Synthesis of novel mannopyranosyl betulinic acid phosphoniohexyl ester

Tsepaeva, O. V.; Nemtarev, A. V.; Kundina, Alexandra V.; Grigor’eva, Leysan R.; Миронов, В. Ф.

doi:10.1016/j.mencom.2021.01.034

Cited by 3 publications

(5 citation statements)

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“…Most existing techniques for such a purpose are based on the use of alkaline agents in a suitable solvent. Deprotection by NaOH in THF/H 2 O/MeOH mixed solvent led to the formation of different products including those lacking a phosphorus group . The use of the K 2 CO 3 /MeOH system allowed us to avoid side reactions and to obtain compounds 5a – c with 65–80% yields (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

“…Previously, optimized synthesis conditions for (4-(2,3,4,6-tetra- O -benzoyl-α- d -mannopyranos-1-yloxybutyl)triphenylphosphonium bromide were utilized to synthesize (6-(3-glycos-1-yloxy-28-oxolup-20(29)-en-28-yloxy)hexyl)triphenylphosphonium bromides 2 (Scheme ) containing fragments of d -glucopyranose, l -rhamnopyranose, and d -mannopyranose at the C-3 position. The choice of monosaccharide moiety was based on existing data on naturally occurring and semisynthetic triterpene glycosides. ,,− ,,, …”

Section: Resultsmentioning

confidence: 99%

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Bifunctionalized Betulinic Acid Conjugates with C-3-Monodesmoside and C-28-Triphenylphosphonium Moieties with Increased Cancer Cell Targetability

Tsepaeva,

Salikhova,

Ishkaeva

et al. 2023

J. Nat. Prod.

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A convenient synthesis is presented for a new class of bioactive bifunctionalized conjugates of lupane-type triterpenoids with triphenylphosphonium (TPP) and glycopyranosyl targeting moieties. The main synthesis steps include glycosylation of haloalkyl esters of the triterpene acid at the C-3 position by the imidate derivatives of glycopyranose followed by the product modification at the C-28 position with triphenylphosphine. The conjugates of betulinic acid (BetA) with TPP and d-glucose, l-rhamnose, or d-mannose moieties were thus synthesized as potential next-generation BetA-derived anticancer compounds. LC-MS/MS analysis in glucose-free physiological solution indicated that the glycosides showed better accumulation in PC-3 prostate cancer cells than both BetA and TPP–BetA conjugate, while the transporting effect of monosaccharide residues increased as follows: d-mannose < l-rhamnose ≈ d-glucose. At saturated concentrations, the glycosides caused a disturbing effect on mitochondria with a more drastic drop in transmembrane potential but weaker overproduction of mitochondrial reactive oxygen species (ROS) compared to TPP–BetA conjugate. Cytotoxicity of the glycosides in culture medium was comparable with or higher than that of the nonglycosylated conjugate, depending on the cancer cell line, whereas the compounds were less active toward primary fibroblasts. Glycosylation tended to increase pro-apoptotic and decrease pro-autophagic activities of the BetA derivatives. Cytotoxicity of the synthesized glycosides was considered in comparison with the summarized data on the natural and modified BetA glycosides. The results obtained are important for the development of bifunctionalized conjugates of triterpenoids with an increased cancer cell targetability.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Bifunctionalized Betulinic Acid Conjugates with C-3-Monodesmoside and C-28-Triphenylphosphonium Moieties with Increased Cancer Cell Targetability

Tsepaeva,

Salikhova,

Ishkaeva

et al. 2023

J. Nat. Prod.

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“…Russian authors [ 75 ] synthesized an interesting mannopyranosyl derivative of betulinic acid, decorated by a phosphoniohexyl group that formed an ester at the C(17)-COOH group. The conjugation of betulinic acid ( 1c ) or its saponine derivative with vector fragments, lipophilic delocalized cations, e.g., triphenylphosphonium salt, can provide targeted delivery of the drug agent to the required organs or tissues, and/or selective interaction with a certain type of transformed cells.…”

Section: Triterpenoids With the Lupane Skeletonmentioning

confidence: 99%

“…This approach achieved an increase in the concentration of the active agent in the mitochondrial matrix by more than 1000 times [ 76 ]. The inclusion of a phosphonium fragment into the structure of betulinic acid-based mannopyranoside saponin ( 17 ; Figure 17 ) led to a significant increase in the cytotoxicity of the target compound 17 in human cancer cell lines, in comparison with the parent betulinic acid ( 1c ; Figure 1 ) [ 75 , 76 ]. Moreover, it was shown in Canada that decorating the C(3)-OH group of betulinic acid ( 1c ) with the d -mannopyranoside or l -rhamnopyranoside units led to a substantial enhancement of cytotoxicity in the respective triterpenoid saponins in comparison with the parent betulinic acid ( 1c ) [ 77 ].…”

Section: Triterpenoids With the Lupane Skeletonmentioning

confidence: 99%

“…Moreover, it was shown in Canada that decorating the C(3)-OH group of betulinic acid ( 1c ) with the d -mannopyranoside or l -rhamnopyranoside units led to a substantial enhancement of cytotoxicity in the respective triterpenoid saponins in comparison with the parent betulinic acid ( 1c ) [ 77 ]. Finally, the Russian authors combined both structural motifs into a single structure 17 , in which they used the α-linked d -mannopyranoside unit to produce saponin, and synthesized a highly cytotoxic compound 17 [ 75 ].…”

Section: Triterpenoids With the Lupane Skeletonmentioning

confidence: 99%

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Saponins of Selected Triterpenoids as Potential Therapeutic Agents: A Review

2023

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Saponins represent important natural derivatives of plant triterpenoids that are secondary plant metabolites. Saponins, also named glycoconjugates, are available both as natural and synthetic products. This review is focused on saponins of the oleanane, ursane, and lupane types of triterpenoids that include several plant triterpenoids displaying various important pharmacological effects. Additional convenient structural modifications of naturally-occurring plant products often result in enhancing the pharmacological effects of the parent natural structures. This is an important objective for all semisynthetic modifications of the reviewed plant products, and it is included in this review paper as well. The period covered by this review (2019–2022) is relatively short, mainly due to the existence of previously published review papers in recent years.

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