Synthesis and Cytotoxicity of 28-<i>N</i>-Propargylaminoalkylated 2,3-Indolotriterpenic acids

Khusnutdinova, É. F.; Petrova, А. V.; Куковинец, О. С.; Казакова, О. Б.

doi:10.1177/1934578x1801300603

Cited by 13 publications

(10 citation statements)

References 21 publications

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“…The introduction of heterocyclic fragments, especially piperazine, has been demonstrated to enhance anticancer properties [ 31 ]. Recently we have found that modification of triterpenoids to indole derivatives on the A-ring with amidation to C28-amide, as well as the introduction of piperazine or N -methyl-piperazine, have a positive effect on anticancer activity [ 32 , 33 ]. Chalcone derivatives of messagenine and platanic acid [ 25 ], polyamino-lupanes [ 34 ], A-azepano-, and 3-amino-3,4-seco-triterpenoids [ 35 ] were also found to be effective antiproliferative agents against different cancer cell lines with submicromolar concentration values of GI 50 < 1 μM.…”

Section: Introductionmentioning

confidence: 99%

Novel A-Ring Chalcone Derivatives of Oleanolic and Ursolic Amides with Anti-Proliferative Effect Mediated through ROS-Triggered Apoptosis

Khusnutdinova

Petrova

Zileeva

et al. 2021

IJMS

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A series of A-ring modified oleanolic and ursolic acid derivatives including C28 amides (3-oxo-C2-nicotinoylidene/furfurylidene, 3β-hydroxy-C2-nicotinoylidene, 3β-nicotinoyloxy-, 2-cyano-3,4-seco-4(23)-ene, indolo-, lactame and azepane) were synthesized and screened for their cytotoxic activity against the NCI-60 cancer cell line panel. The results of the first assay of thirty-two tested compounds showed that eleven derivatives exhibited cytotoxicity against cancer cells, and six of them were selected for complete dose–response studies. A systematic study of local SARs has been carried out by comparative analysis of potency distributions and similarity relationships among the synthesized compounds using network-like similarity graphs. Among the oleanane type triterpenoids, C2-[4-pyridinylidene]-oleanonic C28-morpholinyl amide exhibited sub-micromolar potencies against 15 different tumor cell lines and revealed particular selectivity for non-small cell lung cancer (HOP-92) with a GI50 value of 0.0347 μM. On the other hand, superior results were observed for C2-[3-pyridinylidene]-ursonic N-methyl-piperazinyl amide 29, which exhibited a broad-spectrum inhibition activity with GI50 < 1 μM against 33 tumor cell lines and <2 μM against all 60 cell lines. This compound has been further evaluated for cell cycle analysis to decipher the mechanism of action. The data indicate that compound 29 could exhibit both cytostatic and cytotoxic activity, depending on the cell line evaluated. The cytostatic activity appears to be determined by induction of the cell cycle arrest at the S (MCF-7, SH-SY5Y cells) or G0/G1 phases (A549 cells), whereas cytotoxicity of the compound against normal cells is nonspecific and arises from apoptosis without significant alterations in cell cycle distribution (HEK293 cells). Our results suggest that the antiproliferative effect of compound 29 is mediated through ROS-triggered apoptosis that involves mitochondrial membrane potential depolarization and caspase activation.

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Section: Introductionmentioning

confidence: 99%

Novel A-Ring Chalcone Derivatives of Oleanolic and Ursolic Amides with Anti-Proliferative Effect Mediated through ROS-Triggered Apoptosis

Khusnutdinova

Petrova

Zileeva

et al. 2021

IJMS

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“…reaction of C-28-propargyl amide or ester derivatives of 2,3-indolo-triterpenic acid possess the anticancer activity [16,17].…”

Section: Resultsmentioning

confidence: 99%

“…For example, in the last decade one of the priority topics in the chemistry of triterpenoids is the synthesis of various alkynyl derivatives with subsequent modification by click-chemistry to produce biologically active compounds bearing a 1,2,3-triazolyl fragment [14,15]. The conjugates obtained by click or Mannich reaction of C-28-propargyl amide or ester derivatives of 2,3-indolo-triterpenic acid possess the anticancer activity [16,17].…”

Section: Introductionmentioning

confidence: 99%

N-Propargylation of Indolo-Triterpenoids and Their Application in Mannich Reaction

Khusnutdinova

Petrova

Bashirova

et al. 2019

Molbank

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“…Compounds 2,3-indolouvaol (51) and 2,3-indolo-28-cyanoethoxybetulin (53) showed potential in vitro antitumor activity against NCI-H522 and COLO 205 cells, inducing the death of 12.65% and 42.78% of these cells, respectively [93]. Khusnutdinova et al [94] attempted the modification of the carboxyl group of [3,2b]indolotriterpenic acids (N-propargylation, Cu(I) catalyzed Mannich reaction) with Nmethylpiperazine and morpholine moiety. Among the modified compounds, oleananetype conjugate with N-methylpiperazine 56 (Figure 5) displayed the highest anticancer potency against leukemia cell line SR (−2.2%) and nonsmall cell lung cancer cell line NCI-H460 (−25.3%).…”

Section: Indolementioning

confidence: 99%

“…Khusnutdinova et al [ 94 ] attempted the modification of the carboxyl group of [3,2b]-indolotriterpenic acids (N-propargylation, Cu(I) catalyzed Mannich reaction) with N-methylpiperazine and morpholine moiety. Among the modified compounds, oleanane-type conjugate with N-methylpiperazine 56 ( Figure 5 ) displayed the highest anticancer potency against leukemia cell line SR (‒2.2%) and nonsmall cell lung cancer cell line NCI-H460 (‒25.3%).…”

Section: Indolementioning

confidence: 99%

Pentacyclic Triterpenoids with Nitrogen-Containing Heterocyclic Moiety, Privileged Hybrids in Anticancer Drug Discovery

et al. 2021

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Pentacyclic triterpenoids are well-known phytochemicals with various biological activities commonly found in plants as secondary metabolites. The wide range of biological activities exhibited by triterpenoids has made them the most valuable sources of pharmacological agents. A number of novel triterpenoid derivatives with many skeletal modifications have been developed. The most important modifications are the formation of analogues or derivatives with nitrogen-containing heterocyclic scaffolds. The derivatives with nitrogen-containing heterocyclic compounds are among the most promising candidate for the development of novel therapeutic drugs. About 75% of FDA-approved drugs are nitrogen-containing heterocyclic moieties. The unique properties of heterocyclic compounds have encouraged many researchers to develop new triterpenoid analogous with pharmacological activities. In this review, we discuss recent advances of nitrogen-containing heterocyclic triterpenoids as potential therapeutic agents. This comprehensive review will assist medicinal chemists to understand new strategies that can result in the development of compounds with potential therapeutic efficacy.

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Synthesis and Cytotoxicity of 28-N-Propargylaminoalkylated 2,3-Indolotriterpenic acids

Cited by 13 publications

References 21 publications

Novel A-Ring Chalcone Derivatives of Oleanolic and Ursolic Amides with Anti-Proliferative Effect Mediated through ROS-Triggered Apoptosis

Novel A-Ring Chalcone Derivatives of Oleanolic and Ursolic Amides with Anti-Proliferative Effect Mediated through ROS-Triggered Apoptosis

N-Propargylation of Indolo-Triterpenoids and Their Application in Mannich Reaction

Pentacyclic Triterpenoids with Nitrogen-Containing Heterocyclic Moiety, Privileged Hybrids in Anticancer Drug Discovery

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