1. Synthesis and biological evaluation of novel H6 analogues as drug resistance reversal agents
- Author
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Xiao Wang, Xian xuan Liu, Bing hua Wang, Jing wei Tian, Hongbo Wang, Yi Bi, Yan ting Yang, Rong Zhai, Qian wen Ren, and Jia Grace Qi
- Subjects
Drug ,Male ,media_common.quotation_subject ,Mice, Nude ,Antineoplastic Agents ,Drug resistance ,Pharmacology ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Drug Discovery ,Tumor Cells, Cultured ,Animals ,Humans ,Oleanolic Acid ,Cytotoxicity ,P-glycoprotein ,media_common ,Cell Proliferation ,Mice, Inbred BALB C ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,General Medicine ,Neoplasms, Experimental ,Hederagenin ,Paclitaxel ,Apoptosis ,Drug Resistance, Neoplasm ,biology.protein ,Efflux ,Drug Screening Assays, Antitumor - Abstract
Hederagenin is a naturally occurring pentacyclic triterpenoids compound with multiple pharmacological activities. We recently showed that H6, a synthetic derivative of hederagenin, could enhance the anticancer activity of paclitaxel in drug-resistant cells in vitro and in vivo, but showed poor solubility. With the aim of improving the drug resistant reversal activity of H6, here we designed and synthesized a series of novel H6 analogues. Our results showed that compound 10 at the concentration of 5 μM significantly enhanced the cytotoxicity of paclitaxel to drug-resistant KBV cells and sensitized cells to paclitaxel in arresting cells in G2/M phase and inducing apoptosis. We found that compound 10 might block the drug efflux of P-gp via stimulating P-gp ATPase activity. Importantly, compound 10 enhanced the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors. Finally, we summarized a preliminary structure-activity relationship of hederagenin by the drug resistant reversal activity of H6 analogues in vitro and compound 10 and H6 in vivo. This study highlights the importance of nitrogen-containing derivatives of hederagenin C-28 in the development of novel drug resistance reversal agents.
- Published
- 2018