Synthesis of 30-Amino Derivatives of Lupane Triterpenoids
Abstract
New derivatives of betulin and betulinic acid containing various amines on C-30 that are of interest as potentially biologically active agents were prepared.
References6
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Current Developments in the Discovery and Design of New Drug Candidates from Plant Natural Product Leads
This review article will emphasize recent research in the Natural Products Laboratory, School of Pharmacy, University of North Carolina at Chapel Hill, on various classes of plant-derived compounds that possess potent antitumor or anti-HIV activity. These compounds were obtained by bioactivity- and mechanism of action-directed isolation and characterization coupled with rational drug design-based modification and analogue synthesis. Structural modification, SAR, and mechanism of action studies a...
Despite the continuous advances made in antiretroviral combination therapy, AIDS has become the leading cause of death in Africa and the fourth worldwide. Today, many research groups are exploring the biodiversity of the plant kingdom to find new and better anti-HIV drugs with novel mechanisms of action. In this review, plant substances showing a promising anti-HIV activity are discussed according to the viral targets with which they interact. Most of these compounds, however, interfere with ear...
: The plant-derived terpenoids and analogues are reviewed with respect to their anti-HIV activity, structure-activity relationships, and mechanism of action. The active compounds include diterpenoid lactones, phenolic diterpenes, atisane and kaurane diterpenes, phorbol diterpenes, triterpene glycosides, friedelane triterpenes, taraxerane triterpenes, ursane triterpenes, lanostane triterpene, lupane triterpenes, seco-ring A triterpenes, degraded triterpenes, and cucurbitacin triterpenes. Positive...
Anti-AIDS agents. 34. Synthesis and structure-activity relationships of betulin derivatives as anti-HIV agents.
Succinyl and 3‘-substituted glutaryl betulin derivatives showed stronger anti-HIV activity and higher therapeutic index (TI) values than their dihydrobetulin counterparts, with ratios of 1.2:1 to 15:1 (cf. 7 and 15, 9 and 17, 10 and 18, 11 and 19, and 12 and 20). For various 3‘-substituted glutaryl compounds, the order of anti-HIV effects, from strong to weak inhibition, was 3‘,3‘-dimethyl, 3‘-methyl, 3‘-ethyl-3‘-methyl, followed by 3‘,3‘-tetramethylene glutaryl derivatives (10 > 9 > 11 > 12, 18...
The triterpene betulinic acid inhibits the activity of aminopeptidase N (EC 3.4.11.2) in a dose-dependent manner. An IC 50 of 7.3 ± 1.4 μM was determined for betulinic acid. This inhibitory activity is higher than that of bestatin (IC 50 = 16.9 ± 4.1 μM), a well known inhibitor of this enzyme. The finding supports the idea that betulinic acid acts as anti-melanoma agent via inhibition of aminopeptidase N activity.
Abstract Neuroblastoma has long been recognized to show spontaneous regression during fetal development and in the majority of stage 4s infants in vitro and in vivo model systems. Melanoma, like neuroblastoma, is derived from the neural crest cell. We hypothesised that neuroblastoma cells have the machinery for programmed cell death and that apoptosis could be induced by betulinic acid. Nine human neuroblastoma cell lines were treated in vitro with BA at concentrations of 0–20μg/ml for 0–6 days....
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α,β-Unsaturated lupane and 19β,28-epoxy-18α-oleanane aldehydes were used in the synthesis of triterpenoids bearing substituted 1,2-azole moieties (1-acetyl-3-methyl-4,5-dihydro-1H-pyrazole and 3-methyl-4,5-dihydroisoxazole) at the rings А and Е. The route of synthesis for these 1,2-azole derivatives of triterpenes included an aldol condensation of α,β-unsaturated aldehydes with acetone, the products of which (α,β-unsaturated methyl ketone and β-hydroxy ketone) underwent a further cycloaddition r...
Abstract Betulin (B) and Betulinic acid (BA) are natural pentacyclic lupane-structure triterpenoids which possess a wide range of pharmacological activities. Recent evidence indicates that B and BA have several properties useful for the treatment of metabolic disorders, infectious diseases, cardiovascular disorders, and neurological disorders. In the current review, we discuss B and BA structures and derivatives and then comprehensively explain their pharmacological effects in relation to variou...
Triphenylphosphonium Analogues of Betulin and Betulinic Acid with Biological Activity: A Comprehensive Review.
Naturally occurring pentacyclic lupane triterpenoids such as betulin (1) or betulinic acid (2) and their synthetic derivatives display a broad spectrum of biological activities and, therefore, have been the subject of great interest. However, the use of these compounds as potential therapeutic agents is limited by their low bioavailability, high hydrophobicity, and insufficient intracellular accumulation. In this context, research on modifications of the parent structures that will improve their...
AbstractA new single-stage synthesis of betulin phenylcarbamates is suggested that uses 1-phenylurea as a reagent for betulin O-carbamoylation. A chemoselectivity of hydroxyl-groups in carbamoylation of betulin with 1-phenylurea appeared to occur. Synthesized nitrogen-containing betulin derivatives – phenylcarbamates are valuable as bioactive substances.
Synthesis of Conjugates of Lupane-Type Pentacyclic Triterpenoids with 2-Aminoethane- and N -Methyl-2-Aminoethanesulfonic Acids. Assessment of in vitro Toxicity
Conjugates of betulin and betulinic and betulonic acids with 2-aminoethane- and N-methyl-2-aminoethanesulfonic acids were synthesized for the first time and were interesting as potential biologically active compounds. Experiments in vitro in MDCK cell culture using the MTT assay found that betulin and betulinic-acid derivatives with aminoethanesulfonic acid bound to triterpene C-3 or C-28 through an ester linker were less toxic than the native compounds.
Cytotoxic conjugates of betulinic acid and substituted triazoles prepared by Huisgen Cycloaddition from 30-azidoderivatives.
: In this work, we describe synthesis of conjugates of betulinic acid with substituted triazoles prepared via Huisgen 1,3-cycloaddition. All compounds contain free 28-COOH group. Allylic bromination of protected betulinic acid by NBS gave corresponding 30-bromoderivatives, their substitution with sodium azides produced 30-azidoderivatives and these azides were subjected to CuI catalysed Huisgen 1,3-cycloaddition to give the final conjugates. Reactions had moderate to high yields. All new compoun...
A series of lupane triterpenoid conjugates with the triphenylphosphonium cation, in which the terpenoid molecules are linked to one or two triphenylphosphonium moieties at the С-2, С-28, or С-30 positions by carbon–carbon or ester bonds, have been designed and synthesized as potential anti-cancer agents. The pharmacological results showed that all of the prepared triphenylphosphonium salts displayed considerable antitumor activities against the tested cancer murine tumor (Ehrlich ascites carcino...
Recent Developments on the Synthesis and Applications of Betulin and Betulinic Acid Derivatives as Therapeutic Agents
Abstract Triterpenes are widely found amongst various natural sources and are derived from squalene or related 30-carbon acyclic congeners. Medicinal plants are an excellent source of pharmaceutical agents, and the renewability of these resources renders further significance and importance to the discovery and development of drugs from natural products. Betulin, betulinic acid, and other analogous triterpenoids related to the lupane, oleanane, and ursane families are secondary plant metabolites ...
Methods for preparing sulfobetaines of betulinic acid that contained N,N-(dimethylammonium)butane-1-sulfonate, a new type of Zwitter-ion in a series of lupane-type pentacyclic triterpenoids, were developed in order to prepare new betulinic acid derivatives and to study the structure–biological-activity relationship.
Synthesis and activity of new triphenylphosphonium derivatives of betulin and betulinic acid against Schistosoma mansoni in vitro and in vivo
We studied the antischistosomal activity of betulin, betulinic acid and its 9 triphenylphosphonium derivatives characterized by a covalently linkage of the hydrophobic fragment of triterpenoid at C(2)- or C(30)-position with the triphenylphosphonium moiety via a hydrocarbon bridge. The triphenylphosphonium salts showed in vitro antischistosomal activity against newly transformed schistosomula (NTS) and adult worms of Schistosoma mansoni at low micromolar concentrations. In contrast betulin and b...