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Synthesis and biological evaluation of novel H6 analogues as drug resistance reversal agents
- Source :
- European journal of medicinal chemistry. 161
- Publication Year :
- 2018
-
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.
- 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
Subjects
Details
- ISSN :
- 17683254
- Volume :
- 161
- Database :
- OpenAIRE
- Journal :
- European journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....7a55183056aef17917645d758e0da1f2