Synthesis of dammarane-type triterpenoids with anti-inflammatory activity in vivo

The 17-alpha-substituted triterpene 1 [(17alpha)-23-(E)-dammara-20,23-diene-3beta,25-diol] showed promising activity in animal models of immunosuppression and inflammation. Using a mouse model for inflammatory skin diseases (oxazolone-induced allergic contact dermatitis, ACD) as the directing in vivo test system, Structure-activity-relationship studies with the aim to understand the necessary structural requirements for the biological activity of 1 were conducted. Furthermore, we anticipated to identify biologically active compounds with the 17beta configuration, which are thermodynamically more stable and much easier to synthesize. This was achieved by identifying the 17-beta substituted dammarane 5B and its analogues.     

Synthesis and antiviral activity of lupane triterpenoids with modified cycle E

A reductive transformation of the peroxide products of ozonolysis of derivatives of 3β-O-acetyl-22(17→28)-abeo-lupa-17(28),20(29)-diene and the subsequent intramolecular ketalization led to a compound with a trioxane fragment. This is a new approach to a skeletal modification of triterpenoid cycle E. An activity of the synthesized compounds was found toward the viruses of type A influenza and herpes simplex.     

Synthesis and antiviral activity of lupane triterpenoids with modified cycle E

A reductive transformation of the peroxide products of ozonolysis of derivatives of 3beta-O-acetyl-22(17-->28)-abeo-lupa-17(28),20(29)-diene and the subsequent intramolecular ketalization led to a compound with a trioxane fragment. This is a new approach to a skeletal modification of triterpenoid cycle E. An activity of the synthesized compounds was found toward the viruses of type A influenza and herpes simplex.     

Castanopsone and castanopsol two new triterpenoids from Castanopsis indica

The isolation of two coumarins and five triterpenoids from Castanopsis indica is described. These have not been reported from this genus previously. The structures of two of the three new triterpenoids have been elucidated by chemical reactions and physical methods.     

Synthesis of the lupane group triterpenoids and there hepatoprotective activity

Hemisuccinates, hemiphthalates, acetylsalicylates, cinnamates, and p-methoxycinnamates of lupeol, betulin, and 3-O-acetylbetulin were synthesized via interaction with corresponding acid anhydrides or acid chlorides. A number of betulin esters in position 3 and 28 were shown to exhibit a pronounced hepatoprotective effect similar to that of betulin and silibor. These experimental data were in a good agreement with the computer prediction of their biological activity. Betulin 3,28-bis-hemiphthalate was more effective than carsil in models of experimental hepatitis caused by carbon tetrachloride, tetracycline, and ethanol.     

Synthesis of nuclease-resistant siRNAs possessing benzene-phosphate backbones in their 3'-overhang regions

We describe the synthesis and silencing activities of siRNA possessing N(1)-[3,5-bis(hydroxymethyl)phenyl]thymine (b(t)) in their 3'-overhang regions. We found that an siRNA possessing b(t) in the 3'-overhang region was more effective than an siRNA with natural nucleosides and the siRNA possessing 1,3-bis(hydroxymethyl)benzene (b) without a nucleobase at the 3'-overhang region in in vitro experiment using HeLa cells system. Furthermore, the RNA possessing b(t) at its 3'-end was more resistant to nucleolytic hydrolysis by snake venom phosphodiesterase (a 3'-exonuclease) than the RNA possessing the natural nucleoside 2'-deoxythymidine at the 3'-end. Thus, the compound b(t) will be a novel 3'-overhang moiety that can enhance the silencing activity and nuclease-resistant property of siRNAs.     

Arbuscular mycorrhizal fungus-promoted accumulation of two new triterpenoids in cucumber roots

Cucumber (Cucumis sativus L.) roots were analyzed by HPLC and TLC for their levels of secondary metabolites upon inoculation with the arbuscular mycorrhizal fungus, Glomus caledonium. Three compounds in EtOAc extracts from the mycorrhizal roots showed significant increases six weeks after inoculation. These compounds were isolated by column chromatography and determined to be two novel triterpenes, 2beta-hydroxybryonolic acid (2beta,3beta-dihydroxy-D:C-friedoolean-8-en-29-oic acid) and 3beta-bryoferulic acid [3beta-O-trans-ferulyl-D:C-friedooleana-7,9(11)-diene-29-oic acid], and the known triterpene, bryonolic acid, by spectroscopic methods. Time-course experiments showed that the levels of the three terpenoids in cucumber roots were significantly increased by the application of a 53-microm sieving from a soil inoculum of the arbuscular mycorrhizal fungus containing soil microbes but no mycorrhizal fungi, and that mycorrhizal colonization further promoted the terpenoid accumulation. Inoculation with Glomus mosseae also enhanced the accumulation of the triterpenes, whereas no accumulation was observed by inoculating with the fungal pathogen, Fusarium oxysporum f. sp. cucumerinum. 2Beta-hydroxybryonolic acid was also isolated from the roots of melon and watermelon.     

Epimerization of hydroxyl group in the lupan series of triterpenes

Two methods of obtaining of 3 alpha-betulinic acid and related compounds from their 3 beta-epimers were studied: the reaction of bimolecular substitution and the stereoselective reduction of 3-ketoderivatives. The substitution of acyloxy by formyloxy group in 3-O-tosyllupeol or of the betulin hydroxyl by benzoyloxy group resulted only in delta 2, 3-elimination products, with none of the expected products of bimolecular substitution being found. The catalytic hydrogenation of betulonic acid over Raney nickel resulted only in reduction of the isopropenyl double bond, whereas the use of 5% Ru/C gave a 60:40 mixture of epimers of dihydrobetulinic acid. Practically the same mixture of betulinic acid epimers was obtained when reducing betulonic acid with L-Selectride. The cytotoxic activity of 3 alpha-betulinic acid increased toward melanoma Bro cells and decreased toward melanoma MS cells.     

Phytolaccanol and epiacetylaleuritolic acid,two triterpenoids from Phytolacca acinosa

Two new triterpenoids, phytolaccanol and epiacetylaleuritolic acid, and sitosterol have been isolated and characterized from the defatted ethanolic ext     

Stacking interactions of ApA analogues with modified backbones

CD spectra have been measured as a function of temperature for a number of ApA analogues with modified backbones. Oligonucleotides with these modified backbones are being used as antisense agents having potential as viral therapeutics. Results of these studies show that when a carbonyl is substituted for the phosphate to produce an uncharged backbone, the analogues that have either sugar or morpholino substitution do not stack. In contrast, when a morpholino group is substituted for the sugar and the phosphate is modified so as to be uncharged, there is strong base stacking. Stacking interactions in the phosphorus-linked morpholino analogues are at least as strong as those found in d (ApA). The stacking interactions in ApA are weak by comparison. Singular value decomposition demonstrates that the stacking is two state, and Taylor series decomposition yields a coefficient that measures base stacking interactions. The van't Hoff equation is applied to the base stacking coefficient from the Taylor series fitting to give thermodynamic parameters. © 1992 John Wiley & Sons, Inc.     

Lagerenyl acetate and lagerenol two tetracyclic triterpenoids with the cycloartane skeleton from Lagerstroemia lancasteri

Lagerenyl acetate and lagerenol two new tetracyclic triterpenoids with the cycloartane skeleton together with four other triterpenoids 2α-hydroxy- 3β-E-p-coumaryloxy-urs-12-en-28-oic acid (jacoumaric acid, isolated as its monoacetylmethylcarboxylate derivative), 2α-hydroxyursolic acid (isolated as its diacetate), germanicyl acetate and friedelin, and sitosterol were isolated from the leaves and twigs of Lagerstroemia lancasteri. The structures of lagerenyl acetate and lagerenol were established as 3β-acetoxycycloart-24-one and 3β-hydroxycycloart-24-one, respectively, on the basis of spectral and chemical evidence.     

Synthesis and in vitro antioxidant functions of protein hydrolysate from backbones of Rastrelliger kanagurta by proteolytic enzymes

Every year, a huge quantity of fishery wastes and by-products are generated by fish processing industries. These wastes are either underutilized to produce low market value products or dumped leading to environmental issues. Complete utilization of fishery wastes for recovering value added products would be beneficial to the society and individual. The fish protein hydrolysates and derived peptides of fishery resources are widely used as nutritional supplements, functional ingredients, and flavor enhancers in food, beverage and pharmaceutical industries. Antioxidants from fishery resources have attracted the attention of researchers as they are cheaper in cost, easy to derive, and do not have side effects. Thus the present investigation was designed to produce protein hydrolysate by pepsin and papain digestion from the backbones of Rastrelliger kanagurta (Indian mackerel) and evaluate its antioxidant properties through various in vitro assays. The results reveal that both hydrolysates are potent antioxidants, capable of scavenging 46% and 36% of DPPH (1,1-diphenyl-2 picrylhydrazyl) and 58.5% and 37.54% of superoxide radicals respectively. The hydrolysates exhibit significant (p < 0.05) reducing power and lipid peroxidation inhibition. Among the two hydrolysates produced, pepsin derived fraction is superior than papain derived fraction in terms of yield, DH (Degree of hydrolysis), and antioxidant activity.     

Antiviral effects of two Ganoderma lucidum triterpenoids against enterovirus 71 infection

Enterovirus 71 (EV71) is a major causative agent for hand, foot and mouth disease (HFMD), and fatal neurological and systemic complications in children. However, there is currently no clinical approved antiviral drug available for the prevention and treatment of the viral infection. Here, we evaluated the antiviral activities of two Ganoderma lucidum triterpenoids (GLTs), Lanosta-7,9(11),24-trien-3-one,15;26-dihydroxy (GLTA) and Ganoderic acid Y (GLTB), against EV71 infection. The results showed that the two natural compounds display significant anti-EV71 activities without cytotoxicity in human rhabdomyosarcoma (RD) cells as evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation assay. The mechanisms by which the two compounds affect EV71 infection were further elucidated by three action modes using Ribavirin, a common antiviral drug, as a positive control. The results suggested that GLTA and GLTB prevent EV71 infection through interacting with the viral particle to block the adsorption of virus to the cells. In addition, the interactions between EV71 virion and the compounds were predicated by computer molecular docking, which illustrated that GLTA and GLTB may bind to the viral capsid protein at a hydrophobic pocket (F site), and thus may block uncoating of EV71. Moreover, we demonstrated that GLTA and GLTB significantly inhibit the replication of the viral RNA (vRNA) of EV71 replication through blocking EV71 uncoating. Thus, GLTA and GLTB may represent two potential therapeutic agents to control and treat EV71 infection.     

Friedelin and associated triterpenoids

The literature is reviewed for the natural occurrence of the pentacyclic triterpenes, friedelin and the epimeric 3-friedelanols. A summary of the literature relating to the structure elucidation, physical properties, synthesis and biosynthesis of these friedelane derivatives is presented. Compounds possessing the same carbon skeleton (D: A-friedelooleanane) and occurring with at least one of the above friedelane derivatives are also tabulated.     

Two oleanane triterpenoids from gordonia ceylanica and their conversions to taraxarane triterpenoids

Chemical investigation of the hot hexane extract of the stem bark of Gordonia ceylanica afforded two new oleanane triterpenoids, 3beta-acetoxy-11alpha, 13beta-dihydroxyolean-12-one and 3beta,11alpha-diacetoxy-13beta-hydroxyolean-12-one (2) The attempted acid hydrolysis of these two compounds resulted the dehydration and subsequent methyl group migration to afford the taraxarane triterpenoids 3beta,11alpha-dihydroxytaraxer-14-en-12-one (4) and 3beta-hydroxy-11alpha-acetoxytaraxer-14-en-12-one (5), respectively. These taraxaranes have not been previously reported.     

Synthetic transformations of higher triterpenoids. XXX. Synthesis and cytotoxic activity of betulonic acid amides with fragments of nitroxyl radicals

Interaction of betulonic acid chloride with 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl, 3-amino-2,2,5,5-tetramethylpyrrolidine-1-oxyl, and 3-aminomethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl yielded the corresponding triterpene amides. The synthesized derivatives of betulonic acid were shown to exhibit a cytotoxic activity on models of the CEM-13, U-937, and MT-4 tumor cells. The concentration of the most active N-[3-oxo-28-norlup-20(29)-en-17-carbamoyl-(2,2,6,6-tetramethylpiperidine-4-yl)-1-oxyl that inhibited survival of the tumor cells by 50% (CCID₅₀) proved to be 5.7–33.1 μM.     

Docking of calcium ions in proteins with flexible side chains and deformable backbones

A method of docking Ca²⁺ ions in proteins with flexible side chains and deformable backbones is proposed. The energy was calculated with the AMBER force field, implicit solvent, and solvent exposure-dependent and distance-dependent dielectric function. Starting structures were generated with Ca²⁺ coordinates and side-chain torsions sampled in 1000 Å³ cubes centered at the experimental Ca²⁺ positions. The energy was Monte Carlo-minimized. The method was tested on fourteen Ca²⁺-binding sites. For twelve Ca²⁺-binding sites the root mean square (RMS) deviation of the apparent global minimum from the experimental structure was below 1.3 and 1.7 Å for Ca²⁺ ions and side-chain heavy atoms, respectively. Energies of multiple local minima correlate with the RMS deviations from the X-ray structures. Two Ca²⁺-binding sites at the surface of proteinase K were not predicted, because of underestimation of Ca²⁺ hydration energy by the implicit-solvent method.     

Potentiometric titration of polyelectrolytes having stiff backbones

The potentiometric titration curves of carboxymethylcellulose, which has a relatively stiff backbone, and also of poly(D -glutamic acid) in the helical region are compared with the theoretical curves calculated assuming that the polyions are rods and have smeared charges on their surfaces. For carboxymethylcellulose good agreement is observed when its charge density is high, whereas as the charge density decreases the calculated curves deviate from the observed ones. The main reason for the disagreement at low charge densities may be attributed to the flexibility of the polymer backbone. For helical poly(D -glutamic acid) satisfactory agreement between calculated and observed curves is found if a radius thicker than the realistic radius is employed. The reason for the excessively large radius may be attributed to the inapplicability of the smeared charge model.