Synthesis of new betulinic acid–peptide conjugates and in vivo and in silico studies of the influence of peptide moieties on the triterpenoid core activity

Govdi, Anastasia I.; Sokolova, N. V.; Сорокина, И. В.; Baev, Dmitry S.; Толстикова, Т. Г.; Mamatyuk, V. I.; Fadeev, Dmitry S.; Vasilevsky, S. F.; Nenajdenko, Valentine G.

doi:10.1039/c4md00236a

Cited by 28 publications

(19 citation statements)

References 39 publications

(39 reference statements)

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“…Recently, a number of new articles were published on connecting a terpene with another molecule of interest via Huisgen 1,3-cycloaddition reaction. The first approach used terpenes substituted with alkynes in the position 3 [ 30 – 34 ], second approach used propargylesters or amides prepared at 28-COOH group [ 35 – 45 ], and the third approach used 30-azidoderivatives prepared via 30-bromoderivatives [ 46 ; 47 ]. Rarely, also position 2 is modified [ 48 ] or two position at once (3 and 30) in [ 49 ].…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic conjugates of betulinic acid and substituted triazoles prepared by Huisgen Cycloaddition from 30-azidoderivatives

et al. 2017

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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 compounds were tested for their in vitro cytotoxic activities on eight cancer and two non-cancer cell lines. The most active compounds were conjugates of 3β-O-acetylbetulinic acid and among them, conjugate with triazole substituted by benzaldehyde 9b was the best with IC50 of 3.3 μM and therapeutic index of 9.1. Five compounds in this study had IC50 below 10 μM and inhibited DNA and RNA synthesis and caused block in G0/G1 cell cycle phase which is highly similar to actinomycin D. It is unusual that here prepared 3β-O-acetates were more active than compounds with the free 3-OH group and this suggests that this set may have common mechanism of action that is different from the mechanism of action of previously known 3β-O-acetoxybetulinic acid derivatives. Benzaldehyde type conjugate 9b is the best candidate for further drug development.

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Section: Introductionmentioning

confidence: 99%

Cytotoxic conjugates of betulinic acid and substituted triazoles prepared by Huisgen Cycloaddition from 30-azidoderivatives

et al. 2017

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“…[5][6][7][8] So, 3-ethynyl derivatives of betulinic acid with significant cytotoxic and anti-inflammatory activities were obtained. 5,6 Genet et al 7,8 synthesized a series of betulinic acid derivatives substituted at the C(3) atom by, for example, allyl, methylallyl, cyclopropyl, and aryl radicals via reactions with various Grignard reagents. The C(3) modification of triterpenoids by introducing small substituents was found to lead to the formation of selective TGR5 agonists.…”

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confidence: 99%

Synthesis, Cyclization, and Cytotoxic Activity of 2,3-Secolupane Triterpenoids With an Ethylketone Fragment

Konysheva

Ерошенко

Гришко

2019

Natural Product Communications

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3-Ethyl substituted triterpenoids with a fragmented and 5-membered A ring were synthesized from the lupane ketoxime via the Beckmann reaction and intramolecular oxonitrile cyclization, respectively. Transformations of the triterpenic isopropylidene fragment with the formation of C(30) and C(20) modified derivatives were performed by either allylic C(30) oxidation or ozonolytic cleavage of the C(20)-C(29) double bond. Antitumor activity of the synthesized compounds was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,3-diphenyl-tetrazolium bromide test against 7 human cancer cell lines. Methyl 1-cyano-3-ethyl-3-oxo-2,3-seco-2-norlup-20(29)-en-30-al-28-oate (4), methyl 3-[1-bromoethyl]-1-cyano-3-oxo-2,3-seco-2-norlup-20(29)-en-30-al-28-oate (6), and methyl 1-cyano-3-ethyl-2-norlup-1(3),20(29)-dien-30-al-28-oate (9) were selected as compounds with highest cytotoxicity (IC50 1.38-15.91 μM).

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“…Another example of a simple transformation that has been very useful to functionalize BA 1 is alkylation reactions [54,55,56,57]. The obtained C (2)- or C (3)-alkylated compounds were used as important intermediates to prepare more complex ones as shown in the following sections.…”

Section: Simple Transformationsmentioning

confidence: 99%

“…Govdi et al prepared BA derivatives 91a , b bearing an alkyne group at C-3 via the reaction of ethynylmagnesium bromide with BoA 3 (Scheme 16) [54]. This reaction afforded the major diastereomer 91a with the axially oriented alkynyl group, in 82% yield, together with the minor isomer 91b , having the equatorially oriented ethynyl group (11% yield).…”

Section: Simple Transformationsmentioning

confidence: 99%

Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds

et al. 2019

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Betulinic acid (BA) and its natural analogues betulin (BN), betulonic (BoA), and 23-hydroxybetulinic (HBA) acids are lupane-type pentacyclic triterpenoids. They are present in many plants and display important biological activities. This review focuses on the chemical transformations used to functionalize BA/BN/BoA/HBA in order to obtain new derivatives with improved biological activity, covering the period since 2013 to 2018. It is divided by the main chemical transformations reported in the literature, including amination, esterification, alkylation, sulfonation, copper(I)-catalyzed alkyne-azide cycloaddition, palladium-catalyzed cross-coupling, hydroxylation, and aldol condensation reactions. In addition, the synthesis of heterocycle-fused BA/HBA derivatives and polymer‒BA conjugates are also addressed. The new derivatives are mainly used as antitumor agents, but there are other biological applications such as antimalarial activity, drug delivery, bioimaging, among others.

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Synthesis of new betulinic acid–peptide conjugates and in vivo and in silico studies of the influence of peptide moieties on the triterpenoid core activity

Abstract: Betulinic acid–peptide conjugates exhibit high anti-inflammatory activity.

Cited by 28 publications

References 39 publications

Cytotoxic conjugates of betulinic acid and substituted triazoles prepared by Huisgen Cycloaddition from 30-azidoderivatives

Cytotoxic conjugates of betulinic acid and substituted triazoles prepared by Huisgen Cycloaddition from 30-azidoderivatives

Synthesis, Cyclization, and Cytotoxic Activity of 2,3-Secolupane Triterpenoids With an Ethylketone Fragment

Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds

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