Synthesis of lantadene analogs with marked in vitro inhibition of lung adenocarcinoma and TNF-α induced nuclear factor-kappa B (NF-κB) activation.

Abstract

The new series of pentacyclic triterpenoids reduced lantadene A (3), B (4), and 22β-hydroxy-3-oxo-olean-12-en-28-oic acid (5) analogs were synthesized and tested in vitro for their NF-κB and IKKβ inhibitory potencies and cytotoxicity against A549 lung cancer cells. The lead analog (11) showed sub-micromolar activity against TNF-α induced activation of NF-κB and exhibited inhibition of IKKβ in a single-digit micromolar dose. At the same time, 11 showed promising cytotoxicity against A549 lung cancer cells with IC50 of 0.98 μM. The Western blot analysis further showed that the suppression of NF-κB activity by the lead analog 11 was due to the inhibition of IκBα degradation, a natural inhibitor of NF-κB. The physicochemical evaluation demonstrated that the lead analog 11 was stable in the simulated gastric fluid of pH 2, while hydrolyzed at a relatively higher rate in the human blood plasma to release the active parent moieties. Molecular docking analysis showed that 11 was hydrogen bonded with the Arg-31 and Gln-110 residues of the IKKβ.

• Authors: Monika, Ankesh Sharma, Sharad Kumar Suthar, Vaibhav Aggarwal, Hong Boon Lee, Manu Sharma
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 24 Issue 16 Pg. 3814-8 (Aug 15 2014) ISSN: 1464-3405 [Electronic] England
• PMID: 25027934 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• NF-kappa B
• Tumor Necrosis Factor-alpha
• Oleanolic Acid
• rehmannic acid

Topics

• Adenocarcinoma (drug therapy, metabolism, pathology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Molecular Docking Simulation
• Molecular Structure
• NF-kappa B (metabolism)
• Oleanolic Acid (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Tumor Necrosis Factor-alpha (pharmacology)