ABSTRACT
The only known method for the dearomative trifluoromethoxylation of indoles is preliminary, with only one substrate successfully undergoing the reaction. In this study, we not only developed a broadly applicable method for indole dearomative trifluoromethoxylation but also achieved divergent trifluoromethoxylation by fine-tuning the reaction conditions. Under optimized conditions, with a silver salt and an easily handled OCF3 reagent, various indoles smoothly underwent dearomatization to afford a diverse array of ditrifluoromethoxylated indolines in 50-84% isolated yields with up to 37:1 diastereoselectivity, and fluorinated trifluoromethoxylated indolines were obtained with exclusive trans selectivity. In addition, the reaction conditions were compatible with other heteroaromatic rings as well as styrene moieties.
ABSTRACT
The estrogen receptor α is recognized as important pharmaceutical target for breast cancer therapy, and vascular endothelial growth factor receptors (VEGFRs) play important roles in tumor angiogenesis including breast cancer. A series of 2,3-diaryl isoquinolinone derivatives were designed and synthesized targeting both estrogen receptor α (ERα) and VEGFR-2. Bioactivity evaluation showed that compounds 7c, 7d and 7f exhibited significant anti-proliferative and anti-angiogenesis activities via ERα and VEGFR-2 dependent mechanisms.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Estrogen Receptor alpha/antagonists & inhibitors , Isoquinolines/chemistry , Isoquinolines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Animals , Breast/drug effects , Breast/metabolism , Breast/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Chickens , Estrogen Receptor alpha/metabolism , Female , Humans , Molecular Docking Simulation , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
The estrogen receptors have played important roles in breast cancer development and progression. Selective estrogen receptor modulators, such as Tamoxifen, have showed great benefits in the treatment and prevention of breast cancer. But the disadvantages of induction of endometrial cancer and drug resistance have limited their use. Multiple ligand which act at multiple biomolecular targets may exert favorable advantages of improved efficacy with lower incidence of side effects. In this work, we described the synthesis and evaluation of a series of 6-aryl-indenoisoquinolone derivatives as dual ERα and VEGFR-2 inhibitors. These compounds presented good ERα binding affinity and ERα antagonistic activity, as well as potent VEGFR-2 inhibitory potency. They also possessed excellent anti-proliferative activities against MCF-7, MDA-MB-231, Ishikawa and HUVEC cell lines. Further investigation of selective compound 21c showed that it was able to inhibit the activation of VEGFR-2 and the signaling transduction of Raf-1/MAPK/ERK pathway in MCF-7 cells.