4.7 Article

Synthesis and biological evaluation of cytotoxic activity of novel podophyllotoxin derivatives incorporating piperazinyl-cinnamic amide moieties

Journal

BIOORGANIC CHEMISTRY
Volume 123, Issue -, Pages -

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2022.105761

Keywords

Podophyllotoxin derivatives; Antitumor activity; Apoptosis; Tubulin

Funding

  1. National Natural Science Foundation of China [81872449]
  2. Key Project of Natural Science Research of Universities in Anhui Province [KJ2019A0055]
  3. Key Program in the Youth Elite Support Plan in Universities of Anhui Province [gxyqZD2019020]
  4. Anhui University of Technology

Ask authors/readers for more resources

In this study, podophyllotoxin derivatives incorporating piperazinyl-cinnamic amide moieties at the 4-position were synthesized. Compound 6e showed the best anti-proliferative properties and inhibited mitochondria-associated apoptosis in MCF-7 cells.
Podophyllotoxin, as a natural lignan isolated from the dried rhizomes and roots of several plant species of Podophyllum family, exhibits potent activity of interfering polymerization of tubulin and causes cancer cell apoptosis. Structure-activity relationship research revealed that modification at 4-position was tolerable for its potency. In the present study, podophyllotoxin derivatives incorporating piperazinyl-cinnamic amide moieties at 4-position were designed and synthesized. Their structures were confirmed by H-1 NMR, C-13 NMR, and mass spectral data. ADMET analysis proposed that these compounds had a good distribution and high clearance profile with little toxicity. The cytotoxicity of these derivatives was evaluated against four human cancer cell lines (MCF7, A549, HeLa and PC-3) by MTT assay. Among all the compounds, compound 6e exhibited the best anti proliferative properties with an IC50 = 0.08 +/- 0.01 mu M against MCF-7 cancer cell line. Further cellular mechanism studies by cell colony formation, mitochondrial membrane potential assay, nuclear morphology analysis and western blot confirmed that compound 6e could inhibit cancer cell proliferation and induce mitochondria associated apoptosis in MCF-7 cells. Meanwhile, immunofluorescence assay revealed that compound 6e could apparently disrupt tubulin network in MCF-7 cells, and molecular docking further supported that compound 6e was able to bind into the colchicine site of tubulin. The above results might lay a foundation for further investigation for drug discovery based on podophyllotoxin.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available