Triaminotricarboxylic amino acid oxidation productions of actinoidin and ristomycin]

Aromatic acids with three benzene nuclei bound through oxygen were obtained from actinoidin and ristomycin on their oxydation with permanganates of methylated aglycones and peptides. The structures of the methyl esters of these acids were determined by spectral methods. They are the following: methyl-3,5-bis-(4-methoxycarbonyl-phenoxy)-4-methoxybenzoate (from ristomycin) and methyl-3-(2-chlor-4-methoxycarbonyl-phenoxy)-5-(4-methoxycarbonyl-phenoxy)-4-methoxybenzoate (from actinoidin). The compounds are the aromatic parts of the molecules of the unusual triaminotricarboxylic amino acids present in the aglycones of all antibiotics of the group of polycyclic glycopeptides.     

Structure of the tricyclic triaminotricarboxylic acid (Y) from the antibiotic actinoidin

The products of triaminotricarboxylic acid (Y) transformation in alkaline and reduction (HI/P) hydrolysis and the PMR spectra of the Y-Phe dipeptide were studied and the nature of the 3 amino acid substitutes and their position in the aromatic nuclei were determined. With regard to the data on the structure of the aromatic skeleton published earlier the structure of the Y amino acid as 3-(2-chlor-4-seryl-phenoxy)-5-(4-seryl-phenoxy)-p-hydroxyphenylglycine was suggested. The presence of 2 alcoholic groups of the phenylserine fragments of the Y amino acid in the actinoidine aglycone was shown with additional acetylation (Ac2O/Py) of N-acetylmethoxyaglycone. It was found with O-acetylation of N-acetylmethoxyactinosaminyl aglycone that the actinosamine amino sugar in the actinoidine molecule was bound with one of the above groups.     

Quantitative amino acid makeup and the characteristics of the amino groups of ristomycin and the products of its partial acid hydrolysis]

The quantitative amino acid composition of ristomycin A, a glycopeptide antibiotic, peptides I-IV (from partial acid hydrolysis of the antibiotic) and their dinitrophenylic derivatives was determined. It was shown that both ristomycin and free peptides I-IV contained one residue of ristomycinic acid and one residue of actinoidinic acid, diamino-dicarbonic amino acids of the glycylphenolic type. Peptides I-IV had close molecular weights, i.e. 1100-1200 and differed from each other in the gradually increasing numbers of NH2- and COON- groups, from one in peptide I to four in peptide IV. The quantitative amino acid analysis of the dinitrophenylic derivatives of ristomycin and peptides I-IV showed that the free NH2-group in peptide I belonged to ristomycinic acid, the same as in the antibiotic, while in peptides III-IV at least one of the free NH2-groups belonged to ristomycinic acid and the other belonged to actinoidinic acid.     

Monoamine oxidase inhibitors from Gentiana lutea

Three monoamine oxidase (MAO) inhibitors were isolated from Gentiana lutea. Their structures were elucidated to be 3-3'linked-(2'-hydroxy-4-O-isoprenylchalcone)-(2'-hydroxy-4'-O-isoprenyldihydrochalcone) (1), 2-methoxy-3-(1,1'-dimethylallyl)-6a,10a-dihydrobenzo(1,2-c)chroman-6-one and 5-hydroxyflavanone. These compounds, and the hydrolysis product of 1, displayed competitive inhibitory properties against MAO-B which was more effective than MAO-A.     

Homoisoflavonoids from Ophiopogon japonicus Ker-Gawler

From the ethyl acetate extract of the tuberous roots of Ophiopogon japonicus (Liliaceae) eight known and five new homoisoflavonoidal compounds were isolated. The new compounds are 5,7-dihydroxy-8-methoxy-6-methyl-3-(2'-hydroxy-4'-methoxybenzyl)chroman-4-one (1), 7-hydroxy-5,8-dimethoxy-6-methyl-3-(2'-hydroxy-4'-methoxybenzyl)chroman-4-one (2), 5,7-dihydroxy-6,8-dimethyl-3-(4'-hydroxy-3'-methoxybenzyl)chroman-4-one (3), 2,5,7-trihydroxy-6,8-dimethyl-3-(3',4'-methylenedioxybenzyl)chroman-4-one (4) and 2,5,7-trihydroxy-6,8-dimethyl-3-(4'-methoxybenzyl)chroman-4-one (5). Their structures have been elucidated by mass and NMR spectroscopy. Compounds 4 and 5 are the first isolated homoisoflavonoids with a hemiacetal function at position 2.     

Effect of ristomycin on the electrokinetic properties of Staphylococcus aureus cells

The electrophoretic mobility of the cells of Staph. aureus cultivated on the medium with ristomycin is markedly decreased at pH 3.0-5.0. This indicates that ristomycin added to the cultivation medium lowers the number of the phosphate groups in teichoic acids of the staphylococcal cell wall. The effect of ristomycin on the cells of the staphylococci was studied in vitro during the process of their incubation. It was shown that almost within the first minutes of the incubation ristomycin interacts immediately with the ionogenic groups of the cell wall and first of all with the phosphate groups of teichoic acids.     

Acetyl and butyrylcholinesterase-inhibiting triterpenoid alkaloids from Buxus papillosa.

Three triterpenoid alkaloids, buxakashmiramine [(20S)-20-dimethylamino-4',6'-dimethoxy-5'-hydroxybenzoylamino-3beta-methyl-buxan-31-ol] (1), buxakarachiamine [(20S)-20-dimethylamino-2'-hydroxy-3beta-methyl-3'-methyl-butanoylamino-9,10-seco-buxa-9(11), 10(19)-dien-31-ol] (2) and buxahejramine [(20S)-20-dimethylamino-2'-hydroxy-3beta-methyl-3'-methyl-pentanoylamino-9,10-seco-buxa-9(11), 10(19)-dien-31-ol] (3) were isolated from the leaves of Buxus papillosa. Four known bases, cycloprotobuxine-C (4), cyclovirobuxeine-A (5), cyclomicrophylline-A (6) and semperviraminol (7) were isolated for the first time from this species. Their structures were established through extensive spectroscopic studies. Most of these compounds exhibited anticholinesterase activity.     

Chalconoids from Fissistigma bracteolatum

Phytochemical studies on the leaves of Fissistigma bracteolatum yielded besides the two known compounds 2-hydroxy-3,4,6-trimethoxychalcone (1) and 5,7,8-trimethoxyflav-3-ene (2), five new chalconoids 2-hydroxy-3,4,6-trimethoxychalcene (3), 2-hydroxy-3,4,6-trimethoxydihydrochalcone (4), 2'-hydroxy-3',4',6'-trimethoxydihydrochalcone (5), 2'-hydroxy-3',4',6'-trimethoxy-beta'-methoxychalcane (6) and 2'-hydroxy-3',4',6'-trimethoxy-beta'-ethoxychalcane (7). The structures of these compounds were determined by mass and NMR spectroscopic methods.     

Chemical modification of ristomycin A with bifunctional reagents

Various bifunctional reagents by the free NH2 group of ristomycinic acid of ristomycin A were used for selective chemical modification of the antibiotic. The bifunctional reagents were the following: di-N-hydroxysuccinimide ether of suberic acid and 4,4'-difluoro-3,3'-dinitrodiphenylsulfone. Bis-N,N'-derivatives of ristomycin A were prepared using these reagents. The derivatives inhibited the growth of Bac. subtilis but the concentrations required for the inhibition were 2-4 times higher than those of ristomycin A. It was noted that the MIC of the bis-N,N'-derivatives depended on the length and flexibility of the "binding foot". The MIC of the bis-N,N'-derivative prepared with using suberic acid was 2 times higher than that of the derivative prepared with the use of 4,4'-difluoro-3,3'-dinitrodiphenylsulfone.     

Prenylated flavonoids from Deguelia hatschbachii and their systematic significance in Deguelia

Chemical investigation of dichloromethane and petrol extracts from the roots of D. hatshbachii A. M. G. Azevedo furnished thirteen compounds from which five are described for the first time and their structures were determined to be 3-(4'-hydroxyphenyl)-5-methoxy-6-( 3,3-dimethylallyl)-2"2"-dimethylchromene-(5",6":8,7)-3-(propyl-2-one)-4H-1-benzo-2,3-dihydropyran-2,4-dione; 6,4'-dihydroxy-3-(3,3-dimethylallyl)-2",2"-dimethylchromene (5",6":5,4)-2-methoxy deoxybenzoin; 6.4'-dihydroxy-3-(3,3-dimethylallyl)-2",2"-dimethylchromene (5",6":5,4)-2-methoxy-8-(propyl-2-one) deoxybenzon; 6-(3,3-dimethylallyl)-2",2"-dimethylchromene (5",6":4.5)-4'-hydroxy-3-methoxy stilbene and 3,5-dimethoxy-4'-hydroxy-4-(3,3-dimethylallyl) stilbene by spectral analysis (UV, IR, MS and ID- and 2D- NMR experiments). The root extracts and some isolated compounds were bioactive, as revealed by bioautography and brine shrimp lethality assays.     

Monoterpene coumarins from Ferula ferulago.

Two monoterpene coumarins, designated ferulagol A and B, as well as three known monoterpene coumarins and three sesquiterpene lactones were isolated from the chloroform extract of the roots of Ferula ferulago. The structures of ferulagol A and B were determined to be 7-[(E)-3'-hydroxy-3',7'-dimethyl-4',6'-octadienyloxy]coumarin and 7-[(3'Z,5'E)-7'-hydroxy-3',7'-dimethyl-3',5'-octadienyloxy]coumarin, respectively.     

Synthesis and properties of DNA-duplexes, containing 9-(1'-hydroxy-2'-(hydroxymethyl)ethoxy)methylguanine]

Phosphoramidite derivative of 9-[1'-hydroxy-2'-(hydroxymethyl)ethoxy]methylguanine (glG) is synthesized which allows one to introduce point modifications in any position of the chemically prepared oligonucleotide chain. Oligonucleotides with 5'-terminal glG can be used in chemical ligation promoted by cyanogen bromide. The modified oligonucleotide duplexes were characterized by melting curves and CD spectra.     

Synthesis of 2-(aminocarbonylmethylthio)-1H-imidazoles as novel Capravirine analogues

Different analogues of Capravirine (AG-1549) or S-1153 were prepared by synthesis of 2-(5-benzyl-4-isopropyl-1-methyl-2,3-dihydro-1H-imidazol-2-ylthio)acetamide (3a-c), ethyl [5-benzyl-1-(ethoxymethyl)-4-ethyl-1H-imidazol-2-ylthio]acetate (10), 2-[5-alkyl-4-substituted 1-(pyridin-4-ylmethyl)-1H-imidazol-2-ylthio]acetamides (12a-f), and 2-[5-benzyl-1-(benzyloxymethyl)-4-isopropyl-1H-imidazol-2-ylthio]acetamides (14a-l) from their corresponding amino acids through a sequence of reactions: Dakin-West reaction, hydrolysis, condensation with thiocyanate derivatives, alkylation with 2-iodoacetamide and ethyl chloroacetate, and coupling with 4-pyridylmethyl chloride, ethoxymethyl chloride and benzyloxymethyl chloride. All the synthesized compounds were screened for their activity against HIV-1 (wild type) and some of them (especially Capravirine like structures) were found active.     

Microwave-assisted synthesis of 4'-azaflavones and their N-alkyl derivatives with biological activities

4'-Azaflavone (=2-(pyridin-4-yl)-4H-1-benzopyran-4-one; 4) and 3-[(pyridin-4-yl)methyl]-4'-azaflavone (5) were synthesized by a simple environmentally friendly microwave-assisted one-pot method through the cyclization of 3-hydroxy-1-(2-hydroxyphenyl)-3-(pyridin-4-yl)propan-1-one (1), (E)-2'-hydroxy-4-azachalcone (2; chalcone=1,3-diphenylprop-2-en-1-one), and 2'-hydroxy-2-[(hydroxy)(pyridin-4-yl)methyl]-4'-azachalcone (3) under solventless conditions using silica-supported NaHSO(4), followed by treatment with base. In addition, N-alkyl-substituted 4'-azaflavonium bromides 6 and 7 were prepared from compounds 4 and 5, respectively. The antimicrobial and antioxidant activities of compounds 1-7 were tested. The N-alkyl-substituted 4'-azaflavonium bromides 6 and 7 showed high antimicrobial activity against the Gram-positive bacteria and the fungus tested, with MIC values close to those of reference antimicrobials ampicilline and fluconazole. The alkylated compounds 6 and 7 also showed a good antioxidant character in the two antioxidant methods, DPPH (=1,1-diphenyl-2-picrylhydrazyl) radical-scavenging and ferric reducing/antioxidant power (FRAP) tests.     

The specificity of combination between ristocetins and peptides related to bacterial cell-wall mucopeptide precursors

The affinity of ristocetin B for analogues of the C-terminal tripeptide sequence of bacterial cell wall mucopeptide precursors resembles that of vancomycin. Complex-formation requires a d-configuration in the two amino acid residues of the C-terminal dipeptide, an l-configuration is preferred in the preceding amino acid residue and positive charges on the peptide molecule decrease its affinity. The specificity of ristocetin B, however, differs from that of vancomycin in the requirements for the size of the side chains on the C-terminal dipeptide. These differences may explain the observed differences in antibiotic behaviour of vancomycin and ristocetin with particular micro-organisms. The optical rotatory dispersion and u.v.-absorption characteristics of the ristocetins are very different from those of vancomycin but nearly identical with those of ristomycin A. Aglycones prepared from ristomycin A were antibiotically active and also combined with a specific peptide.     

CD22-antagonists with nanomolar potency: the synergistic effect of hydrophobic groups at C-2 and C-9 of sialic acid scaffold

In earlier studies, we identified the C-9 amido derivative 1 (9-(4'-hydroxy-4-biphenyl)acetamido-9-deoxy-Neu5Gcα2-6GalOMP) and the C-9 amino derivative 2 (9-(4'-hydroxy-4-biphenyl)methylamino-9-deoxy-Neu5Gcα2-6GalOMP) have the most promising affinity for mouse CD22 and human CD22, respectively. Replacing the subterminal galactose residue (2-6Gal-OMP) of 1 with benzyl (5) or biphenylmethyl (6) as aglycone led to even higher potency for mCD22. In this study, both compounds showed improved potency and selectivity for CD22 (IC(50) 70 nM) and 712-fold more selective for CD22 than for MAG. The corresponding derivatives of 2, compounds 8 and 9, showed comparable activity to 2 but lower potency and selectivity than 5 and 6. Although compounds 5-9 are simple and small molecular weight antagonists, they showed much high potency and selectivity than the corresponding compounds having α 2-6Gal linkage. Both biological and computational docking simulation studies suggest that the 2-6Gal-OMP residues of 1 and 2 are not critical for binding process and could be replaced with hydrophobic non-carbohydrate moieties. The data presented herein has significant implications for the design and discovery of next-generation CD22-antagonists.     

Pterocarpans and Isoflavans from Astragalus membranaceus (Fisch.) Bunge

A new pterocarpan, (6aR, llaR)-3, 9-dimethoxy-l0-hydroxypterocarpan with four known compounds, (6aR,11aR)-3,9,10-tri-methoxypterocarpan,9,l0-di-methoxypterocarpan-3-O-β-D-glucopyranoside, (3R)-2'-hydroxy-7, 3', 4'-trimethoxy-isoflavan, 2'-hydroxy-3', 4'- dimethoxyisoflavan-7-O-β-D-glucopyranoside, were isolated from ethanolic extract of the root of Astragalus membranaceus (Fisch.) Bunge. Their structures were elucidated by means of spectral analysis and chemical conversions.     

Minor phenolics from Crinum bulbispermum bulbs

From the bulbs of Crinum bulbispermum Milne, four new minor compounds were isolated viz. 4-hydroxy-2',4'-dimethoxydihydrochalcone (1), 4,5-methylenedioxy-4'-hydroxy-2-aldehyde[1,1'-biphenyl] (4), hippacine (6), and 4'-hydroxy-7-methoxyflavan-3-ol (7). In addition, four known compounds were isolated and identified as 2(S),3',4'-dihydroxy-7-methoxy flavan (2), isolarrien (3), isoliquiritigenin (5) and liquiritigenin (8). The structures of the isolated compounds were established by spectral evidence.     

Inhibitory effects of 2-substituted-1-naphthol derivatives on cyclooxygenase I and II

Naphthol derivatives, 2-(3'-hydroxypropyl)-naphthalen-1-ol (2), 2-(3'-hydroxy-2'-methylpropyl)-naphthalen-1-ol (3) and 2-(3'-hydroxy-2',2'-dimethylpropyl)-naphthalen-1-ol (7) were synthesized and already reported by our group. Therefore in this paper we described further synthesis of their ether derivatives, 3-(1-methoxy-naphthalen-2-yl)-propan-1-ol (4), 3-(1-methoxy-naphthalen-2-yl)-2methyl-propan-1-ol (5), 3-(1-methoxy-naphthalen-2-yl)-2,2-dimethyl-propan-1-ol (8), 2-(3-methoxy-propyl)-naphthalen-1-ol (10) and 2-(3-methoxy-2,2-dimethyl-propyl)-naphthalen-1-ol (13). Compounds 4, 5 and 8 were prepared by methylation of compounds 2, 3 and 7, respectively while compounds 10 and 13 were prepared in good yield from naphthols 2 and 7, respectively. When tested for inhibitory activity, five compounds (2, 3, 7, 10 and 13) showed preferential inhibition of COX-2 over COX-1, while compounds 4, 5 and 8 lacked inhibitory effect on either the COX-1 or COX-2 isozyme. The structure-activity relationships of these naphthols analyzed by docking experiments, indicated that the presence of hydroxyl group at C-1 position on the naphthalene nucleus enhanced the anti-inflammatory activity towards COX-2 via hydrogen bonding to the COX-2 Val 523 side chain. When this hydroxyl group was replaced by methoxy group, there was no inhibition. C-2' Dimethyl substituents on the propyl chain also increased the inhibitory activity. All active compounds have the C-1 hydroxyl group aligned so as to form hydrogen bond with Val 523. The results provide a model for the binding of the naphthol derivatives to COX-2 and facilitate the design of more potent or selective analogs prior to synthesis.     

Synthesis of N-(1-deoxyhexitol-1-yl)amino acids, reference compounds for the nonenzymic glycosylation of proteins

The N-(1-deoxy-D-mannitol-1-yl) and N-(1-deoxy-D-glucitol-1-yl) derivatives of L-valine, L-alanine, L-threonine, and L-leucine were prepared by reductive amination of D-mannose and D-glucose with the appropriate amino acids, in the presence of sodium cyanoborohydride. N epsilon-(1-Deoxy-D-mannitol-1-yl)- and N epsilon-(1-deoxy-D-glucitol-1-yl)-L-lysine were prepared by similar reactions of hexoses with N alpha-tert-butoxycarbonyl and N alpha-benzyloxycarbonyl-L-lysine, followed by removal of the protecting groups. The structures were confirmed by 1H-n.m.r. spectroscopy, which showed that each compound was completely free of its C-2 epimer. The synthetic compounds may be used as reference compounds for the identification of N-(1-deoxyhexitol-1-yl)amino acids formed when N-(1-deoxy-D-fructose-1-yl) groups of nonenzymically glycosylated proteins, of the hemoglobin A1c type, are reduced with sodium borohydride, and the protein is subjected to acid-catalyzed hydrolysis.