Chen, ZhongZhongChenHuang, Kuo-YenKuo-YenHuangLing, YongYongLingGoto, MasuoMasuoGotoDuan, Hua-QingHua-QingDuanTong, Xiao-HangXiao-HangTongLiu, Yan-LiYan-LiLiuCheng, Yung-YiYung-YiChengMorris-Natschke, Susan LSusan LMorris-NatschkePAN-CHYR YANGYang, Shi-LinShi-LinYangLee, Kuo-HsiungKuo-HsiungLee2023-01-092023-01-092019-11-220163-3864https://scholars.lib.ntu.edu.tw/handle/123456789/627034Natural 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 μM), while hederagenin inhibited the growth of only A549 tumor cells (IC50 > 10 μM). Furthermore, compound 13 showed stronger inhibitory effects on EGFR-LTC kinase activity (IC50 0.01 μM) than hederagenin (IC50 > 20 μM) and inhibited the proliferation of gefitinib-resistant H1975 (IC50 8.1 μM) and osimertinib-resistant H1975-LTC (IC50 7.6 μM) 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.enRESISTANCE; DRUGS; DERIVATIVES; RECEPTOR; THERAPY; METHYL; ACID[SDGs]SDG3journal article10.1021/acs.jnatprod.9b00659317181822-s2.0-85075166789WOS:000499741400017https://scholars.lib.ntu.edu.tw/handle/123456789/523433