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Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents
Published on: May 28, 2014
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Hederagenin amide derivatives as potential antiproliferative agents
Diego Rodríguez-Hernández1, Luiz C A Barbosa2, Antonio J Demuner3
1Department of Chemistry, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil.
European Journal of Medicinal Chemistry
|March 7, 2019
Summary
New hederagenin amide derivatives show potent cytotoxic activity against various human cancer cell lines. Acetylated compounds were generally more effective, with derivative 2c showing high potency and selectivity, indicating potential as anticancer agents.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Pharmacology
Background:
- Hederagenin, a natural triterpenoid, serves as a scaffold for developing novel therapeutic agents.
- Cytotoxic agents are crucial in cancer chemotherapy, necessitating the discovery of new compounds with improved efficacy and selectivity.
- Modifications of natural products can lead to enhanced pharmacological properties.
Purpose of the Study:
- To synthesize novel C-28 amide derivatives of hederagenin.
- To evaluate the cytotoxic potential of these derivatives against a panel of human cancer cell lines.
- To investigate the mechanism of cell death induced by the active compounds.
Main Methods:
- Synthesis of hederagenin C-28 amide derivatives with and without acetylation at positions 3 and 23.
- Structural characterization using mass spectrometry (MS), infrared (IR), proton nuclear magnetic resonance (1H NMR), and carbon-13 nuclear magnetic resonance (13C NMR) spectroscopy.
- Cytotoxicity screening using the sulforhodamine B (SRB) assay against six human cancer cell lines.
- Cellular staining and fluorescence microscopy to observe cell death pathways.
- Molecular docking studies to predict potential protein targets.
Main Results:
- The majority of synthesized hederagenin amide derivatives exhibited significant cytotoxic activity.
- Acetylated derivatives (2a-2n) were generally more potent and active than their hydroxylated counterparts (1a-1d).
- Derivative 2c demonstrated the highest potency and selectivity against A2780, FaDu, and SW1736 cell lines (EC50 0.4–1.7 μM, SI 5.6–24).
- Cellular studies indicated membrane permeability and secondary necrosis as modes of cell death.
- Docking analysis suggested a higher affinity of acetylated compounds to HER2 compared to USP7, identifying HER2 as a probable target in A2780 cells.
Conclusions:
- The synthesized C-28 amide derivatives of hederagenin represent a promising class of cytotoxic agents.
- Acetylation of the hederagenin scaffold enhances cytotoxic potency and selectivity.
- Derivative 2c is a potent and selective anticancer candidate, potentially targeting HER2.
- Further investigation into the mechanism of action and in vivo efficacy is warranted.
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The IUPAC and common names of amides are derived from the parent carboxylic acid, by replacing the suffix “oic acid” and “ic acid,” respectively, with “amide.” In the following example, the IUPAC name ethanamide is derived from ethanoic acid, and the common name, acetamide, is obtained from acetic acid.
The IUPAC and common names of amides are derived from the parent carboxylic acid, by replacing the suffix “oic acid” and “ic acid,” respectively, with “amide.” In the following example, the IUPAC name ethanamide is derived from ethanoic acid, and the common name, acetamide, is obtained from acetic acid.
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The DCC-promoted synthesis of amides begins with the protonation of DCC by carboxylic acid. The protonation makes it a better acceptor. Next, the addition of carboxylate to the protonated carbodiimide gives a reactive acylating agent.
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Acid-catalyzed hydrolysis:
Hydrolysis of amides under acidic conditions yields carboxylic acids. Since the reaction occurs slowly, hydrolysis requires the conditions of heat.
The mechanism begins with the protonation of the carbonyl oxygen by the acid catalyst. The protonation makes the amide carbonyl carbon more...
Acid-catalyzed hydrolysis:
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The mechanism begins with the protonation of the carbonyl oxygen by the acid catalyst. The protonation makes the amide carbonyl carbon more...
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Next, the second equivalent of amine serves as a Brønsted base and deprotonates the quaternary...
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Amide reduction requires two equivalents of the reducing agent, acting as a source of hydride ions. As shown in the figure, the reaction is initiated with a nucleophilic attack by the hydride ion at the carbonyl carbon to form a tetrahedral intermediate.
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