Synthesis of novel α-aminophosphonates under microwave irradiation, biological evaluation as antiproliferative agents and apoptosis inducers

  • Erika L. Loredo-Calderón
  • Carlos A. Velázquez-Martínez
  • Mónica A. Ramírez-Cabrera
  • Eugenio Hernández-Fernández
  • Verónica M. Rivas-Galindo
  • Eder Arredondo Espinoza
  • Susana T. López-CortinaEmail author
Original Research


The synthesis of two series of α-aminophosphonates was achieved by Microwave Irradiation (MW), using the one-pot Kabachnik–Fields reaction. Based on a green chemistry approach, the reactions were carried out using ethanol as the only solvent and without any catalyst, and short reaction times (20–40 min), in variable yields. Both series were tested to determine their cell proliferation inhibition activity in MDA-MB-231, MCF-7 and MCF-10A cell lines. Ethyl 4-(((diphenoxyphosphoryl)(4-(diphenylamino)phenyl)methyl)amino) benzoate 4e and diphenyl (((4-(((S)-2-hydroxy-1-phenylethyl)carbamoyl)phenyl)amino)(4-hydroxyphenyl)methyl)phosphonate 6b, showed cell proliferation inhibition activity only in the cancer cell line MCF-7 and no effect on the normal cell line MFC-10A, both compounds caused cell death by inducing apoptosis.


Aminophosphonates Green synthesis Kabachnik–Fields Cell proliferation inhibition activity Apoptosis 



The authors thank the National Council for Science and Technology (CONACYT) for its financial support via Project 180854. ELLC, also thanks CONACYT for a Graduate Scholarship 229877.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2019_2436_MOESM1_ESM.docx (2.1 mb)
Supplementary Item


  1. Abdel-Megeed MF, Badr BE, Azaam MM, El-Hiti GA (2012) Synthesis, antimicrobial and anticancer activities of a novel series of diphenyl 1-(pyridin-3-yl)ethylphosphonates. Bioorg Med Chem 20:2252–2258. CrossRefGoogle Scholar
  2. Afshari M, Gorjizadeh M, Naseh M (2017) Supported sulfonic acid on magnetic nanoparticles used as a reusable catalyst for rapid synthesis of α-aminophosphonates. Inorg Nano-Met Chem 47:591–596. CrossRefGoogle Scholar
  3. Avril MF, Aamdal S, Grob JJ et al. (2004) Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 22:1118–1125. CrossRefGoogle Scholar
  4. Bálint E, Tripolszky A, Tajti Á (2018) 6. Synthesis of α-aminophosphonates by the Kabachnik–Fields reaction and by the Pudovik reaction. In: Keglevich G (ed) Organophosphorus Chemistry. De Gruyter, Berlin, Boston, p 108–147CrossRefGoogle Scholar
  5. Berridge MV, Tan AS (1993) Characterization of the cellular reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT): subcellular localization, substrate dependence, and involvement of mitochondrial electron transport in MTT reduction. Arch Biochem Biophys 303:474–482. CrossRefGoogle Scholar
  6. Bhagat S, Chakraborti AK (2007) An extremely efficient three-component reaction of aldehydes/ketones, amines, and phosphites (Kabachnik−Fields reaction) for the synthesis of α-aminophosphonates catalyzed by magnesium perchlorate. J Org Chem 72:1263–1270. CrossRefGoogle Scholar
  7. Caldwell N, Jamieson C, Simpson I, Watson AJB (2013) Development of a sustainable catalytic ester amidation process. ACS Sustain Chem Eng 1:1339–1344. CrossRefGoogle Scholar
  8. Deshmukh SU, Kharat KR, Yadav AR et al. (2018) Synthesis of novel α-aminophosphonate derivatives, biological evaluation as potent antiproliferative agents and molecular docking. ChemistrySelect 3:5552–5558. CrossRefGoogle Scholar
  9. Fang Y-L, Wu Z-L, Xiao M-W et al. (2016) One-pot three-component synthesis of novel diethyl((2-oxo-1,2-dihydroquinolin-3-yl)(arylamino)methyl)phosphonate as potential anticancer agents. Int J Mol Sci 17:653. CrossRefGoogle Scholar
  10. Fischel JL, Barbé V, Berlion M et al. (1993) Tamoxifen enhances the cytotoxic effects of the nitrosourea fotemustine. Results on human melanoma cell lines. Eur J Cancer 29:2269–2273. CrossRefGoogle Scholar
  11. Fulda S, Debatin K-M (2006) Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 25:4798–4811. CrossRefGoogle Scholar
  12. Guida M, Tommasi S, Strippoli S et al. (2018) The search for a melanoma-tailored chemotherapy in the new era of personalized therapy: a phase II study of chemo-modulating temozolomide followed by fotemustine and a cooperative study of GOIM (Gruppo Oncologico Italia Meridionale). BMC Cancer 18:552. CrossRefGoogle Scholar
  13. Gundluru M, Sarva S, Kandula MKR et al. (2016) Phosphosulfonic acid-catalyzed green synthesis and bioassay of α-aryl-α ′-1,3,4-thiadiazolyl aminophosphonates. Heteroat Chem 27:269–278. CrossRefGoogle Scholar
  14. Hosseini-Sarvari M (2008) TiO2 as a new and reusable catalyst for one-pot three-component syntheses of α-aminophosphonates in solvent-free conditions. Tetrahedron 64:5459–5466. CrossRefGoogle Scholar
  15. Huang X-C, Wang M, Pan Y-M et al. (2013) Synthesis and antitumor activities of novel α-aminophosphonates dehydroabietic acid derivatives. Bioorg Med Chem Lett 23:5283–5289. CrossRefGoogle Scholar
  16. Hudson HR, Lee RJ (2014) A brief review of the anticancer activity of α-aminophosphonic acid derivatives and a report on the in vitro activity of some dialkyl α-aryl- (or Heteroaryl)-α-(diphenylmethylamino)methanephosphonates. Phosphorus Sulfur Silicon Relat Elem 189:1149–1155. CrossRefGoogle Scholar
  17. Keglevich G, Bálint E (2012) The kabachnik–fields reaction: mechanism and synthetic use. Molecules 17:12821–12835. CrossRefGoogle Scholar
  18. Kenawy E-RS, Azaam MM, Saad-Allah KM (2015) Synthesis and antimicrobial activity of α-aminophosphonates containing chitosan moiety. Arab J Chem 8:427–432. CrossRefGoogle Scholar
  19. Kiseleva LN, Kartashev AV, Vartanyan NL et al. (2018) The effect of fotemustine on human glioblastoma cell lines. Cell Tissue Biol 12:93–101. CrossRefGoogle Scholar
  20. Kraicheva I, Tsacheva I, Vodenicharova E et al. (2012) Synthesis, antiproliferative activity and genotoxicity of novel anthracene-containing aminophosphonates and a new anthracene-derived Schiff base. Bioorg Med Chem 20:117–124. CrossRefGoogle Scholar
  21. Li Y-J, Wang C-Y, Ye M-Y et al. (2015) Novel coumarin-containing aminophosphonatesas antitumor agent: synthesis, cytotoxicity, dna-binding and apoptosis evaluation. Molecules 20:14791–14809. CrossRefGoogle Scholar
  22. Maddina VA, Kalyankar MB, Kulkarni PA (2014) One-pot and catalyst-free synthesis of novel α - aminophosphonates under microwave irradiation and their Bioactivity. IOSR J Pharm Biol Sci 9:16–19. Google Scholar
  23. Magedov IV, Manpadi M, Van slambrouck S et al. (2007) Discovery and investigation of antiproliferative and apoptosis-inducing properties of new heterocyclic podophyllotoxin analogues accessible by a one-step multicomponent synthesis. J Med Chem 50:5183–5192. CrossRefGoogle Scholar
  24. Marinelli A, Lamberti G, Cerbone L et al. (2018) High-dose fotemustine in temozolomide-pretreated glioblastoma multiforme patients. Medicine 97:e11254. CrossRefGoogle Scholar
  25. Mirzaei M, Eshghi H, Rahimizadeh M et al. (2015) An eco-friendly three component manifold for the synthesis of α -aminophosphonates under catalyst and solvent-free conditions, X-ray characterization and their evaluation as anticancer agents. J Chin Chem Soc 62:1087–1096. CrossRefGoogle Scholar
  26. Mungara AK, Park Y-K, Lee KD (2012) Synthesis and antiproliferative activity of novel α-aminophosphonates. Chem Pharm Bull 60:1531–1537Google Scholar
  27. Rádai Z, Kiss NZ, Mucsi Z, Keglevich G (2016) Synthesis of α- hydroxyphosphonates and α -aminophosphonates. Phosphorus Sulfur Silicon Relat Elem 191:1564–1565. CrossRefGoogle Scholar
  28. Reddy NB, Sundar CS, Rani CR et al. (2016) Triton X-100 catalyzed synthesis of α-aminophosphonates. Arab J Chem 9:S685–S690. CrossRefGoogle Scholar
  29. Rezaei Z, Firouzabadi H, Iranpoor N et al. (2009) Design and one-pot synthesis of α-aminophosphonates and bis(α-aminophosphonates) by iron(III) chloride and cytotoxic activity. Eur J Med Chem 44:4266–4275. CrossRefGoogle Scholar
  30. Rezaei Z, Khabnadideh S, Zomorodian K et al. (2011) Design, synthesis, and antifungal activity of new α-aminophosphonates. Int J Med Chem 2011:1–11. Google Scholar
  31. Riss TL, Moravec RA, Niles AL et al. (2016) Cell viability assays. In Assay Guidance Manual [Internet eBook]. Eli Lilly & Company and the National Center for Advancing Translational Sciences.
  32. Sampath C, Harika P, Revaprasadu N (2016) Design, green synthesis, anti-microbial, and anti-oxidant activities of novel α -aminophosphonates via Kabachnik-Fields reaction. Phosphorus Sulfur Silicon Relat Elem 191:1081–1085. CrossRefGoogle Scholar
  33. Subba Reddy G, Maheswara Rao KU, Syama Sundar C et al. (2014) Neat synthesis and antioxidant activity of α-aminophosphonates. Arab J Chem 7:833–838. CrossRefGoogle Scholar
  34. Tiwari S, Sharif N, Gajare R et al. (2018) New 2-oxoindolin phosphonates as novel agents to treat cancer: a green synthesis and molecular modeling. Molecules 23:1981. CrossRefGoogle Scholar
  35. Venkata Ramana K, Rasheed S, Chandra Sekhar K et al. (2012) One-pot and catalyst-free synthesis of novel α-aminophosphonates under microwave irradiation and their biological activity. Der Pharm Lett 4:456–463Google Scholar
  36. Wu J, Duan L, Zhang L et al. (2018) Fotemustine, teniposide and dexamethasone versus high-dose methotrexate plus cytarabine in newly diagnosed primary CNS lymphoma: a randomised phase 2 trial. J Neurooncol 140:427–434. CrossRefGoogle Scholar
  37. Xia M, Lu Y (2007) Ultrasound-assisted one-pot approach to α-amino phosphonates under solvent-free and catalyst-free conditions. Ultrason Sonochem 14:235–240. CrossRefGoogle Scholar
  38. Ye M-Y, Yao G-Y, Pan Y-M et al. (2014) Synthesis and antitumor activities of novel α-aminophosphonate derivatives containing an alizarin moiety. Eur J Med Chem 83:116–128. CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Erika L. Loredo-Calderón
    • 1
  • Carlos A. Velázquez-Martínez
    • 2
  • Mónica A. Ramírez-Cabrera
    • 1
  • Eugenio Hernández-Fernández
    • 1
  • Verónica M. Rivas-Galindo
    • 3
  • Eder Arredondo Espinoza
    • 1
  • Susana T. López-Cortina
    • 1
    Email author
  1. 1.Universidad Autónoma de Nuevo León, Facultad de Ciencias Químicas, Laboratorio de Química Industrial y Laboratorio de Ingeniería Genética y Genómica Av. Universidad s/n, Cd. UniversitariaSan Nicolás De Los GarzaMexico
  2. 2.Faculty of Pharmacy and Pharmaceutical SciencesUniversity of AlbertaEdmontonCanada
  3. 3.Universidad Autónoma de Nuevo León, Facultad de MedicinaMonterreyMexico

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