Betulinic acid structure

Fujioka T, Kashiwada Y, Kilkuskie RE, Cosentino EM, Balias LM, Jiang JB, Janzen WP, Chen IS, Lee K-H. (1994) Anti-AIDS agents, 11. betulinic acid and platanic acid as anti-HIV principles from syzigium claviflorum, and the anti-HIV activity of structurally related triterpenoids. J Nat Prod 57 243-247. 

Several naturally occurring triterpenes have been reported to show anti-HIV activity, e.g. betulinic acid, platanic acid, glycyrrhizin, mimusopic acid, gano-deriol and geumonoid.16 20 These active compounds hold the potential to serve as hits or leads for anti-HIV drug development.21,22 The focus of this chapter is bevirimat, the first in a new class of compounds termed HIV maturation inhibitors (Mis). Our discussion covers modification, structure-activity relationship (SAR), mechanism of action studies and clinical trials of bevirimat. 

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

Figure 9-11. Structures of C-28 substituted betulinic acid derivatives (207 256).

TABLE 9-12. Structures and Activities of Bifunctional Betulinic Acid Derivatives ... 

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. 

Fujioka, T. Kashiwada, Y. Kilkuskie, R.E. Cosentino, L.M. Balias, L.M. Jiang, J.B. Janzen, W.P. Chen, I.S. Lee, K.-H. Anti-AIDS Agenta, 11. Betulinic Acid and Platanic Acid as Anti-HIV Principles from Syzigum claviflorum and The Anti-HIV Activity of Structurally Related Triterpenoids. J. Nat. Prod. 1994, 57, 243-247. 

Wen Z, Stern ST, Martin DE, Lee K-H, Smith PC. Structural characterization of anti-HIV drug candidate PA-457 [3-0-(3, 3 -dimethylsuccinyl)-betulinic acid] and its acyl glucuronides in rat bile and evaluation of in vitro stability in human and animal liver microsomes and plasma. Drug Metab Dispos 2006 34 1436-1442. 

Bringmann G, Saeb W, Assi LA, Francois G, Sankara Narayanan AS, Peters K, Peters EM (1997) Betulinic acid isolation from Triphyophyllum peltatum and Ancistrocladus heyneanus, antimalarial activity, and oystal structure of the benzyl ester. Planta Med... 

The triterpene sapogenins betulinic acid, oleanolic acid and ursolic acid show cytotoxic and anti-inflammatory effects, and based on their structures novel chemopreventive and anticancer agents are being developed (Liby et al., 2007). A derivative of betulinic acid, beviri-mat, is the first member of a new class of anti HIV therapeutics, maturase inhibitors. These... 

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]. 

Incubation of betulinic acid (1) and 23-hydroxybetulinic acid (19) (Figure 28.6) with Nocardia sp. NRRL 5646 afforded their corresponding methyl esters, betulinic acid methyl ester (20), and 23-hydroxybetulinic acid methyl ester (21), respectively [42]. FTowever, microbial transformation of betulonic acid (7) by the same Nocardia sp. NRRL 5646 at a preparative scale [43] resulted in addition in the isolation of an imex-pected a-hydroxylation product, methyl 2a-acetoxy-3-oxo-lup-20(29)-en-28-oate (22) (6.5% yield), beside the expected compoxmd methyl 3-oxo-lup-20(29)-en-28-oate (23) (50% yield). The structures of metabolites were elucidated unambiguously by ESI-MS and 2D NMR spectroscopy. 

Some T. have major physiological significance. Thus, lanosterol is converted biosynthetically to cholesterol, the precursor of all steroid hormones, bile acids, and vitamin D3. In fungi, lanosterol is converted to er-gosterol (see sterols), an essential component of the fungal cell membrane. Plant cell membranes also incorporate steroids (phytosterols). In prokaryotes, the hopanoids take over the functions of steroids in the cell membranes. As a component of animal and plant waxes T. strengthen the structures. They protect the plant surface from desiccation and attack by microorganisms (e.g., betulin, lupeol, oleanolic acid, and ursolic acid). 

Betulin, extracted from birch bark, has been used as a difunctional monomer to undergo polycondensations with acid chlorides, resulting in hyperbranched (networks) or linear polyesters (Scheme 12). The stiff sfructure of betulin and the geometric positioning of the OH groups prevent close packing of polymer chains to yield a microporous structure, making these polycondensates candidates for gas separation membranes [112]. 

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