Discovery of anti-metastatic chiral ionone alkaloid derivatives targeting HIF-1α/VRGF/VEGFR2 pathway
Discovery of anti-metastatic chiral ionone alkaloid derivatives targeting HIF-1α/VRGF/VEGFR2 pathway
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发现针对 HIF-1α/VRGF/VEGFR2 通路的抗转移手性紫罗兰酮生物碱衍生物
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通讯作者：
段宏泉
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作者：
刘菁菁;刘欣遥;聂江平;贾美琪;于阳;秦楠;段宏泉
合成了新型手性紫罗兰酮生物碱衍生物，并使用趋化性测定评估了它们在人乳腺癌细胞中的抗转移作用。与阳性对照LY294002相比，PI3K抑制剂衍生物10a、11a、11c、11g、11j、11k和11w对癌细胞迁移表现出显着的抑制作用。特别是，化合物 11g 的 IC50 低至 0.035 ± 0.004 μM。对化合物11g的进一步研究表明，其对MDA-MB-231细胞的粘附、迁移和侵袭具有抑制作用。 11g抗肿瘤转移作用的机制可能是通过抑制HIF-1α/VEGF/VEGFR2/Akt通路，从而抑制下游信号分子，包括Akt1/mTOR/p70S6K和Akt2/PKCζ/整合素β1通路。综上所述，手性紫罗兰酮生物碱衍生物11g可能是治疗乳腺癌的潜在抗肿瘤转移剂
Novel chiral ionone alkaloid derivatives were synthesized, and their anti-metastatic effects were evaluated in human breast cancer cells using chemotaxis assay. Compared with positive control LY294002, a PI3K inhibitor, derivatives 10a, 11a, 11c, 11g, 11j, 11k and 11w exhibited significant inhibitory effects against cancer cell migration. Especially, the IC50 for compound 11g was as low as 0.035 ± 0.004 μM. Further investigations on compound 11g revealed that it could exert inhibitory effects on the adhesion, migration, and invasion of MDA-MB-231 cells. The mechanisms for the anti-tumor metastatic effects of 11g might be through the inhibition of HIF-1α/VEGF/VEGFR2/Akt pathway, which suppressed the downstream signaling molecules, including Akt1/mTOR/p70S6K and Akt2/PKCζ/integrin β1 pathways. Taken together, chiral ionone alkaloid derivative 11g may be a potential anti-tumor metastasis agent for the treatment of breast cancer