ABSTRACT
A series of new glycyrrhetinic acid derivatives was synthesized via the opening of its ring A along with the coupling of an amino acid. The antiproliferative activity of the derivatives was evaluated against a panel of nine human cancer cell lines. Compound 17 was the most active compound, with an IC50 of 6.1 µM on Jurkat cells, which is 17-fold more potent than that of glycyrrhetinic acid, and was up to 10 times more selective toward that cancer cell line. Further biological investigation in Jurkat cells showed that the antiproliferative activity of compound 17 was due to cell cycle arrest at the S phase and induction of apoptosis.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Glycyrrhetinic Acid/chemical synthesis , Glycyrrhetinic Acid/pharmacology , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Glycyrrhetinic Acid/analogs & derivatives , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
A new series of glycyrrhetinic acid derivatives has been synthesized via the introduction of different heterocyclic rings conjugated with an α,ß-unsaturated ketone in its ring A. These new compounds were screened for their antiproliferative activity in a panel of nine human cancer cell lines. Compound 10 was the most active derivative, with an IC50 of 1.1 µM on Jurkat cells, which is 96-fold more potent than that of glycyrrhetinic acid, and was 4-fold more selective toward that cancer cell line. Further biological studies performed in Jurkat cells showed that compound 10 is a potent inducer of apoptosis that activates both the intrinsic and extrinsic pathways.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Survival/drug effects , Glycyrrhetinic Acid/chemical synthesis , Glycyrrhetinic Acid/pharmacology , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Chemistry Techniques, Synthetic , Glycyrrhetinic Acid/analogs & derivatives , Glycyrrhetinic Acid/chemistry , Humans , Molecular StructureABSTRACT
Natural pentacyclic triterpenoids (PTs) have been often reported to exhibit a wide range of biological activities. Among them, the anticancer and anti-inflammatory activities are the most studied. Over the last two decades, the number of publications reporting the anticancer effects of PTs has risen exponentially, reflecting the increasing interest in these natural products for the development of new antineoplastic drugs. Among of the most investigated PTs regarding their anticancer properties are oleanane-, ursane and friedelane-types, including oleanolic, glycyrrhetinic, ursolic and asiatic acids, and celastrol, among others. The extensive research in this field shows that the anticancer effects of PTs are mediated by several mechanisms, as they modulate a diverse range of molecular targets and signaling pathways, involved in cancer cell proliferation and survival. Considering the anticancer potential of this class of compounds, a number of semisynthetic derivatives has been synthetized aiming to improve their therapeutic activity and pharmacokinetic properties, and decrease their toxicity. Some of these new semisynthetic derivatives have shown improved anticancer activity in various cancer cell lines and animal models compared with the parent compound. Moreover, some of these compounds have been assessed in clinical trials, proving to be safe for human use. This review updates the most recent findings on the semisynthetic derivatives of oleanane-, ursane- and quinone methide friedelane-type PTs with anticancer activity. A brief introduction concerning the PTs and their anticancer activity is given, and the main semisynthetic modifications that have been performed between 2012 and early 2017 are reviewed and discussed.
