Abstract
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.
Highlights
Plants have always played an important role in human health care [1]
We designed a new series of oleanonic (3) and ursonic (4) acids derivatives by the introduction of nitrogen-containing heterocycles to C2, C3, and C28 positions or A-ring skeleton transformation. (3- or 4)-Pyridinylidene and furfurylidene fragments were coupled at the C2-position; the nicotinoyloxy-fragment was introduced at C3-position; Nmethylpiperazinyl, piperazinyl- and morpholinyl-amides were synthesized at the C28position
A series of new oleanane and ursane triterpenic acids and their C28 amides with a modified A-ring was synthesized and screened for cytotoxic activity against the National Cancer Institute (NCI)-60 cancer cell line panel
Summary
Plants have always played an important role in human health care [1]. The discovery of novel bioactive compounds from natural plants is one of the most effective trends in natural product research [2]. Naturally occurring triterpenoids have found direct application as drug entities and play an important role as templates for the design, synthesis, and semi-synthesis of novel substances [3,4] Pentacyclic triterpenoids, such as oleanolic (1) and ursolic (2) acids, contain a biologically active scaffold with a high safety profile in cancer therapy and are suitable to carry out different chemical transformations. Sci. 2021, 22, x FOR PEER REVIEW as several key positions (C2, C3, C12, C13, and C28, Figure 1) This inspires scientists to develop new methods for the chemical modification of the triterpene core, or to use wellknown approaches to expand the effective pharmacological agents amo3nogf 3t3he different types of triterpenoids
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