Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Scheme 1
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Fig. 15

Similar content being viewed by others

References

  • Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL, Chang G (2009) Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323:1718–1722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bailly C (2012) Contemporary challenges in the design of topoisomerase II inhibitors for cancer chemotherapy. Chem Rev 112:3611–3640

    Article  CAS  PubMed  Google Scholar 

  • Baldwin EL, Osheroff N (2005) Etoposide, topoisomerase II and cancer. Curr Med Chem 5:363–372

    CAS  Google Scholar 

  • Binkhathlan Z, Lavasanifar A (2013) P-glycoprotein inhibition as a therapeutic approach for overcoming multidrug resistance in cancer: current status and future perspectives. Curr Cancer Drug Targets 13:326–346

    Article  CAS  PubMed  Google Scholar 

  • Bommagani S, Ponder J, Penthala NR, Janganati V, Jordan CT, Borrelli MJ, Crooks PA (2017) Indole carboxylic acid esters of melampomagnolide B are potent anticancer agents against both hematological and solid tumor cells. Eur J Med Chem 136:393–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cao B, Chen H, Gao Y, Niu C, Zhang Y, Li Y (2015) CIP-36, a novel topoisomerase II-targeting agent, induces the apoptosis of multidrug-resistant cancer cells in vitro. Int J Mol Med 35:771–776

    Article  CAS  PubMed  Google Scholar 

  • Chen H, Bi W, Cao B, Yang Z, Chen S, Shang H, Yu P, Yang J (2010) A novel podophyllotoxin derivative (YB-1EPN) induces apoptosis and down-regulates express of P-glycoprotein in multidrug resistance cell line KBV200. Eur J Pharmacol 627:69–74

    Article  CAS  PubMed  Google Scholar 

  • Cheng WH, Cao B, Shang H, Niu C, Zhang LM, Zhang ZH, Tian DL, Zhang S, Chen H, Zhou ZM (2014) Synthesis and evaluation of novel podophyllotoxin derivatives as potential antitumor agents. Eur J Med Chem 85:498–507

    Article  CAS  PubMed  Google Scholar 

  • Dadashpour S, Emami S (2018) Indole in the target-based design of anticancer agents: a versatile scaffold with diverse mechanism. Eur J Med Chem 150:9–29

    Article  CAS  PubMed  Google Scholar 

  • Gottesman MM (2002) Mechanisms of cancer drug resistance. Annu Rev Med 53:615–627

    Article  CAS  PubMed  Google Scholar 

  • Han HW, Qiu HY, Hu C, Sun WX, Yang RW, Qi JL, Wang XM, Lu GH, Yang YH (2016) Design, synthesis and anti-cancer activity evaluation of podophyllotoxin-norcantharidin hybrid drugs. Bioorg Med Chem Lett 26:3237–3242

    Article  CAS  PubMed  Google Scholar 

  • Kamal A, Ali Hussaini SM, Rahim A, Riyaz S (2015) Podophyllotoxin derivatives: a patent review (2012-2014). Expert Opin Ther Pat 25:1025–1034

    Article  CAS  PubMed  Google Scholar 

  • Kathawala RJ, Gupta P, Ashby CR, Chen ZS (2015) The modulation of ABC transporter-mediated multidrug resistance in cancer: a review of the past decade. Drug Resist Update 18:1–17

    Article  Google Scholar 

  • Kim SY, Ryu JS, Li H, Park WJ, Yun HY, Beak KJ, Kwon NS, SOHN UD, Kim DS (2010) UVB-activated indole-3-acetic acid induces apoptosis of PC-3 prostate cancer cells. Anticancer Res 30:4607–4612

    CAS  PubMed  Google Scholar 

  • Lai JL, Liu YH, Liu C, Qi MP, LIu RN, Zhu XF, Zhou QG, Chen YY, Guo AZ, Hu CM (2017) Indirubin inhibits LPS-induced inflammation via TLR4 abrogation mediated by the NF-kB and MAPK signaling pathways. Inflammation 40:1–12

    Article  CAS  PubMed  Google Scholar 

  • Leneva IA, Russell RJ, Boriskin YS, Hay AJ (2009) Characteristics of arbidol-resistant mutants of influenza virus: implications for the mechanism of anti-influenza action of arbidol. Antivir Res 81:132–140

    Article  CAS  PubMed  Google Scholar 

  • Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132:27–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levy JMM, Towers CG, Thorburn A (2017) Targeting autophagy in cancer. Nat Rev Cancer 17:528–542

    Article  CAS  PubMed  Google Scholar 

  • Li W, Zhang H, Assaraf YG, Zhao K, Xu X, Xie J, Yang DH, Chen ZS (2016) Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies. Drug Resist Update 27:14–29

    Article  CAS  Google Scholar 

  • Liu X, Zhang LL, Xu XH, Hui L, Zhang JB, Chen SW (2013) Synthesis and anticancer activity of dichloroplatinum (II) complexes of podophyllotoxin. Bioorg Med Chem Lett 23:3780–3784

    Article  CAS  PubMed  Google Scholar 

  • LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA (2008) Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Update 11:32–50

    Article  CAS  Google Scholar 

  • Lum JJ, Bauer DE, Kong M, Harris MH, Li C, Lindsten T, Thompson CB (2005) Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120:237–248

    Article  CAS  PubMed  Google Scholar 

  • Martínez-Reyes I, Diebold LP, Kong H, Schieber M, Huang H, Hensley CT, Mehta MM, Wang T, Santos JH, Woychik R, Dufour E, Spelbrink JN, Weinberg SE, Zhao Y, DeBerardinis RJ, Chandel NS (2016) TCA cycle and mitochondrial membrane potential are necessary for diverse biological functions. Mol Cell 61:199–209

    Article  CAS  PubMed  Google Scholar 

  • Merzouki A, Buschmann MD, Jean M, Young RS, Liao S, Gal S, Li Z, Slilaty SN (2012) Adva-27a, a novel podophyllotoxin derivative found to be effective against multidrug resistant human cancer cells. Anticancer Res 32:4423–4432

    CAS  PubMed  Google Scholar 

  • Mihaylova MM, Shaw RJ (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13:1016–1023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mishra S, Singh P (2016) Hybrid molecules: the privileged scaffolds for various pharmaceuticals. Eur J Med Chem 124:500–536

    Article  CAS  PubMed  Google Scholar 

  • Polivka Jr J, Janku F (2014) Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther 142:164–175

    Article  CAS  PubMed  Google Scholar 

  • Romero DL, Olmsted RA, Poel TJ, Morge RA, Biles C, Keiser BJ, Kopta LA, Friis JM, Hosley JD, Stefanski KJ, Wishka DG, Evans DB, Morris J, Stehle RG, Sharma SK, Yagi Y, Voorman RL, Adams WJ, Tarpley WG, Thomas RC (1996) Targeting delavirdine/atevirdine resistant HIV-1: identification of (alkylamino)piperidine-containing bis(heteroaryl)piperazines as broad spectrum HIV-1 reverse transcriptase inhibitors. J Med Chem 39:3769–3789

    Article  CAS  PubMed  Google Scholar 

  • Saiki S, Sasazawa Y, Imamichi Y, Kawajiri S, Fujimaki T, Tanida I, Kobayashi H, Sato F, Sato S, Ishikawa KI, Imoto M, Hattori N (2011) Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition. Autophagy 7:176–187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shukla S, Wu CP, Ambudkar SV (2008) Development of inhibitors of ATP-binding cassette drug transporters-present status and challenges. Expert Opin Drug Metab Toxicol 4:205–223

    Article  CAS  PubMed  Google Scholar 

  • Singh BN, Kumar D, Shankar S, Srivastava RK (2012) Rottlerin induces autophagy which leads to apoptotic cell death through inhibition of PI3K/Akt/mTOR pathway in human pancreatic cancer stem cells. Biochem Pharmacol 84:1154–1163

    Article  CAS  PubMed  Google Scholar 

  • Stone RM, Manley PW, Larson RA, Capdeville R (2018) Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. Blood Adv 2:444–453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sui X, Kong N, Ye L, Han W, Zhou J, Zhang Q, He C, Pan H (2014) p38 and JNK MAPK pathways control the balance of apoptosis and autophagy in response to chemotherapeutic agents. Cancer Lett 344:174–179

    Article  CAS  PubMed  Google Scholar 

  • Szakács G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5:219–234

    Article  CAS  PubMed  Google Scholar 

  • Valentini A, Conforti F, Crispini A, De Martino A, Condello R, Stellitano C, Rotilio G, Ghedini M, Federici G, Bernardini S, Pucci D (2009) Synthesis, oxidant properties, and antitumoral effects of a heteroleptic palladium (II) complex of curcumin on human prostate cancer cells. J Med Chem 52:484–491

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Long L, Chen Y, Xu Y, Zhang L (2018) Design, synthesis and antineoplastic activity of novel hybrids of podophyllotoxin and indirubin against human leukaemia cancer cells as multifunctional anti-MDR agents. Bioorg Med Chem Lett 28:1817–1824

    Article  CAS  PubMed  Google Scholar 

  • Wang ZZ, Sun WX, Wang X, Zhang YH, Qiu HY, Qi JL, Pang YJ, Lu GH, Wang XM, Yu FG, Yang YH (2017) Design, synthesis, biological evaluation, and 3D-QSAR analysis of podophyllotoxin-dioxazole combination as tubulin targeting anticancer agents. Chem Biol Drug Des 90:236–243

    Article  CAS  PubMed  Google Scholar 

  • Yi X, Zhang X, Jeong H, Shin YM, Park DH, You S (2015) A novel bispidinone analog induces S‑phase cell cycle arrest and apoptosis in HeLa human cervical carcinoma cells. Oncol Rep 33:1526–1532

    Article  CAS  PubMed  Google Scholar 

  • You Y (2005) Podophyllotoxin derivatives: current synthetic approaches for new anticancer agents. Curr Pharm Des 11:1695–1717

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Chen F, Zhang Z, Chen Y, Lin Y, Wang J (2016a) Design, synthesis and evaluation of the multidrug resistance-reversing activity of pyridine acid esters of podophyllotoxin in human leukemia cells. Bioorg Med Chem Lett 26:4466–4471

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Liu L, Zheng C, Wang Y, Nie X, Shi D, Chen Y, Wei G, Wang J (2017a) Synthesis and biological evaluation of novel podophyllotoxin-NSAIDs conjugates as multifunctional anti-MDR agents against resistant human hepatocellular carcinoma Bel-7402/5-FU cells. Eur J Med Chem 131:81–91

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Liu L, Zheng C, Wang Y, Wang J, Yao Q (2017b) Synthesis of novel indirubin derivatives and their effects on the proliferation, cell cycle and apoptosis in acute myeloblastic leukemia HL-60 cells. Chin J Org Chem 37:1523–1529

    Article  CAS  Google Scholar 

  • Zhang L, Zhang Z, Chen F, Chen Y, Lin Y, Wang J (2016b) Aromatic heterocyclic esters of podophyllotoxin exert anti-MDR activity in human leukemia K562/ADR cells via ROS/MAPK signaling pathways. Eur J Med Chem 123:226–235

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Zheng J, Rong Y, Yang C, Long L, Xu Y, Chen Y, Wang J, Yao Q (2018) Synthesis, antitumor evaluation and molecular docking study of a novel podophyllotoxin-lonidamine hybrid. Med Chem Res 27:2231–2238

    Article  CAS  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. Generic Drug Research Center of Guizhou Province, Green Pharmaceuticals Engineering Research Center of Guizhou Province, School of Pharmacy, Zunyi Medical University, 563003, Zunyi, China

    Lei Zhang, Xian Zeng, Nengyin Tao, Chengli Yang, Yingshu Xu, Yongzheng Chen & Jing Wang

  2. Department of Pharmacy, Guizhou Provincial People’s Hospital, 550002, Guiyang, China

    Xiaodong Ren

  3. State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, 610041, Chengdu, China

    Chengli Yang

Authors
  1. Lei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xian Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaodong Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nengyin Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chengli Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yingshu Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yongzheng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Lei Zhang or Jing Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, L., Zeng, X., Ren, X. et al. Design, synthesis, and biological evaluation of indole carboxylic acid esters of podophyllotoxin as antiproliferative agents. Med Chem Res 28, 81–94 (2019). https://doi.org/10.1007/s00044-018-2266-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-018-2266-x

Keywords

Search

Navigation