Novel lung adenocarcinoma and nuclear factor-kappa B (NF-κB) inhibitors: synthesis and evaluation of lantadene congeners.
The C-3, C-17 and C-22 congeners of pentacyclic triterpenoids reduced lantadene A (3), B (4) and 22β-hydroxyoleanolic acid (5) were synthesized and were tested in vitro for their NF-κB and IKKβ inhibitory potencies and cytotoxicity against A549 lung cancer cells. The lead congeners 12 and 13 showed IC50 of 0.56 and 0.42 μmol, respectively against TNF-α induced activation of NF-κB. The congeners 12 and 13 exhibited inhibition of IKKβ in a single-digit micromolar dose and at the same time, 12 and 13 showed marked cytotoxicity against A549 lung cancer cells with IC50 of 0.12 and 0.08 μmol, respectively. The lead ester congeners were stable in the acidic pH, while hydrolyzed readily in the human blood plasma to release the active parent moieties.
Department of Pharmacy, Jaypee University of Information Technology, Waknaghat 173234, India.
Sharad Kumar
SK
Suthar
Cancer Research Initiative Foundation, Drug Discovery Laboratory, 12A Jalan TP5, Taman Perindustrian UEP, 47600 Subang Jaya, Selangor Darul Ehsan, Malaysia.
Hong L
HL
Boon
Department of Pharmacy, Jaypee University of Information Technology, Waknaghat 173234, India. Electronic address: lantadene@hotmail.com.
Manu
M
Sharma
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D009682:Magnetic Resonance Spectroscopy; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009828:Oleanolic Acid / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D021241:Spectrometry, Mass, Electrospray Ionization
D016328:NF-kappa B; D009828:Oleanolic Acid
A549 lung cancer cells; Inhibitor of nuclear factor-kappa B kinase β; Lantadene congeners; Nuclear factor-kappa B; Tumor necrosis factor-alpha