Cytotoxic Potential of a-Azepano- and 3-Amino-3,4-SeCo-Triterpenoids

Abstract

Semi-synthetic triterpenoids, holding an amino substituted seven-membered A-ring (azepano-ring), which could be synthesized from triterpenic oximes through a Beckmann type rearrangement followed by a reduction of lactame fragment, are considered to be novel promising agents exhibiting anti-microbial, alpha-glucosidase, and butyrylcholinesterase inhibitory activities. In this study, in an attempt to develop new antitumor candidates, a series of A-ring azepano- and 3-amino-3,4-seco-derivatives of betulin, oleanolic, ursolic, and glycyrrhetinic acids were evaluated for their cytotoxic activity against five human cancer cell lines and non-malignant mouse fibroblasts by means of a colorimetric sulforhodamine assay. Azepanoallobetulinic acid amide derivative 11 was the most cytotoxic compound of this series but showed little selectivity between the different human tumor cell lines. Flow cytometry experiments showed compound 11 to act mainly by apoptosis (44.3%) and late apoptosis (21.4%). The compounds were further screened at the National Cancer Institute towards a panel of 60 cancer cell lines. It was found that compounds 3, 4, 7, 8, 9, 11, 15, 16, 19, and 20 showed growth inhibitory (GI50) against the most sensitive cell lines at submicromolar concentrations (0.20–0.94 μM), and their cytotoxic activity (LC50) was also high (1–6 μM). Derivatives 3, 8, 11, 15, and 16 demonstrated a certain selectivity profile at GI50 level from 5.16 to 9.56 towards K-562, CCRF-CEM, HL-60(TB), and RPMI-8226 (Leukemia), HT29 (Colon cancer), and OVCAR-4 (Ovarian cancer) cell lines. Selectivity indexes of azepanoerythrodiol 3 at TGI level ranged from 5.93 (CNS cancer cell lines SF-539, SNB-19 and SNB-75) to 14.89 for HCT-116 (colon cancer) with SI 9.56 at GI50 level for the leukemia cell line K-562. The present study highlighted the importance of A-azepano-ring in the triterpenic core for the development of novel antitumor agents, and a future aim to increase the selectivity profile will thus lie in the area of modifications of azepano-triterpenic acids at their carboxyl group.

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

“…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.…”

Synthesis and evaluation of diterpenic Mannich bases as antiviral agents against influenza A and SARS-CoV-2

“…Natural terpenoids and their synthetic analogs are a promising source of new drugs for treating various diseases. These compounds are characterized by a massive variety of molecular structures, low toxicity, and the ability to affect several specific targets inside cells, which determines a wide range of their biological activity, including anti-inflammatory, antitumor, and antiviral properties ( Paduch and Kandefer-Szerszen, 2014 , Rodriguez-Rodriguez, 2015 , Kazakova et al, 2021 , Chen et al, 2022 ).…”

Synthesis and Structural Characterization of a New 1,2,3-Triazole Derivative of Pentacyclic Triterpene

“…The different biological activities of pentacyclic triterpenoids may be due to the presence of following functional groups: ketone, ester, amino, oxime, sulfonate, and alkyne attached to the lupane skeleton. Unfortunately, the use of betulin as a potential therapeutic substance is limited by its poor solubility in water and low bioavailability [1,[3][4][5][6][7][8][9][10][11][12].…”