Tannin and Related Compounds from Terminalia catappa and Terminalia parviflora

Continuing chemical examination on tannins and related compounds of Combretaceous plants has led to the isolation of one novel complex type tannin, catappanin A, together with two phenolcarboxylic acids, two phenol glucoside gallates, seven ellagic tannins, one other hydrolyzable tannin, four flavan-3-ols and two complex type tannins from the bark of Terminalia catappa. In addition, from the bark of Terminalia parviflora one new methyl glucoside gallate, methyl 3,6-di-O-galloyl-β-D-glucoside, three phenolcarboxylic acids, three gallotannins, six ellagitannins and three other hydrolyzable tannins were isolated. Their structures were elucidated on the basis of chemical and spectroscopic evidence.     

Ferroptosis-Inhibitory Difference between Chebulagic Acid and Chebulinic Acid Indicates Beneficial Role of HHDP

The search for a safe and effective inhibitor of ferroptosis, a recently described cell death pathway, has attracted increasing interest from scientists. Two hydrolyzable tannins, chebulagic acid and chebulinic acid, were selected for the study. Their optimized conformations were calculated using computational chemistry at the B3LYP-D3(BJ)/6-31G and B3LYP-D3(BJ)/6-311 + G(d,p) levels. The results suggested that (1) chebulagic acid presented a chair conformation, while chebulinic acid presented a skew-boat conformation; (2) the formation of chebulagic acid requires 762.1729 kcal/mol more molecular energy than chebulinic acid; and (3) the 3,6-HHDP (hexahydroxydiphenoyl) moiety was shown to be in an (R)- absolute stereoconfiguration. Subsequently, the ferroptosis inhibition of both tannins was determined using a erastin-treated bone marrow-derived mesenchymal stem cells (bmMSCs) model and compared to that of ferrostatin-1 (Fer-1). The relative inhibitory levels decreased in the following order: Fer-1 > chebulagic acid > chebulinic acid, as also revealed by the in vitro antioxidant assays. The UHPLC–ESI-Q-TOF-MS analysis suggested that, when treated with 16-(2-(14-carboxytetradecyl)-2-ethyl-4,4-dimethyl-3-oxazolidinyloxy free radicals, Fer-1 generated dimeric products, whereas the two acids did not. In conclusion, two hydrolyzable tannins, chebulagic acid and chebulinic acid, can act as natural ferroptosis inhibitors. Their ferroptosis inhibition is mediated by regular antioxidant pathways (ROS scavenging and iron chelation), rather than the redox-based catalytic recycling pathway exhibited by Fer-1. Through antioxidant pathways, the HHDP moiety in chebulagic acid enables ferroptosis-inhibitory action of hydrolyzable tannins.     

Tannins from leaves of Hippophaë rhamnoides

Four individual hydrolyzable tannins have been isolated for the first time from the leaves of the common sea buckthorn, two of which have been identified as strictinin and isostrictinin. The structure of the new tannin hipporhamnin has been established (6-O-galloyl-1,3-O-hexahydroxydiphenoyl-β-D-glucose). It has been shown that the free gallic acid in the leaves of the common sea buckthorn is an artifact.     

Prolyl endopeptidase inhibitory activity of fourteen Kampo formulas and inhibitory constituents of Tokaku-joki-to

Prolyl endopeptidase (PEP, EC 3.4.21.26) is an enzyme playing a role in the metabolism of proline-containing neuropeptides which have been suggested to be involved in learning and memory processes. In screening for PEP inhibitors from fourteen traditional Kampo formulas, we found that Tokaku-joki-to shows a significant inhibitory activity. Examination of the constituents of the Kampo formula resulted in the isolation of two new compounds, cis-3,5,4'-trihydroxystilbene 4'-O-beta-D-(6-O-galloyl)glucopyranoside (10) and 4-(4-hydroxyphenyl)-2-butanone 4'-O-beta-D-(6-O-galloyl-2-O-cinnamoyl)glucopyranoside (16), along with twenty-five known compounds, cinnamic acid (1), protocatechuic acid (2), gallic acid (3), torachrysone 8-O-beta-D-glucoside (4), emodin (5), emodin 8-O-beta-D-glucoside (6), 3,5,4'-trihydroxystilbene 4'-O-beta-D-glucopyranoside (7), 3,5,4'-trihydroxystilbene 4'-O-beta-D-(2-O-galloyl)glucopyranoside (8), 3,5,4'-trihydroxystilbene 4'-O-beta-D-(6-O-galloyl)glucopyranoside (9), 4-(4-hydroxyphenyl)-2-butanone 4'-O-beta-D-glucopyranoside (11), isolindleyin (12), lindleyin (13), 4(4-hydroxyphenyl)-2-butanone 4'-O-beta-D-(2,6-di-O-galloyl)glucopyranoside (14), 4-(4-hydroxyphenyl)-2-butanone 4'-O-beta-D-(2-O-galloyl-6-O-cinnamoyl)glucopyranoside (15), 1-O-galloylglucose (17), 1,2,6-tri-O-galloylglucose (18), gallic acid 4-O-beta-D-(6-O-galloyl)glucopyranoside (19), liquiritigenin (20), liquiritigenin 4'-O-beta-D-glucoside (21), liquiritigenin 7,4'-diglucoside (22), liquiritigenin 4'-O-beta-D-apiofuranosyl-(1-->2)-beta-D-glucopyranoside (23), licuroside (24), (-)-epicatechin (25), (-)-epicatechin 3-O-gallate (26) and (+)-catechin (27). Among these compounds, twelve (7-10, 14-16, 18, 19, 24-26) showed noncompetitive inhibition with an IC50 of 22.9, 3.0, 14.9, 2.8, 10.5, 0.69, 8.2, 0.44, 9.39, 26.5, 28.1 and 0.052 microM, respectively.     

Hydrolyzed Tannins from Geranium pusillum

The polyphenolic compound 1-O-galloyl-3,6-hexahydroxybiphenyl-D-galactopyranoside (pusilagin) was isolated from the aerial part. The tannin structure was established using acid hydrolysis and IR, PMR, and ¹³C NMR spectral methods.     

3,6-二苯氧甲基-1,2,4-三唑并[3,4-b]- 1,3,4-噻二唑衍生物的合成及生物活性

以4-氨基-5-苯氧甲基-3-巯基-1,2,4-三唑与取代苯氧乙酸为原料,三氯氧磷为溶剂,回流反应, 合成了3,6-二苯氧甲基-1,2,4-三唑并[3,4-b]-1,3,4-噻二唑衍生物。通过IR、1H NMR和元素分析确定了各化合物分子结构,并对其进行了室内毒力测试,结果表明此类化合物具有较好的杀菌、抑菌活性。     

Woodfordin D and oenothein A, trimeric hydrolyzable tannins of macro-ring structure with antitumor activity

Two new antitumor trimeric hydrolyzable tannins, woodfordin D (5) and oenothein A (13), were isolated from the dried flowers of Woodfordia fruticosa, and their macrocyclic structures, which have a novel constituent unit (woodfordinoyl group) connecting the monomers, have been elucidated on the basis of spectral and chemical evidence. Oenothein A (13) was also isolated from the leaves of Oenothera biennis.     

Withanolide derivatives from the roots of Withania somnifera and their neurite outgrowth activities

Five new withanolide derivatives (1, 9-12) were isolated from the roots of Withania somnifera together with fourteen known compounds (2-8, 13-19). On the basis of spectroscopic and physiochemical evidence, compounds 1 and 9-12 were determined to be (20S,22R)-3 alpha,6 alpha-epoxy-4 beta,5 beta,27-trihydroxy-1-oxowitha-24-enolide (1), 27-O-beta-D-glucopyranosylpubesenolide 3-O-beta-D-glucopyranosyl (1-->6)-beta-D-glucopyranoside (withanoside VIII, 9), 27-O-beta-D-glucopyranosyl (1-->6)-beta-D-glucopyranosylpubesenolide 3-O-beta-D-glucopyranosyl (1-->6)-beta-D-glucopyranoside (withanoside IX, 10), 27-O-beta-D-glucopyranosylpubesenolide 3-O-beta-D-glucopyranoside (withanoside X, 11), and (20R,22R)-1 alpha,3 beta,20,27-tetrahydroxywitha-5,24-dienolide 3-O-beta-D-glucopyranoside (withanoside XI, 12). Of the isolated compounds, 1, withanolide A (2), (20S,22R)-4 beta,5 beta,6 alpha,27-tetrahydroxy-1-oxowitha-2,24-dienolide (6), withanoside IV (14), withanoside VI (15) and coagulin Q (16) showed significant neurite outgrowth activity at a concentration of 1 microM on a human neuroblastoma SH-SY5Y cell line.     

Tannins and Related Compounds from Quisqualis Indica

Continuous exploration of the chemical constituents of Combretaceous plants has led to the discovery of two novel ellagitannins, quisqualin A ( 1 ) and quisqualin B ( 2 ), from the fruits of Quisqualis indica. A total of twenty-one other tannins were also isolated from either the fruits or leaves of Q. indica. including [I] eleven ellagitannins: 2,3-(S)-HHDP-D-glucose ( 3 ), 2,3-(S)-HHDP-4-O-galloyl-D-glucose ( 4 ), 2,3-(S)-HHDP-6-O-galloyl-D-glucose ( 5 ), 2,3-(S)-HHDPA6-di-O-galloyl-D-glucose ( 6 ). pedunculagin ( 7 ), punicalagin ( 8 ), eugeniin ( 9 ), 1-desgalloyleugeniin ( 10 ), casuariin ( 11 ), 5-desgalloylstachyurin ( 12 ), castalagin ( 13 ); [II] five gallotannins-. 6-O-galloyl-D-glucose ( 14 ), 1,6-di-O-galloyl-β-D-glucose ( 15 ), 2,3-di-O-galloyl-D-glucose ( 16 ), 3,4-di-O-galloyl-D-glucose ( 17 ), 4,6-di-O-galloyl-D-glucose ( 18 ); [III] four phenol-carboxylic acids: gallic acid ( 19 ), ellagic acid ( 20 ), flavogallonic acid ( 21 ), brevifolin carboxylic acid ( 22 ) and [IV] one other hydrolyzable tannin: punicalin ( 23 ).     

Effects of interaction of tannins with co-existing substances. VII. Inhibitory effects of tannins and related polyphenols on xanthine oxidase

The inhibitory effects of hydrolyzable tannins, condensed tannins and related polyphenols on the activity of xanthine oxidase (XOD), catalyzing uric acid formation from xanthine, were investigated. Marked differences in the strength of the inhibition were observed. Some of the differences among the monomeric hydrolyzable tannins were due to their molecular weights, reflecting the number of phenolic hydroxyl groups in the molecule. However, the inhibitory activity of several oligomeric hydrolyzable tannins seemed particularly low in spite of their large molecular size. It was also observed that differences in location of acyl groups on the carbohydrate cores caused differences in the inhibitory activity among monomeric and oligomeric hydrolyzable tannins. A caffeic acid derivative (caffeetannin), 3,5-di-O-caffeoylquinic acid (24), also inhibited this enzyme. Galloylation and the degree of polymerization in proanthocyanidins were also shown to affect remarkably the strength of the inhibition. Among the compounds tested in the present study, valoneic acid dilactone (29), isolated from Mallotus japonicus, inhibited the enzyme most effectively. A kinetic study showed that this dilactone inhibited XOD non-competitively. Comparison of the inhibitory effect on XOD, with the binding activity to hemoglobin, for each tannin, suggests that their inhibition of XOD is not based on non-specific binding to the protein. Similar comparison of the inhibitory effect on XOD with the inhibitory effect on the generation of superoxide anion radical (O2-.) from the hypoxanthine-XOD system revealed that the inhibition of O2-. generation by tannins is due to their radical-scavenging activity, and not due to their inhibitory activity upon the enzyme.     

Tannins of cornaceous plants. I. Cornusiins A, B and C, dimeric monomeric and trimeric hydrolyzable tannins from Cornus officinalis, and orientation of valoneoyl group in related tannins

Cornusiin A (1), cornusiin B (2) and cornusiin C (3), new dimeric, monomeric and trimeric hydrolyzable tannins, were isolated from the fruits of Cornus officinalis (Cornaceae). Their structures, including the orientation of the valoneoyl group in 1 and 3, were established on the basis of chemical and spectroscopic data. 2,3-Di-O-galloyl-D-glucose (7), 1,2,3-tri-O-galloyl-beta-D-glucose, 1,2,6-tri-O-galloyl-beta-D-glucose, 1,2,3,6-tetra-O-galloyl-beta-D-glucose, gemin D (5), isoterchebin, tellimagrandin I (6) and tellimagrandin II were also isolated from the fruits. The orientation of the valoneoyl group in camptothin A (14) and that in camptothin B (15), which had been isolated from Camptotheca acuminata (Nyssaceae), were also determined based on that in 1.     

Pteridines. Part XLII. Synthesis and properties of 8-substituted 2,4-dithiolumazines

Condensation reactions of the 5-amino-6-(subst. amino)-2,4-dithiouracils 12 and 13 with diacetyl or benzil led to the 6,7,8-trisubstituted 2,4-dithiolumazines 14 – 16 . Methylation of these compounds affected both thio functions forming various types of 2,4-bis(methylthio)lumazine derivatives depending on the nature of the substituents at C(7) and N(8). The 6,7,8-trimethyl-2,4-dithiolumazine ( 14 ) was converted into 7,8-dihydro-6,8-dimethyl–7-methylidene-2,4-bis(methylthio)pteridine ( 17 ), whereas the 8-methyl-6,7-diphenyl-(15) and the 8-(2-hydroxyethyl)-6,7-diphenyl-2,4-dithiolumazine ( 16 ) yielded the corresponding covalent inter- or intramolecular 7,8-adducts 18 – 21 . The unusual structures were proven by spectroscopic means and those of the alcohol adducts 20 and 21 , furthermore, confirmed by X-ray analysis.     

Simiranes A and B: erythroxylanes diterpenes and other compounds from Simira eliezeriana (Rubiaceae)

The first phytochemical study of Simira eliezeriana Peixoto (Rubiaceae) allowed the isolation and structural determination of two new diterpenes named simirane A [(5R,6R,8R,9R,10S,11S,13S)-6β,11β-dihydroxy-2,4(18),15-erythroxylatrien-1-one] (1) and simirane B [(5S,8R,9R,10S,11S,13S)-11β-hydroxy-2,4(18),15-erythroxylatrien-1-one] (2), together with seven known compounds: sitosterol (3), stigmasterol (4), campesterol (5), coniferaldehyde (6), vanillin (7), pinoresinol (8) and harman (9) from the bark of the plant. The structures of the compounds were established on the basis of spectroscopic methods, including 1-D and 2-D NMR, HRESI-MS and CD analysis and comparisons with available literature data of known compounds.     

Investigation of the products of the ozonolysis of sclareol and the pathways for their formation

It has been established that the main products of the ozonolysis of sclareol (I) under various conditions are “sclareol oxide” (III), 8α-hydroxy-14,15-bisnorlabdan-13-ome (IV), and the new compound (13R,14R)-14-hydroperoxy-13,14-epoxy-14-nor-labdan-8α-ol (X), and structure of which has been shown on the basis of its transformations. The acid fraction of the ozonation products, the yield of which was low (<8%) included two compounds: sclareolic acid (85%) and 18α-hydroxy-14,15,-16-trisnorlabdan-13-oic acid (3%). The mechanism for the formation of the above-mentioned compounds is discussed. Institute of Chemistry, Academy of Sciences of the Moldavian SSR, Kishenev. Translated from Khimiya Prirodnykh Soedinenii, No. 4, pp. 502–511, July–August, 1991.     

Studies on the synthesis of heterocyclic compounds. Part IX. Action of N,N-dimethylformamide dimethylacetal on some oximino-β-dicarbonyl compounds

3-Oximino-2,4-pentanedione ( 1 ) and ethyl 2-oximino-3-oxobutanoate ( 6 ) reacted with N,N-dimethylformamide dimethylacetal (DFDA) to give 1,7-bisdimethylamino-3,5-dioxo-4-methoximinohepta-1,6-diene ( 4 ) and ethyl 5-dimethylamino-2-methoximino-3-oxo-4-pentenoate ( 8 ), respectively. When compounds 4 and 8 were treated with hydrazine hydrate, they gave O-methyldipyrazol-3(5)-ylketoxime ( 5 ) and ethyl 2-methoximino-3(5)-pyrazolylethanoate ( 9 ) together with its corresponding hydrazide 10 , respectively. Upon action of DFDA on 3-oximino-2,4-pentanedione ( 1 ) at -20° an explosive crystalline product was obtained. On the other hand, the reaction of 3-acetoximino-2,4-pentanedione ( 11 ) with DFDA at -20° afforded a product which in ethanol solution, spontaneously deacetylated to give 1-dimethylamino-3,5-dioxo-4-oximinohexa-1-ene ( 13 ). The structures of all the new compounds were assigned on the basis of satisfactory analytical and spectroscopic data.     

Tannins from leaves of Hippopha? rhamnoides

Four individual hydrolyzable tannins have been isolated for the first time from the leaves of the common sea buckthorn, two of which have been identified as strictinin and isostrictinin. The structure of the new tannin hipporhamnin has been established (6-O-galloyl-1,3-O-hexahydroxydiphenoyl--D-glucose). It has been shown that the free gallic acid in the leaves of the common sea buckthorn is an artifact.All-Union Scientific Research Institute of Medicinal Plants, Moscow. Khimiya Prirodnykh Soedinenii, No. 6, pp. 902–907, November–December, 1097.     

Phenolic Compounds from the Fresh Leaves of Eucalyptus maideni

Four new phenolic compounds, 7‐O‐methylcatechin 5‐O‐β‐D ‐glucopyranoside ( 1 ), 6‐O‐feruloyl‐D ‐glucopyranose ( 2 ), demethylpiperitol 4‐O‐β‐D ‐glucopyranoside ( 3 ), and 2‐episesaminol 2‐O‐β‐D ‐glucopyranoside ( 4 ) were isolated from the fresh leaves of Eucalyptus maideni, together with six hydrolyzable tannins, 5 – 10 , a flavonol glycoside, 11 , three simple phenolics, 12 – 14 , a monoterpene glucoside, 15 , and a rosenoside, 16 . Their structures were determined on the basis of detailed spectroscopic analysis, acidic hydrolysis, and enzymatic hydrolysis. The known compounds 10 and 13 were obtained from the genus Eucalyptus for the first time.     

New quinoxaline and pyrimido[4,5-b]quinoxaline derivatives. Potential antihypertensive and blood platelet antiaggregating agents

Starting with 3-amino-2-quinoxalinecarbonitrile 1,4-dioxide 1 , a new series of quinoxaline derivatives 2-12 was synthetized through chemical modification of the 3-amino group, the 2-cyano group and selective mono-deoxygenation of the 1-oxide or 4-oxide groups. On the other hand, two 2,4-diaminopyrimido[4,5-b]quinoxa-line derivatives 13, 14 were obtained condensing 3-amino-2-quinoxaline carbonitriles with quanidine. Some of the new compounds were studied as inhibitors of blood platelet aggregation as well as antihypertensive agents.     

3,6-Thioanhydro sugar derivatives. An enantiospecific synthesis of (2R,3R,4S)-3-benzyloxy-4-hydroxy-2-[(R)-1-benzyloxy-4-hydroxybutyl]thiolane as the key intermediate for thioswainsonine

Methyl 2-O-benzyl-3,6-thioanhydro-α-D-mannopyranoside ( 9 ) was obtained in eight steps from the commercially available methyl α-D-glucopyranoside. Compound 9 was transformed into (2R,3R,4S)-3-benzyloxy-4-hydroxy-2-[(R)-1-benzyloxy-4-hydroxybutyl]thiolane ( 14 ) by acid hydrolysis of its 2,4-di-O-benzyl derivative 10 followed by reaction of the not isolated 2,4-di-O-benzyl-3,6-thioanhydro-D-mannose ( 11 ) with ethoxycarbonylmethylenetriphenylphosphorane to give an = 1:1 E/Z mixture of the corresponding α,β-unsaturated ester ( 12 ). Finally, catalytic hydrogenation of 12 to ethyl (R)-4-benzyloxy-4-[(2′R)3′R,4′S)-3′-benzyloxy-4′-hydroxythiolan-2′-yl]butanoate ( 13 ) and subsequent reduction with lithium aluminum hydride gave the title compound 14 .     

The structure of psoralidin

Psoralidin, C₂₀H₁₆O₅ the phenolic coumarin of Psoralea corylifolia Linn. has been shown to possess two hydroxyl groups, one conjugated δ-lactone, one isopentenyl group and an intramolecular ether linkage. On systematic degradation dihydropsoralidin dimethyl ether gave 2-hydroxy-4-methoxybenzaldehyde and 2,4-dimethoxy-5-(-3-methylbutyl)-benzoic acid. The synthesis of the latter compound has been described. On the basis of the degradation experiments coupled with ultra-violet and infra-red absorption data, the structure of psoralidin has been established as 6-(3-methylbut-2-enyl)-coumestrol (IV, R = H).