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Medicinal Chemistry Research

, Volume 28, Issue 1, pp 81–94 | Cite as

Design, synthesis, and biological evaluation of indole carboxylic acid esters of podophyllotoxin as antiproliferative agents

  • Lei ZhangEmail author
  • Xian Zeng
  • Xiaodong Ren
  • Nengyin Tao
  • Chengli Yang
  • Yingshu Xu
  • Yongzheng Chen
  • Jing WangEmail author
Original Research
  • 39 Downloads

Abstract

A series of indole carboxylic acid conjugates of the podophyllotoxin were synthesized and evaluated as antiproliferative agents against two human chronic myeloid leukemia cell lines. Several compounds (In-2, In-8 and In-9) not only showed antiproliferative activity against normal K562 cells but also exhibited potent antineoplastic effect against resistant K562/VCR cells. The indole-6-formyl conjugate, In-9, revealed potent cytotoxic activity against K562 and K562/VCR cell lines, with IC50 values of 0.100 ± 0.008 and 0.227 ± 0.011 μM, respectively. Preliminary mechanism studies indicated that In-9 could disrupt the microtubule network in K562/VCR cells via occupying the colchicine binding site of the tubulin. Molecular dynamics simulation results revealed that the complex of In-9 and tubulin were stable. Furthermore, In-9 induced intracellular ROS generation, apoptosis, and cycle arrest at the G2 phase by inhibition of CDKs, loss of mitochondrial membrane potential and cleavage of caspase. In-9 simultaneously induced K562/VCR cells autophagy by upregulating the levels of Beclin1 and LC3-II, and exhibited anti-MDR ability by downregulating the levels of P-gp and MRP1. Finally, In-9 activated the AMPK and JNK signaling, and inhibited the ERK, P38, and PI3K/AKT/mTOR signaling in K562/VCR cells. In silico prediction indicated that In-9 mainly obeyed Lipinski rule for druglikeness. Together, In-9 possessed potent antiproliferative activity, and may be a promising agent for the potential treatment of resistant leukemia cancer.

Keywords

Podophyllotoxin Indole carboxylic acid Anti-MDR activity Apoptosis Autophagy 

Notes

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (81860622), Department of Science and Technology of Guizhou Province ([2017]1219), Joint Fund of the Department of Science and Technology of Zunyi City and Zunyi Medical University ([2018]27), and National First-Rate Construction Discipline of Guizhou Province (Pharmacy) (YLXKJS-YX-04).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2018_2266_MOESM1_ESM.pdf (2.1 mb)
Supplementary Information

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Generic Drug Research Center of Guizhou Province, Green Pharmaceuticals Engineering Research Center of Guizhou Province, School of PharmacyZunyi Medical UniversityZunyiChina
  2. 2.Department of PharmacyGuizhou Provincial People’s HospitalGuiyangChina
  3. 3.State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China HospitalSichuan UniversityChengduChina

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