Lupanes betulin

The plant is known to produce norbisabolane diterpenes, including phyllanthusols A and B, which are both cytotoxic (36). From the bark, pentacyclic triterpenoids, phyl-lanthol, and olean-12en-3[3-ol (p-amyrin) have been isolated (37). Note lupane- and oleanane-type triterpenoids isolated from the bark of Phyllanthus flexuosus, such as olean-12-en-3 (3,15 a-diol, olean-12-en-3 [3,15 a,24-triol, lupeol, and betulin inhibited the enzymatic activity of topoisomerase II activity with IC50 values in the range of 10 to 39 p.M (38). 

Betulin and lupeol, together with low amounts of lupenone, betulone and betulinic acid, are characteristic of birch bark [87,153 157]. All these compounds are pentacyclic triterpenoids with a lupane skeleton. In addition to triterpenoids, birch bark contains high amounts of a lipid material, called suberin [158]. 

Regert et al. studied [9] a series of 30 Neolithic hafting adhesives from lake dwellings at Chalain (France) using an analytical procedure based on GC/MS analysis involving solvent extraction (dichloromethane) and trimethylsilylation. In the majority of the samples a series of triterpenoid compounds with a lupane structure was clearly identified on the basis of their TMS mass spectra. In particular, the presence of betulin, betulone, lupenone, lupeol and lupa-2,20(29)-dien-28-ol allowed birch bark tar to be identified. In other samples the co-occurrence of other plant biomarkers such as a-amyrin,(3-amyrin... 

Induction of epidermal ODC is a characteristic biochemical alteration elicited by TPA and may be representative of the effects of phorbol esters with strong tumor promoting activity [81]. A single application of TPA (5 pg) resulted in a substantial and transient increase of epidermal ODC activity in mice with a peak at about 4 h after TPA treatment, and the induction was potently inhibited by treatment (5 pM) of the mouse skin with sitosterol (33, 65% inhibition) and three lupane type triterpenoids betulin (255 79%), betulinic acid (257 89%), and lupeol (264,96%) [30]. The inhibitory effect on TPA-induced ODC activity was further reported for ursolic acid (210 45% inhibition at 2.0 pM/5nM of TPA) [31]. 

Betulinic acid (lupane triterpene) Widespread Rhododendron arboreum (Ericaceae) Candida albicans secreted aspartic protease (14 pM) (HIV-1 protease) [36]... 

A variety of plant bioactives inhibit the metallopeptidase aminopeptidase N [63-68], the most potent inhibitors (variously active at 1-7 pM) being the phenolics curcumin, phloretin and quercetin [64-67] and the lupane triterpene betulinic acid (IC5o value 7 pM) [68] (Table 2). 

Betulinic acid (lupane triterpene) Widespread Tovomita krukovii (Clusiaceae), Diospyros perigrina (Ebenaceae) Aminopeptidase N (7 pM) [68]... 

Catalytic hydrogenation of the diene (96), from mercuric acetate oxidation of betulin diacetate, yielded (97) and (98). The latter was further reduced to the 18/3H,19/8-lupane (99).70 Isomerization of betulin diacetate with hydrobromic acid in acetic acid-acetic anhydride afforded (97), instead of the usual products with ring E enlarged.71 Glochidone (100) is readily prepared from lupen-3-one by oxidation with 2,3-dichloro-5,6-dicyanobenzoquinone.72 73... 

Figure 9-10. Structures of lupane triterpenes and betulinic acid derivatives (182-196).

In a similar study of the ozonolysis of betulin diacetate, Vystrcil and Budesinsky obtained inter alia compounds (168), (169), and (170). Continuing their studies of epimerisation at C-19 in the lupane series, these authors have reported the formation of the lactone (171) by acid equilibration of the bisnor-acid (172). Performic acid oxidation of the isopropenyl group in a number of lupene derivatives has been described. Most of the products can be rationalised by assuming the rearrangement of an initially formed epoxide. 

A plant-derived compound with a long history is the lupane-type triterpene, betulinic acid (53), which has been isolated from many taxonomically diverse plant genera. " A major source is the birch tree, Betula spp., which is also a primary source of its C-28 alcohol precursor, betulin, the isolation of which was first reported in 1788. 

Betulin and betulinic acid are the best studied lupanes as antiinflammatory derivatives, and a great deal of research on their activity and mechanism of action has been published (Table 11). While the lupanes are widespread in plants, the occurrence of neolupanes is reduced to a small number of compounds and plants. 

In connection with the work on the relationship between chemical structure and anti-inflammatory activity, the effect of ursolic acid, betulin, betulinic acid and erythrodiol on a system of chronic dermal edema and cellular proliferation caused by repeated administration of TPA has recently been examined [89], This experimental model of chronic inflammation has considerable selectivity for corticosteroids and leukotriene synthesis inhibitors. Erythrodiol and ursolic acid were significantly effective and also reduced the neutrophil infiltration detected by MPO activity. The lupane derivatives, betulin and betulinic acid, despite their possible steroid-like mechanism of action [47], were not effective in the chronic model. This result could mean that a six-member E ring of the pentacyclic structure is necessary for the activity against a multiple dose of TPA. The data confirm that a hydroxyl group at the C-28 position is important for the activity, as is also true in the case of erythrodiol, and it may explain the anti-inflammatory effect of this compound in each of the methods. 

Several papers have appeared which provide further evidence for the course of the mercuric acetate oxidation of lupane derivatives (see Vol. 1, p. 186). The norketolactone (116), derived from the mercuric acetate oxidation product of acetyl betulinic acid, undergoes a ring E-homo rearrangement to (117) on treatment with t-butoxide. 

Lupanes are another example of plant-derived pentacyclic triterpenoids that are represented by friedelin, lupeol and betulin. Several representative family members, for example, ochraceolide A, ochraceolide B, dihydroochraceolide A, betulin and lupeol, were isolated from the mixed... 

The lupane triterpene, betulin (163) showed inhibitory effects on Epstein-Barr virus activation and bacteriostatic activities against Escherichia coli. Salmonella typhi, Shigella flexneri and Staphylococcus aureus. Antitumor activity was reported against human epidermoid... 

Sholichin M, Yamasaki K, Kasai R, Tanaka O (1980) C Nuclear magnetic resonance of lupane-type triterpenes, lupeol, betulin and betulic acid. Chem Pharm Bull 28 1006-1008... 

Betulinic acid (51) and its close structural anolog, betulin (52), are lupane triterpenoids widely distributed in the plant kingdom, with the latter especially abundant in the bark of the white birch tree [133], Betulin can serve as the semi-synthetic precursor of betulinic acid, which is considered biologically more active than betulin. Important biological activities attributed to betulinic acid and its derivatives, are anti-EHV activity and selective cytotoxicity against melanoma cancer cells [133-135]. Betulinic acid can indnce apoptosis by acting on the mitochondria of various tumor cells. This compound is currently under phase I/n clinical trials launched by National Cancer Institute (NCI) as a chemotherapeutic agent for the treatment of dysplastic melanocytic nevi, which are considered associated with cutaneous melanomas [136]. 

Steroids (Cjq) with four Cg q cles and one Cg cycle E, which are derived from the hydrocarbon lupane, are lupeol (3-96) and a product of its oxidation on C-28 known as betulinic acid (3-97). CjQ Steroids also occur with hve Cg cycles. The most important of these compounds are a-amyrin (3-98), derived from the hydrocarbon ursane, and P-amyrin (3-99), which is derived from the... 

Betulin (lup-20(29)-ene-3,28-diol) is an abundant naturally occurring triterpene, and it is found predominantly in bushes and trees forming the principal extractive (up to 30% of dry weight) of the bark of birch trees. Betulin and its derivatives such as betulinic acid have many interesting pharmacological properties, such as cytotoxic activity against many tumour cell lines and anti-HIV activity with a new mechanism of action. Several synthetic betulin derivatives that have been chemically modified at the positions C-3 and C-28 of the lupane skeleton were produced, and the anti-leishmanial inhibition activity of compounds was evaluated at 50 pM against Leishmania donovani and Leishmania tropica. Betulonic acid had the best anti-leishmanial activity with... 

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