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Bioorg Med Chem Lett. 2014 Aug 15;24(16):3814-8. doi: 10.1016/j.bmcl.2014.06.068. Epub 2014 Jun 28.

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

Author information

1
Department of Pharmacy, Jaypee University of Information Technology, Waknaghat 173234, India.
2
Cancer Research Initiative Foundation, Drug Discovery Laboratory, 12A Jalan TP5, Taman Perindustrian UEP, 47600 Subang Jaya, Selangor Darul Ehsan, Malaysia.
3
Department of Pharmacy, Jaypee University of Information Technology, Waknaghat 173234, India. Electronic address: lantadene@hotmail.com.

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.

KEYWORDS:

A549 lung cancer cells; Inhibitor of nuclear factor-kappa B kinase β; Lantadene analogs; Nuclear factor-kappa B; Tumor necrosis factor-alpha

PMID:
25027934
DOI:
10.1016/j.bmcl.2014.06.068
[Indexed for MEDLINE]

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