Synthesis and Anticancer Activity of Indole-Functionalized Derivatives of Betulin

Abstract

Pentacyclic triterpenes, including betulin, are widespread natural products with various pharmacological effects. These compounds are the starting material for the synthesis of substances with promising anticancer activity. The chemical modification of the betulin scaffold that was carried out as part of the research consisted of introducing the indole moiety at the C-28 position. The synthesized new 28-indole-betulin derivatives were evaluated for anticancer activity against seven human cancer lines (A549, MDA-MB-231, MCF-7, DLD-1, HT-29, A375, and C32). It was observed that MCF-7 breast cancer cells were most sensitive to the action of the 28-indole-betulin derivatives. The study shows that the lup-20(29)-ene-3-ol-28-yl 2-(1H-indol-3-yl)acetate caused the MCF-7 cells to arrest in the G1 phase, preventing the cells from entering the S phase. The performed cytometric analysis of DNA fragmentation indicates that the mechanism of EB355A action on the MCF-7 cell line is related to the induction of apoptosis. An in silico ADMET profile analysis of EB355A and EB365 showed that both compounds are bioactive molecules characterized by good intestinal absorption. In addition, the in silico studies indicate that the 28-indole-betulin derivatives are substances of relatively low toxicity.

The anti‐breast cancer potential of indole/isatin hybrids

“…Indole-betulin hybrid EB355A (11, half maximal effective concentration/EC 50 : 67 µM) displayed modest efficacy against MCF-7 cancer cells, while betulin displayed no activity (EC 50 : >226 µM), implying that the activity was improved by decorating the botulin with indole at position C-26. [39] Further SARs study demonstrated that (1) esterification of the C-3 positional hydroxyl group of botulin decreased the activity [39] ; (2) EB367 (12, IC 50 :…”

“…Indole‐betulin hybrid EB355A ( 11 , half maximal effective concentration/EC 50 : 67 µM) displayed modest efficacy against MCF‐7 cancer cells, while betulin displayed no activity (EC 50 : >226 µM), implying that the activity was improved by decorating the botulin with indole at position C‐26. [ 39 ] Further SARs study demonstrated that (1) esterification of the C‐3 positional hydroxyl group of botulin decreased the activity [ 39 ] ; (2) EB367 ( 12 , IC 50 : 35 µM) demonstrated greater activity against MCF‐7 cancer cells, indicating that moving the indole fragment from the C‐28 to the C‐3 position of the botulin backbone might somewhat boost up activity. [ 40 ] Mechanistically, MCF‐7 cells might be stopped in the G1 phase by EB355A, which also causes apoptotic cell death.…”

Synthesis, Pharmacological Properties, and Potential Molecular Mechanisms of Antitumor Activity of Betulin and Its Derivatives in Gastrointestinal Cancers

“…In the acylation of betulin 1 and 3-acetyl betulin 3a with indolyl acetic acid, derivatives were formed, combining two pharmacophoric fragments in their structure: the betulin skeleton and the heterocyclic indole system, compounds 5a and 5b , respectively ( Figure 8 ) [ 71 ].…”

“…Anhydrous dichloromethane was used as the solvent. The cytotoxic activity of the obtained derivatives 5a and 5b was tested on human colorectal adenocarcinoma cells HT-29 and DLD-1 [ 71 ].…”

Steglich esterification: A versatile synthetic approach toward the synthesis of natural products, their analogues/derivatives

“…Fig. 1 contains the structures and biological significance of some important natural compounds and derivatives of natural compounds ((−)-Herdmanine D 1 , Gallinamide A 2 , Betulin derivative 3 , Leoligin 4 ) [ [19] , [20] , [21] , [22] ].

Fig.

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