N. I. Uvarova

Synthesis of steroid and triterpenoid glycosides by the orthoester method

Abstract Lanosteryl D -glucopyranoside, as well as the D -glucopyranosides and maltosides of β-sitosterol, cholesterol, and 16-dehydropregnenolone have been synthesized by means of the orthoester glycosylation method. For the first time, six betulin glycosides have been prepared, including the di-glucoside and di-maltoside. Ethyl and tert -butyl orthoacetate derivatives of D -glucose and the methyl orthoacetate of maltose were the glycosylation components. The formation of considerable amounts of acetates and ethers of the alcohols accompanied glycosylation.

Synthesis of Glycosides of Lupane-Type Triterpene Acids

A preparative synthesis of glucosides of the lupane-type triterpene acids betulinic, dihydrobetulinic, betulonic, dihydrobetulonic, and 3,20-dioxo-30-norlupan-28-oic was proposed. Glycosylation of 3-hydroxyacids by α-acetobromoglucose (ABG) with Ag2O was performed in pyridine (Py)to formglycosides at C-28, repeated glycosylation of which by these same reagents but in CH2Cl2 generated a glycoside bond at C-3 to form bisglucosides. 28-Glucosides of ketoacids were formed in high yields in both Py and CH2Cl2.

Synthesis of ginsenoside Rg3, a minor constituent of Ginseng Radix

Glycosylation of 12beta-acetoxy-dammar-24-en-3beta,20(S)-diol (4), with hepta-O-acetyl-alpha-sophorosyl bromide (5) under catalysis by Ag2CO3 or Ag2O afforded a chromatographically unseparated mixture of the alpha- and beta-linked octaacetates 6 and 7 in an approximately 2.5:1 ratio. After deprotection and chromatographic purification, the free alpha- (8) and beta-glycosides (9) were obtained. Sophoroside 9 was identical in all respects with ginsenoside Rg3, the minor component of Ginseng Radix rubra. All compounds were fully characterized by 1H and 13C NMR spectroscopy.

SIMPLIFIED PREPARATION OF THE GINSENOSIDE-RH2 MINOR SAPONIN FROM GINSENG

Abstract Condensation of the 12- O -acetylderivative of 20(S)-protopanaxadiol [dammar-24-ene-3β,12β,20(S)-triol] with tetra- O -acetyl-α- d -glucopyranosyl bromide in the presence of silver oxide in dichloroethane, followed by deprotection with sodium methoxide in methanol, results in formation of the 3- O -β- d -glucopyranosyldammar-24-ene-3β,12β,20(S)-triol identical with natural ginsenoside-Rh 2 . The 12- O -acetyl-20(S)-protopanaxadiol is easily prepared from betulafolienetriol via the 3-keto-12- O -acetylderivative followed by NaBH 4 reduction. This comparatively simple five-step synthesis makes this hitherto rare ginsenoside relatively accessible.

The Antimetastatic and Immunomodulating Activities of Ginseng Minor Glycosides

Metastasizing of malignant tumors is a multistage process, pathogenetic mechanism of which is insufficiently studied. Chemotherapeutic suppression of tumor metastasizing is neither effective nor reliable. For this reason, the search and design of antimetastatic agents remain a topical problem. In the gastrointestinal tract, bacterial enzymes catalyze the transformation of triterpene glycosides (components of the extract from the roots of ginseng Panax ginseng C.A. Meyer) into biologically active compounds. These compounds exhibit antitumor and antimetastatic activities in vivo , induce apoptosis of different tumor cell cultures, and suppress their invasion and migration in vitro [1–4]. Pharmacokinetic studies of one of the major ginseng glycosides, ginsenoside Rb 1 , and its metabolite M1 (20-Oβ D -glucopyranoside of 20(S)-protopanaxadiol) (2) showed that ginsenoside Rb 1 was not detected in blood plasma for 24 h, whereas the level of its metabolite M1 in plasma reached the peak within 8 h ( 8.5 ± 0.4 μ g/ml). When M1 was administered per os , its content in plasma was already maximum within 2 h ( 10.3 ± 1.0 μ g/ml) [4]. In this work, we studied the antimetastatic and immunomodulating activities of four minor ginseng glycosides (1)–(4), which are the most probable metabolites of the major ginseng glycosides 20(S)-protopanaxadiol, 20(S)-protopanaxatriol, and oleanolic acid. Glycosides (1) and (2) were obtained by chemical transformation of betulafolienetriol [5], a component of birch leaves. Glycosides (3) and (4) were isolated from the roots of P. ginseng [6]. Their chemical structures are shown in Fig. 1. Experimental lung metastases were induced in nonpurebred albino mice by injecting 0.1 ml of Ehrlich carcinoma tumor cells (diluted with saline to 5 × 10 7 cells per ml) into the lateral caudal vein. Preliminary experiments showed that optimal therapeutic doses of active glycosides fell within the range of 10–50 mg/kg. The chemicals were administered per os for five days 24 h after tumor inoculation. Twenty days later, the mice were euthanized, and their lungs were placed into the fixing solution. The frequency of metastasizing (percentage of animals with metastases in the group), average number of metastases per animal, and metastasis suppression index (MSI) served as criteria of the antimetastatic activities of the chemicals.

Glycosylation of triterpene alcohols of the lupane series

The glycosylation of lupeol, allobetulin, 3β-28-dihydroxy-18-lupene, 3β-28-dihydroxy-18β, 19β-epoxylupane and of betulin monoacetates in acetonitrile with mercury cyanide has been studied. The 3- and 28-mono- and the 3,28-di-O-β-D-glucopyranosides of 3β-28-dihydroxy-18-lupene and of 3β-28-dihydroxy-18β, 19β-epoxylupane have been synthesized for the first time. Preparative methods for the synthesis of glucosides of lupeol, of allobetulin, and of betulin 3- and 28-monoacetates are proposed.

A new triterpene from the leaves ofBetula mandschurica

A new triterpene (I) has been isolated from the unsaponifiable fraction of an ethereal extract of the leaves ofBetula mandschurica to which, on the basis of the results of a physicochemical investigation and a comparison of the13C spectra with the spectra of known triterpenes — ocotillone (II) and 20(S)-hydroxydammar-24-en-3-one (III) — the structure of 20(S),24(S)-dihydroxydammar-25-3n-3-one has been assigned. An approach to the determination of the configuration of the asymmetric center at C24 in 24-hydroxy derivatives of tetracyclic triterpenoids with an open side chain by the use of13C NMR spectroscopy is proposed.

Glycosylation of betulin and its acetates in the presence of cadmium carbonate

The glycosylation of betulin and its acetates by α-acetobromoglucose in toluene in the presence of cadmium carbonate is considered. It has been shown that the reaction is accompanied by Wagner-Meerwein rearrangements of the initial alcohols in rings A and E. This leads to the formation — in addition to acetates of betulin glycosides — of derivatives of allobetulin — A-nor-Δ3(5)-allobetulin and A-nor-Δ3(5)-betulin — as was shown by1H and13C NMR spectroscopy.

Ruthenium tetroxide oxidation of 3β-acetoxy-28-hydroxy-18-lupene to tricyclic products

Abstract By gradual addition 3β-acetoxy-28-hydroxy-18-lupene with stirring at ∼50°C EtOAc-H 2 O biphase system, containing F 3 CCOOH and RuO 4 , regenerated in situ from RuO 2 ·xH 2 O and NaIO 4 , satisfactory yields of 3β-acetoxy-28-nor-17,18;18,19-disecolupan-17,19-dion-18-oic acid and 3β-acetoxy-19,20,21,22,28,29,30-heptanor-17,18-secolupan-17,18-dioic acid were obtained.

Retro-michael reaction of 28-methoxy-18,19-secolupane-18,19-dione derivatives

The interactions with KOH in boiling diethyleneglycol of 3β,28-dimethoxy- and 3β-acetoxy-28-methoxy-18,19-secolupane-18,19-diones have been studied. In the first case, 3β-methoxy-19,20,21,22,29,30-hexanor-18,19-seco(17βH)lupan-18-one and the corresponding 18-ol were isolated from the mixture of products, and in the second case 3β-hydroxy-19,20,21,22,29,30-hexanor-18,19-seco(17βH)lupan-18-one — which was also obtained by an analogous reaction from 3β-acetoxy-18,19-secolupan-18,19-dione — and 3β-hydroxy-19,20,21,22,28,29,30-heptanor-18,19-secolupan-18-one. Thus, it has been found that in this case the retro-Michael reaction is accompanied by 28-demethoxylation and partially by 28-demethoxy-methylation.