Anti-HIV triterpenes

Licorice root For the triterpene glycyrrhizin (extracted from the licorice root Glycyr-rhiza radix) the mode of anti-HIV action may be attributed at least in part to interference with virus-cell binding. 

Ethanol extract of the fruit peel of G. mangostana showed potent inhibiting activity against HIV-1 protease the compound responsible was isolated and established as mangostin (Chen et al., 1996). Protostane triterpenes, e.g. garciosaterpenes A, B and C, obtained from methanol extracts of bark and stems of G. speciosa, showed anti-HIV-1 activity (Rukachaisirikul et al., 2003c). 

Rukachaisirikul, V., Pailee, P., Hiranrat, A., Tuchinda, P., Yoosook, C., Kasisit, J., Taylor, W.C. and Reutrakul, V. (2003c) Anti-HIV 1 protostane triterpenes and digeranylbenzophenone from trunk bark and stems of Carcinia speciosa. Planta Medica 69(12), 1 141-1 146. 

With nearly 20 years of experience on plant-derived natural products, NPRL has identified numerous active anti-HIV compounds including polycyclic diones, saponins, alkaloids, triterpenes, polyphenols, flavonoids and coumarins. Triterpenes have diverse structures and pharmacological activities. 

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. 

Interestingly, the anti-HIV-1 targets of triterpene analogues can vary depending on the side chain modification positions.21 Some C-28 modified BA analogues are potent HIV entry inhibitors, while some C-3 modified BA derivatives... 

Platanic acid (triterpene) Melaleuca leucadendron, Syzygium claviflorum (Myrtaceae) PKC [anti-HIV]... 

TRITERPENE BETULINIC ACID DERIVATIVES AS ANTI-HIV AGENTS... 

Our group modified the anti-HIV lead compounds BA (182) and dihydrobetulinic acid (186) to produce another series of compounds with substituents at C-3 and a free C-28 carboxylic acid. These 3-0-acyl derivatives (262-275) were obtained by treating the triterpenes with an acid anhydride and DMAP in pyridine or with an acid chloride in pyridine. The anti-HIV activities of active 3-O-acyl derivatives are listed in Table 9-11. Among them, 3-0-(3, 3 -dimethylsuccinyl)-betulinic acid (263, DSB, PA-457) and -dihydrobetulinic acid (268) both demonstrated extremely potent anti-HIV activity in acutely infected H9 lymphocytes, with EC50 values of <0.35 nM, and remarkable TI values of >20,000 and >14,000, respectively. In contrast, 262 and 267, the 2, 2 -dimethyl isomers, showed significantly lower anti-HIV activity. Compounds 264-266, 269, and 270 were 10-100-fold less active than 263 and 268. Compounds without a carboxylic acid in the C-3 side chain... 

Huang, L. Chen, C. H. Molecular targets of anti-HIV-1 triterpenes. Curr. Drug Targets Infect. Disorders, 2002, 2 33-36. 

Bioassay-guided fractionation of an aqueous extract from a Philippine Islands collection of the soft coral Lohophytum spp. yielded cembranoid diterpenes, Fig. (3), which exhibited moderate HIV-inhibitory activity in a cell-based in vitro anti-HIV assay [44], while new isomalabaricane triterpenes. Fig. (4), have been isolated from the sponge Stelletta spp. [45]. Other anti-HIV diterpenes also included the dolabellane diterpenes isolated from the Brazilian brown algae Dictyota pfaffi [46] and Dictyota menstrualis [47]. To investigate the effect of these diterpenes in the reverse transcription of the viral genomic RNA, the recombinant HIV-1 RT was assayed in vitro in the presence of each compound. All compounds inhibited the RNA-dependent DNA-polymerase activity of HIV-1 RT and consequently virus replication. 

In 2005, Kambourakis et al. reported the biocatalytic reduction of a-alkyl-1,3-diketones and a-alkyl-/l-ketoesters by employing isolated NADPH-dependent ketoreductases (KREDs). The corresponding optically pure single keto alcohols and hydroxy esters were obtained in quantitative yields (Scheme 3.9). The same group had previously reported the total synthesis of a new class of triterpene derivatives with anti-HIV activity, statin and statin analogues, based on a diastereoselective reduction of a 2-alkyl-substituted 3-ketoglutarate by a KRED. The results are summarised in Scheme 3.9. 

Quassinoids are degraded triterpenes, reported from the members of the Simarouboidaea subfamily of Simaroubaceae. Legend states that a man named Quassi treated fever using the bitter extracts derived from the bark of these trees and hence named quassin [2]. Quassinoids have received attention due to their antiplasmodial, anticancer, and anti-HIV properties. Its efficacy as combinatorial drug coupled with the structure-activity analysis has reclaimed novel structural leads for new drug development. 

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... 

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... 

Anti-HIV activity has been reported for many triterpenes (e.g., micrandilactones and lancifodilactones) and a few lignans (e.g., rubrisandrins A and B) from different Schisandra species. 

U. tomentosa is a significant traditional medicinal plant that is an important source of monoterpenoid oxindole alkaloids (MOAs) with bioactivities including immunomodulatory, cytotoxic, anti-HIV, and antileukemic activities [100]. It will be of interest to understand biosynthetic insights of bioactive compounds of this plant as an example here. Studies have reported the regulation of biosynthesis of sterols and triterpenes in U. tomentosa [100]. Administration of pectin to U. tomentosa cell suspension cultures increased the activity of isopentyl diphosphate isomerase of ursolic and oleanolic acid. The treated cells also transformed a higher percentage of labeled mevalonic acid precursors into triterpenes and resulted in the decrease in activity of far-nesyl diphosphatase by a factor of two when compared to the control. The... 

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