Skip to main content
SpringerLink
Log in

Design, synthesis and evaluation of alkylphosphocholine-gefitinib conjugates as multitarget anticancer agents

  • Research Article
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

The evolving resistance to the currently used chemotherapeutic agents requires continuous efforts to develop new anticancer agents overcoming resistance and with lower side effects. Polypharmacology via designing a single molecule intercepting multiple signaling pathways is more effective than targeting a single one. Several alkylphosphocholines show anticancer activity via inhibition of Akt phosphorylation. On the other hand, several molecules having quinazoline scaffold elicit anticancer activity through inhibition of epidermal growth factor receptor (EGFR) tyrosine kinases. We report our efforts to develop alkylphosphocholines-gefitinib conjugates as multitarget anticancer agents. The antiproliferative activities of the newly synthesized compounds were evaluated against cell lines representing lung, breast, liver and skin cancers. In addition, the capability of the newly synthesized compounds to inhibit Akt phosphorylation and EGFR tyrosine kinases were determined. The results emphasized the influence of the linkers’ length on the elicited bioactivity. The long chain linkers possessing conjugates were more active regarding both of the elicited antiproliferative effect and inhibition of Akt phosphorylation, while maintained the ability to inhibit EGFR tyrosine kinases. Their cytotoxic activities were superior or comparable to erlotinib and miltefosine.

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
Scheme 1
Scheme 2

Similar content being viewed by others

References

  • Alam MM, Joh E-H, Kim Y, Oh YI, Hong J, Kim B, Kim D-H, Lee YS (2012) Synthesis and biological evaluation of cyclopentane-linked alkyl phosphocholines as potential anticancer agents that act by inhibiting Akt phosphorylation. Eur J Med Chem 47:485–492

    Article  CAS  PubMed  Google Scholar 

  • Alam MM, Joh E-H, Park H, Kim B, Kim D-H, Lee YS (2013) Synthesis, characterization and Akt phosphorylation inhibitory activity of cyclopentanecarboxylate-substituted alkylphosphocholines. Biorgan Med Chem 21:2018–2024

    Article  CAS  Google Scholar 

  • Beloribi-Djefaflia S, Vasseur S, Guillaumond F (2016) Lipid metabolic reprogramming in cancer cells. Oncogenesis 5:e189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Block M, Grundker C, Fister S, Kubin J, Wilkens L, Mueller MD, Hemmerlein B, Emons G, Gunthert AR (2012) Inhibition of the AKT/mTOR and erbB pathways by gefitinib, perifosine and analogs of gonadotropin-releasing hormone I and II to overcome tamoxifen resistance in breast cancer cells. Int J Oncol 41:1845–1854

    Article  CAS  PubMed  Google Scholar 

  • Calay D, Vind-Kezunovic D, Frankart A, Lambert S, Poumay Y, Gniadecki R (2010) Inhibition of Akt signaling by exclusion from lipid rafts in normal and transformed epidermal keratinocytes. J Invest Dermatol 130:1136–1145

    Article  CAS  PubMed  Google Scholar 

  • Clive S, Gardiner J, Leonard RC (1999) Miltefosine as a topical treatment for cutaneous metastases in breast carcinoma. Cancer Chemother Pharmacol 44(Suppl):S29–S30

    Article  CAS  PubMed  Google Scholar 

  • Danker K, Reutter W, Semini G (2010) Glycosidated phospholipids: uncoupling of signalling pathways at the plasma membrane. Br J Pharmacol 160:36–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Desbois-Mouthon C, Cacheux W, Blivet-Van Eggelpoel MJ, Barbu V, Fartoux L, Poupon R, Housset C, Rosmorduc O (2006) Impact of IGF-1R/EGFR cross-talks on hepatoma cell sensitivity to gefitinib. Int J Cancer 119:2557–2566

    Article  CAS  PubMed  Google Scholar 

  • Dragowska WH, Weppler SA, Qadir MA, Wong LY, Franssen Y, Baker JH, Kapanen AI, Kierkels GJ, Masin D, Minchinton AI, Gelmon KA, Bally MB (2011) The combination of gefitinib and RAD001 inhibits growth of HER2 overexpressing breast cancer cells and tumors irrespective of trastuzumab sensitivity. BMC Cancer 11:420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Faustino M (2014) Editorial (thematic issue: antitumor alkylphospholipid analogs: a promising and growing family of synthetic cell membrane-targeting molecules for cancer treatment). Anticancer Agents Med Chem 14:495–498

    Article  Google Scholar 

  • Fedida-Metula S, Elhyany S, Tsory S, Segal S, Hershfinkel M, Sekler I, Fishman D (2008) Targeting lipid rafts inhibits protein kinase B by disrupting calcium homeostasis and attenuates malignant properties of melanoma cells. Carcinogenesis 29:1546–1554

    Article  CAS  PubMed  Google Scholar 

  • Fielding CJ, Fielding PE (2004) Membrane cholesterol and the regulation of signal transduction. Biochem Soc Trans 32:65–69

    Article  CAS  PubMed  Google Scholar 

  • Girgert R, Emons G, Grundker C (2017) 17beta-estradiol-induced growth of triple-negative breast cancer cells is prevented by the reduction of GPER expression after treatment with gefitinib. Oncol Rep 37:1212–1218

    Article  PubMed  Google Scholar 

  • Godugu C, Doddapaneni R, Patel AR, Singh R, Mercer R, Singh M (2016) Novel gefitinib formulation with improved oral bioavailability in treatment of A431 skin carcinoma. Pharm Res 33:137–154

    Article  CAS  PubMed  Google Scholar 

  • Gomez-Serranillos IR, Minones J Jr, Dynarowicz-latka P, Miniones J, Iribarnegaray E (2004) Miltefosine–cholesterol interactions: a monolayer study. Langmuir 20:928–933

    Article  CAS  PubMed  Google Scholar 

  • Gutteridge E, Agrawal A, Nicholson R, Leung Cheung K, Robertson J, Gee J (2010) The effects of gefitinib in tamoxifen-resistant and hormone-insensitive breast cancer: a phase II study. Int J Cancer 126:1806–1816

    CAS  PubMed  Google Scholar 

  • Höpfner M, Sutter AP, Huether A, Schuppan D, Zeitz M, Scherubl H (2004) Targeting the epidermal growth factor receptor by gefitinib for treatment of hepatocellular carcinoma. J Hepatol 41:1008–1016

    Article  PubMed  Google Scholar 

  • Kazandjian D, Blumenthal GM, Yuan W, He K, Keegan P, Pazdur R (2016) FDA approval of gefitinib for the treatment of patients with Metastatic EGFR mutation-positive non-small cell lung cancer. Clin Cancer Res 22:1307–1312

    Article  CAS  PubMed  Google Scholar 

  • Kostadinova A, Topouzova-Hristova T, Momchilova A, Tzoneva R, Berger MR (2015) Antitumor lipids—structure, functions, and medical applications. In: Rossen D (ed) Advances in protein chemistry and structural biology. Academic Press, pp 27–66

  • Li H, Zhou S, Li X, Wang D, Wang Y, Zhou C, Schmid-Bindert G (2013) Gefitinib-resistance is related to BIM expression in non-small cell lung cancer cell lines. Cancer Biother Radiopharm 28:115–123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malta de Sá M, Sresht V, Rangel-Yagui CO, Blankschtein D (2015) Understanding miltefosine–membrane interactions using molecular dynamics simulations. Langmuir 31:4503–4512

    Article  Google Scholar 

  • Murray M, Hraiki A, Bebawy M, Pazderka C, Rawling T (2015) Anti-tumor activities of lipids and lipid analogues and their development as potential anticancer drugs. Pharmacol Ther 150:109–128

    Article  CAS  PubMed  Google Scholar 

  • Pachioni Jde A, Magalhaes JG, Lima EJ, Bueno Lde M, Barbosa JF, de Sa MM, Rangel-Yagui CO (2013) Alkylphospholipids—a promising class of chemotherapeutic agents with a broad pharmacological spectrum. J Pharm Pharm Sci 16:742–759

    Article  PubMed  Google Scholar 

  • Pike LJ (2003) Lipid rafts: bringing order to chaos. J Lipid Res 44:655–667

    Article  CAS  PubMed  Google Scholar 

  • Raghavan S, Krishnaiah V (2010) An efficient stereoselective synthesis of penaresidin A from (E)-2-protected amino-3,4-unsaturated sulfoxide. J Org Chem 75:748–761

    Article  CAS  PubMed  Google Scholar 

  • Reis-Sobreiro M, Roué G, Moros A, Gajate C, de la Iglesia-Vicente J, Colomer D, Mollinedo F (2013) Lipid raft-mediated Akt signaling as a therapeutic target in mantle cell lymphoma. Blood Cancer J 3:e118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schwan G, Barbar Asskar G, Höfgen N, Kubicova L, Funke U, Egerland U, Zahn M, Nieber K, Scheunemann M, Sträter N, Brust P, Briel D (2014) Fluorine-containing 6,7-dialkoxybiaryl-based inhibitors for phosphodiesterase 10 A: synthesis and in vitro evaluation of inhibitory potency, selectivity, and metabolism. ChemMedChem 9:1476–1487

    Article  CAS  PubMed  Google Scholar 

  • Shao J, Xu Z, Peng X, Chen M, Zhu Y, Xu L, Zhu H, Yang B, Luo P, He Q (2016) Gefitinib synergizes with irinotecan to suppress hepatocellular carcinoma via antagonizing Rad51-Mediated DNA-repair. PLoS ONE 11:e0146968

    Article  PubMed  PubMed Central  Google Scholar 

  • Simons K, Toomre D (2000) Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 1:31–39

    Article  CAS  PubMed  Google Scholar 

  • van Blitterswijk WJ, Verheij M (2013) Anticancer mechanisms and clinical application of alkylphospholipids. BBA Mol Cell Biol Lipids 1831:663–674

    Article  Google Scholar 

  • Verma YK, Reddy BS, Pawar MS, Bhunia D, Sampath Kumar HM (2016) Design, synthesis, and immunological evaluation of benzyloxyalkyl-substituted 1,2,3-triazolyl α-GalCer analogues. ACS Med Chem Lett 7:172–176

    Article  CAS  PubMed  Google Scholar 

  • Weichert JP, Clark PA, Kandela IK, Vaccaro AM, Clarke W, Longino MA, Pinchuk AN, Farhoud M, Swanson KI, Floberg JM, Grudzinski J, Titz B, Traynor AM, Chen H-E, Hall LT, Pazoles CJ, Pickhardt PJ, Kuo JS (2014) Alkylphosphocholine analogs for broad-spectrum cancer imaging and therapy. Sci Transl Med 6(240):275

    Article  Google Scholar 

  • Wu Y, Zhang D, Wu B, Quan Y, Liu D, Li Y, Zhang X (2017) Synergistic activity of an antimetabolite drug and tyrosine kinase inhibitors against breast cancer cells. Chem Pharm Bull. doi:10.1248/cpb.c17-00261

    Google Scholar 

  • Zhuang L, Kim J, Adam RM, Solomon KR, Freeman MR (2005) Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts. J Clin Invest 115:959–968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research was supported by the “Basic Science Research Program” through the “National Research Foundation of Korea (NRF)” funded by MEST, Republic of Korea (#2012-006431).

Author information

Authors and Affiliations

  1. Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea

    Md. Maqusood Alam, Yeong Ho Kwon, Hyo Jong Lee, Nam Yong Kim, Dong-Hyun Kim & Yong Sup Lee

  2. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt

    Ahmed H. E. Hassan

  3. Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea

    Ahmed H. E. Hassan & Yong Sup Lee

  4. Department of Pharmacy, College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea

    Kyung Hoon Min

  5. Neuroscience Research Institute, Gachon University, Incheon, 20565, Republic of Korea

    Sang-Yoon Lee

Authors
  1. Md. Maqusood Alam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahmed H. E. Hassan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yeong Ho Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hyo Jong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nam Yong Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kyung Hoon Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sang-Yoon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dong-Hyun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yong Sup Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yong Sup Lee.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alam, M.M., Hassan, A.H.E., Kwon, Y.H. et al. Design, synthesis and evaluation of alkylphosphocholine-gefitinib conjugates as multitarget anticancer agents. Arch. Pharm. Res. 41, 35–45 (2018). https://doi.org/10.1007/s12272-017-0977-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-017-0977-z

Keywords

Search

Navigation