Synthesis and biological evaluation of novel H6 analogues as drug resistance reversal agents

Xiao Wang, Qian wen Ren, Xian xuan Liu, Yan ting Yang, Bing hua Wang, Rong G Zhai, Jia Grace Qi, Jing wei Tian, Hong bo Wang, Yi Bi

Research output: Contribution to journalArticle

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.

LanguageEnglish (US)
Pages364-377
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume161
DOIs
StatePublished - Jan 1 2019

Fingerprint

P-Glycoprotein
Drug Resistance
Paclitaxel
Pharmaceutical Preparations
G2 Phase
Derivatives
Structure-Activity Relationship
Heterografts
Cell Division
Solubility
Adenosine Triphosphatases
Cytotoxicity
Neoplasms
Nitrogen
Tumors
Pharmacology
Apoptosis
Cells
hederagenin
In Vitro Techniques

Keywords

  • Drug resistance reverse activity
  • H6 analogues
  • P-glycoprotein
  • Synthesis

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Synthesis and biological evaluation of novel H6 analogues as drug resistance reversal agents. / Wang, Xiao; Ren, Qian wen; Liu, Xian xuan; Yang, Yan ting; Wang, Bing hua; Zhai, Rong G; Qi, Jia Grace; Tian, Jing wei; Wang, Hong bo; Bi, Yi.

In: European Journal of Medicinal Chemistry, Vol. 161, 01.01.2019, p. 364-377.

Research output: Contribution to journalArticle

Wang, Xiao ; Ren, Qian wen ; Liu, Xian xuan ; Yang, Yan ting ; Wang, Bing hua ; Zhai, Rong G ; Qi, Jia Grace ; Tian, Jing wei ; Wang, Hong bo ; Bi, Yi. / Synthesis and biological evaluation of novel H6 analogues as drug resistance reversal agents. In: European Journal of Medicinal Chemistry. 2019 ; Vol. 161. pp. 364-377.
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