Journal
JOURNAL OF NATURAL PRODUCTS
Volume 82, Issue 11, Pages 3065-3073Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jnatprod.9b00659
Keywords
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Funding
- National Natural Science Foundation of China [81302660]
- Provincial Universities of Jiangsu Province Natural Science Foundation [13KJB350006]
- Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD)
- NIH from the National Cancer Institute [CA177584]
- Eshelman Institute for Innovation, Chapel Hill, North Carolina
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Natural triterpenoids, such as oleanolic acid (OA) and hederagenin, display anti-lung cancer effects, and nitric oxide (NO) is associated with some oncogenic signaling pathways. Accordingly, 17 OA/hederagenin-NO donor hybrids were designed, synthesized, and evaluated against tumor cells. The most potent compound, 13, significantly inhibited the proliferation of five tumor cell lines (IC50 4.6-5.2 mu M), while hederagenin inhibited the growth of only A549 tumor cells (IC50 > 10 mu M). Furthermore, compound 13 showed stronger inhibitory effects on EGFR-LTC kinase activity (IC50 0.01 mu M) than hederagenin (IC50 > 20 mu M) and inhibited the proliferation of gefitinib-resistant H1975 (IC50 8.1 mu M) and osimertinib-resistant H1975-LTC (IC50 7.6 mu M) non-small-cell lung cancer (NSCLC) cells. Moreover, compound 13 produced the most NO in H1975 tumor cells, which indicated that NO may play a synergistic role. Collectively, compound 13, a novel hederagenin-NO donor hybrid with a different chemical structure from those of the current FDA-approved EGFR-targeted anti-NSCLC drugs, may be a promising lead compound for the treatment of NSCLC expressing gefitinib-resistant EGFR with a T790 M mutation or osimertinib-resistant EGFR-LTC with an L858R/T790M/C797S mutation. This work should shed light on the discovery of new anti-NSCLC drugs targeting EGFR from natural products.
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