-dimethylcholest-8-en-3 beta-ol, which were shown to accumulate in plants treated with fungicides belonging to two important classes, N-substituted morpholines and triazoles, respectively. These two sterols exhibit a behavior very similar to that of stigmasterol. The results are discussed in terms of sterol effects on the molecular packing of soybean PC bilayers.
Truncated N-terminal fragments of parathyroid hormone (PTH), [Tyr34]bovine PTH(7-34)NH2, and parathyroid hormone related protein (PTHrP), PTHrP(7-34)NH2, inhibit [Nle8,18,[125I]iodo-Tyr34]-bPTH(1-34)NH2 binding and PTH-stimulated adenylate cyclase in bone and kidney assays. However, the receptor interactions of these peptides are 2-3 orders of magnitude weaker than those of their agonist counterparts. To produce an antagonist with increased receptor-binding affinity but lacking agonist-like properties, structure-function studies were undertaken. Glycine at position 12 (present in all homologues of PTH and in PTHrP), which is predicted in both hormones to participate in a beta-turn, was examined by substituting conformational reporters, such as D- or L-Ala, Pro, and alpha-aminoisobutyric acid (Aib), in both agonist and antagonist analogues. Except for N-substituted amino acids, which substantially diminished potency, substitutions were well tolerated, indicating that this site can accept a wide latitude of modifications. To augment receptor avidity, hydrophobic residues compatible with helical secondary structure were introduced. Incorporation of the nonnatural amino acids D-Trp, D-alpha-naphthylalanine (D-alpha-Nal), or D-beta-Nal into either [Tyr34]bPTH(7-34)NH2 or [Nle8,18,Tyr34]bPTH(7-34)NH2 resulted in antagonists that were about 10-fold more active than their respective 7-34 parent compound. Similarly, [D-Trp12]PTHrP(7-34)NH2 was 6 times more potent than the unsubstituted peptide but retained partial agonistic properties, although markedly reduced, similar to PTHrP(7-34)NH2. The antagonistic potentiating effect was configurationally specific.(ABSTRACT TRUNCATED AT 250 WORDS)
A series of tripeptides which contain alpha,alpha-difluorostatone residues at P1-P1' and span the S3-S1' subsites have been shown to be potent inhibitors of human leukocyte elastase (HLE). The tripeptides described contain the nonproteinogenic achiral residue N-(2,3-dihydro-1H-inden-2-yl)glycine at the P2-position. This redidue has previously been shown in the case of HLE to be a good bioisosteric replacement for L-proline. Of the peptides prepared, those which contain the alpha,alpha-difluoromethylene keton derivative of L-valine (difluorostatone) are the preferred residue at the P1-primary specificity position. Substitution at P1 by the corresponding alpha,alpha-difluoromethylene ketones of L-leucine and L-phenylalanine gives inactive compounds. Of the tripeptides described the most potent in vitro compound is ethyl N-[N-CBZ-L-valyl-N-(2,3-dihydro-1H-inden-2-yl)glycyl]- 4(S)-amino-2,2-difluoro-3-oxo-5-methylhexanoate (17B) (IC50 = 0.635 microM). It is presumed that the inhibitor 17b interacts with the S3-S1' binding regions of HLE. Additionally extended binding inhibitors were prepared which interact with the S3-S3' binding subsites of HLE. In order to effect interaction with the S1'-S3' subsites of HLE, the leaving group side of cleaved peptides, spacers based upon Gly-Gly, and those linked via the N epsilon of L-lysine were utilized. One of the most potent extended compounds (P3-P3') in vitro is methyl N6-[4(S)-[[N-[N-CBZ-L-valyl-N- (2,3-dihydro-1H-inden-2-yl)glycyl]amino]-2,2-difluoro-3-oxo-5- methylhexanoyl]-2(S)-(acetylamino)-6-aminohexanoate (24b) (IC50 = 0.057 microM). The described in vitro active inhibitors were also evaluated in hamsters in an elastase-induced pulmonary hemorrhage (EPH) model. In this model, intratracheal (it.) administration of 22c, 5 min prior to HLE challenge (10 micrograms, it.) effectively inhibited hemorrhage (94.6%) in a dose-dependent manner. The described alpha,alpha-difluoromethylene ketone inhibitors are assumed to act as transition-state analogs. The inhibition process presumably acts via hemiketal formation with the active site Ser195 of HLE, and is facilitated by the strongly electron withdrawing effect of the alpha,alpha-difluoromethylene functionality.
Eight S- and N-substituted L-cysteinylglycines were prepared by condensation of S-benzyl-L-cysteinylglycine or S-(p-bromobenzyl)-L-cysteinylglycine with glutaric anhydride, succinic anhydride, or the appropriately blocked and activated amino acids. In contrast to the previously prepared S-substituted glutathiones, all of the title compounds exhibited noncompetitive inhibition of yeast glyoxalase I. A kinetic evaluation under Yonetani-Thorell conditions established the existence of two binding sites on the glyoxalase I enzyme.
A new series of antifungal antibiotics, Ro 09-1470 and its 6 congeners were isolated from the fermentation broth of Penicillium sp. NR6564. Their structures were determined as tetrahydropyran derivatives with an alkenyl side chain on the basis of their spectroscopic and physico-chemical properties. Among these compounds, Ro 09-1470 and Ro 09-1545 possessing a glycyl N-substituted glycyl ester residue had high antifungal activity. Ro 09-1469, one of the congeners, was found in the fermentation broth of several strains of Aspergillus sclerotiorum Huber.