Betulinic Acid Derivatives:  A New Class of Human Immunodeficiency Virus Type 1 Specific Inhibitors with a New Mode of Action

Abstract

A series of omega-undecanoic amides of lup-20(29)-en-28-oic acid derivatives were synthesized and evaluated for activity in CEM 4 and MT-4 cell cultures against human immunodeficiency virus type 1 (HIV-1) strain IIIB/LAI. The potent HIV inhibitors which emerged, compounds 5a, 16a, and 17b, were all derivatives of betulinic acid (3beta-hydroxylup-20(29)-en-28-oic acid). No activity was found against HIV-2 strain ROD. Compound 5a showed no inhibition of HIV-1 reverse transcriptase activity with poly(C).oligo(dG) as template/primer, nor did it inhibit HIV-1 protease. Additional mechanistic studies revealed that this class of compounds interfere with HIV-1 entry in the cells at a postbinding step.

Biotransformation of the Antimelanoma Agent Betulinic Acid by Bacillus megaterium ATCC 13368

“…1), 3␤-hydroxy-lup-20(29)-en-28-oic acid, is a pentacyclic lupane type of triterpene that is widely distributed in the plant kingdom (8,19). Betulinic acid has been shown to exhibit a variety of biological activities, including inhibition of human immunodeficiency virus (HIV) replication in H9 lymphocyte cells (11), blockage of HIV type 1 entry into cells (20), and inhibition of DNA polymerase ␤ (18). Synthetic derivatives of betulinic acid have also been investigated as specific inhibitors of HIV type 1 (11)(12)(13).…”

“…Betulinic acid has been shown to exhibit a variety of biological activities, including inhibition of human immunodeficiency virus (HIV) replication in H9 lymphocyte cells (11), blockage of HIV type 1 entry into cells (20), and inhibition of DNA polymerase ␤ (18). Synthetic derivatives of betulinic acid have also been investigated as specific inhibitors of HIV type 1 (11)(12)(13). In addition, betulinic acid has been reported to be a melanomaspecific cytotoxic agent in both in vitro cell culture and in vivo studies (24).…”

Natural Product‐Like Combinatorial Libraries

“…5,2003 An identical approach was followed for the preparation of combinatorial libraries from ursolic acid and betulinic acid, two pentacyclic triterpenes which have been the subject of numerous biological investigations. [141][142][143][144][145] The triterpene scaffold (110) was immobilized onto a prederivatized amino acid 2-chlorotrityyl or Sieber amide resins, and then treated with a variety of aliphatic, aromatic and amino acids, to generate a library of C-3 and C-28 derivatives (111) (Figure 37). 146 In another series of diversity, the C-3 oxime esters 112 were prepared from the immobilized triterpenoid keto scaffolds 113.…”

“…160 Using IRORI radiofrequency tagging and MacroKans, trichloroacetimidates of D-glucose, D-xylose and L-rhamnose (146) were coupled onto three types of phenol-containing scaffolds (145), to afford selectively the β-glycosides 147, which, after deacetylation and cleavage from the resin, gave the chromene glycoside plus eight analogues 148 ( Figure 41). 151 In alternative to the radiofrequency tagging, the authors introduced the IRORI NanoKan optical encoding system for the high-throughput nonchemical tagging and sorting of library members during split-and- pool synthesis.…”

Contribution à la synthèse de dérivés de l acide bétulinique à partir du bétulinol extrait de l écorce du bouleau blanc (Betula papyrifera)

“…Suite à une étude plus approfondie, l'acide bétulinique (3) a été identifié comme étant l'un des principes actifs de l'extrait. D'autres chercheurs, déjà au courant de cette activité, ont préparé des dérivés d'acide bétulinique (3) afin d'en bonifier l'activité Evers, M. et al;. Cependant, cette équipe n'a jamais réussi à surpasser les résultats obtenus avec l'acide 3-O-(3',3'-dimethylsuccinyl)-bétulinique (6) .…”