Chemical Papers

, Volume 72, Issue 11, pp 2753–2768 | Cite as

Microwave promoted synthesis and anticological screening of β-aminobisphosphonates-based benzothiazole motif against human breast and colon cancer diseases

  • Wafaa M. AbdouEmail author
  • Maha D. Khidre
  • Abeer A. Shaddy
Original Paper


New antineoplastic series of substituted benzothiazolo-β-aminobisphosphonic acids have been developed on the basis of the prospecting potency of the benzothiazole motifs and the aminomethylenebisphosphonate moiety as well as on the prediction of the biological activity utilizing computer program PASS, version 2014-1. Target compounds were obtained in excellent yields (70–90%) via Phospha–Michael-type addition reaction of tetraethyl methylene-1,1-bisphosphonate reagent to a group of Schiff bases incorporating benzothiazole moiety. The reactions proceeded under microwave irradiation, utilizing the advantages of the environment, friendly protocol such as high efficiency, short reaction time, and excellent yields. In consistency with the prospected results, the new NBP acids revealed positive properties against human breast and colon tumor cell lines. Remarkable potency for six lead compounds (out of 12) was observed against breast (MCF7, MDAMB/435, MDAMB/231/ATCC, HS-578T with GI50: 2.05–6.47 μM) and colon (COLO-205, HCT-116, HCC-2998, and SW-620 with GI50: 3.03–7.92 μM) carcinoma cell lines when compared with the positive control Adriamycin (breast, GI50: 3.27–6.64 μM; colon, GI50: 4.09–8.75 μM). Notably, there is a consistency between the prediction and the determined biological results.


β-Aminobisphosphonates Benzothiazoles Antitumor agents Phospha–Michael addition Structure activity relationships 



Authors like to thank the National Research Centre, Dokki, Cairo, Egypt (project # 10010340) for the financial support of the present work. They also are grateful to Cancer Research Institute, NY, USA, for handling the antitumor properties.

Supplementary material

11696_2018_505_MOESM1_ESM.rar (827 kb)
Supplementary material 1 (RAR 826 kb)


  1. Abdou WM, Shaddy AA (2008) Novel microwave-assisted one-pot synthesis of heterocycle phosphor esters and cyclic oxophospholes with antibiotic activity. Lett Org Chem (LOC) 5:569–575. CrossRefGoogle Scholar
  2. Abdou WM, Ganoub NA; Geronikaki A, Sabry E (2008) Synthesis, properties, and perspectives of gem-diphosphono substituted-thiazoles. Eur J Med Chem (EMdC) 43: 1015-1024. 10.1016/j.ejmech.2007.07.005Google Scholar
  3. Abdou WM, Barghash RF, Sediek AA (2012a) Design of new 2-hydroxyphenylamino- and benzoxazole-methylenebisphosphonates vs chronic inflammation and cancer diseases. From hydrophobicity prediction to synthesis and biological evaluation. Eur J Med Chem 57:362–372. CrossRefPubMedGoogle Scholar
  4. Abdou WM, Kamel AA, Khidre RE, Geronikaki A, Ekonomopoulou MT (2012b) Synthesis of 5- and 6-N-heterocyclic methylenebisphosphonate derivatives and evaluation of their cytogenetic activity in normal human lymphocyte cultures. Chem Biol Drug Des 79:719–730. CrossRefPubMedGoogle Scholar
  5. Abdou WM, Khidre RE, Kamel AA (2012c) Elaborating on efficient anti-proliferation agents of cancer cells and anti-inflammatory-based n-bisphosphonic acids. Arch Pharm Chem Life Sci 345:123–136. CrossRefGoogle Scholar
  6. Abdou WM, Barghash RF, Bekheit MS, Geronikaki A (2016a) Cytotoxicity and anti-inflammation profiles of synthesized thiazoles-based N-bisphosphonates and relevant bisphosphonic acids. ChemSelect 1:3797–3803. CrossRefGoogle Scholar
  7. Abdou WM, Shaddy AA, Khidre RE, Awad GEA (2016b) Synthesis and antimicrobial evaluation of newly synthesized N, S-bisphosphonate derivatives. J Heterocycl Chem 53:525–532. CrossRefGoogle Scholar
  8. Abdou WM, Bekheit MS, Barghash RF (2016c) Microwave-assisted synthesis and diabetic/antioxidant assessments of 1,3,2-benzothiazaphosphole-3(2H) carbothioamide, and -diazaphosphole-3(2H)dicarbothioamide 2-oxide derivatives. Monatsh Chem 147:1797–1808. CrossRefGoogle Scholar
  9. Abdou WM, Ganoub NA, Ismail MAH, Sabry E, Barghash RF, Geronikaki A (2017) Developing efficient protocols for synthesis, antiosteoarthritic, antiinflammatory assessments and docking studies of nitrogen-containing bisphosphonate derivatives. Arabian J Chem 10:1084–1097. CrossRefGoogle Scholar
  10. Baron RA, Tavaré R, Figueiredo AC, Baewska KM, Kashemirov BA, McKenna CE, Ebetino FH, Taylor A, Rogers MJ, Coxon FP, Seabra MC (2009) Phosphono-carboxylates inhibit the second geranylgeranyl addition by rab geranylgeranyl transferase. Biol Chem 284:6861–6868. CrossRefGoogle Scholar
  11. Brown JE, Robert EC (2002) The role of bisphosphonates in breast cancer: the present and future role of bisphosphonates in the management of patients with breast cancer. Breast Cancer Res 4:24–29. CrossRefPubMedGoogle Scholar
  12. Busch M, Rave-Frank M, Hille A, Duhmke E (1998) Influence of clodronate on breast cancer cells in vitro. Eur. J. Med. Res. 3:427–431 PMID: 9737889 PubMedGoogle Scholar
  13. Ebetino FHM, Francis D, Rogers MJ, Russell RGG (1998) Mechanisms of action of Etidronate and other bisphosphonates. Rev Contemp Pharmacother 9:233–243Google Scholar
  14. Ebrahimpour A, Francis MD (1995) Bisphosphonate therapy in acute and chronic bone loss: Physical chemical considerations in bisphosphonate-related therapies. In: Bijvoet O, Fleisch HA, Canfield RE, Russell RGG (eds) Bisphosphonates on Bones. Elsevier Science, Amsterdam, pp 125–136Google Scholar
  15. Ergenç N, Çapan G, Günay NS, Özkirimli S, Güngör M, Özbey S, Kendi E (1999) Synthesis and hypnotic activity of new 4-thiazolidinone and 2-thioxo-4,5-imidazolidinedione derivatives. Arch Pharm 332:343–347 PMID: 10575366 CrossRefGoogle Scholar
  16. Fleisch H (1988) Bisphosphonates: A new class of drugs in diseases of bone and calcium metabolism. In: Baker PF (ed) Handbook of experimental pharmacology. Springer, Berlin/Heidelberg, pp 441–466Google Scholar
  17. Fleisch H (2002) The role of bisphosphonates in breast cancer: development of bisphosphonates. Breast Cancer Res 4:30–34 PMID: 11879557 CrossRefPubMedGoogle Scholar
  18. Gerth K, Bedorf N, Hofle G, Irschik H, Reichenbach H (1996) Epothilons A and B: antifungal and cytotoxic compounds from sorangium cellulosum (myxobacteria) production, physico-chemical and biological properties. J Antibiot 49:560–563. CrossRefPubMedGoogle Scholar
  19. Kaboudin B, Nazari R (2001) Microwave-assisted synthesis of 1-aminoalkyl phosphonates under solvent-free conditions. Tetrahedron Lett 42:8211–8213. CrossRefGoogle Scholar
  20. Kitamura T, Itoh M, Noda T, Matsuura M, Wakabayashi K (2004) Combined effects of cyclooxygenase-1 and cyclooxygenase-2 selective inhibitors on intestinal tumorigenesis in adenomatous polyposis coli gene knockout mice. Int J Cancer 109:576–580. CrossRefPubMedGoogle Scholar
  21. Lipton A, Theriault RL, Hortobagyi GN, Simeone J, Knight RD, Mellars K, Reitsma DJ, Heffernan M, Seaman J (2000) Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases. J. Cancer 88:1082–1090CrossRefGoogle Scholar
  22. Maksymowych WP (2002) Bisphosphonates: anti-inflammatory properties. Curr Med Chem Anti- Inflamm & Anti-Allergy Agents 1:15–28. CrossRefGoogle Scholar
  23. Mckenna CE, Kashemirov BA, Li ZM (1999) Synthetic approaches to biologically active bisphosphonates and phosphonocarboxylates. Phosphorus, Sulfur, and Silicon and the Relat Elem 144:313–316. CrossRefGoogle Scholar
  24. Panico AM, Geronikaki A, Mgonzo R, Cardile V, Gentile B, Doytchinova I (2003) Aminothiazole derivatives with antidegenerative activity on cartilage. Bioorg Med Chem 11:2983–2989. CrossRefPubMedGoogle Scholar
  25. Plotkin LI, Aguirre JI, Kousteni S, Manolagas SC, Bellido T (2005) Bisphosphonates and estrogens inhibit osteocyte apoptosis via distinct molecular mechanisms downstream of extracellular signal-regulated kinase activation. J Biol Chem 280:7317–7325. CrossRefPubMedGoogle Scholar
  26. Poroikov V, Filimonov D (2005) PASS: Prediction of biological activity spectra for substances. In: Helma C (ed), Predictive toxicology, Taylor & Francis, pp 459-478Google Scholar
  27. Poroikov V, Filimonov D, Associates (1992-2014) Prediction of activity spectra for substances. Website:
  28. Russel RG (2006) Bisphosphonates: from bench to bedside. Ann NY Acad Sci. 1068:367–401. CrossRefGoogle Scholar
  29. Russell RG (1999) The bisphosphonate odyssey. A journey from chemistry to the clinic. Phosphorus, Sulfur, and Silicon 144–146:793–830Google Scholar
  30. Saleh TS, Bogami AS (2016) A simplified green chemistry approach to synthesis of azolo[1,5-a]pyrimidine incorporated thiophene moiety. Heterocycles 92:2066–2077. CrossRefGoogle Scholar
  31. Sasse F, Steinmetz H, Höfle G, Reichenbach H (2003) Archazolids, new cytotoxic macrolactones from archangium gephyra (myxobacteria) production, isolation, physico-chemical and biological properties. J Antibiot 56:520–525. CrossRefPubMedGoogle Scholar
  32. Shaddy AA, Kamel AA, Abdou WM (2013) Synthesis, quantitative structure–activity relationship, and anti-inflammatory profiles of substituted 5- and 6-N-heterocycle bisphosphonate esters. Synth Communs 43:236–252. CrossRefGoogle Scholar
  33. Siddiqui N, Arshad MF, Khan SA (2009) Synthesis of some new coumarin incorporated thiazolyl semicarbazones as anticonvulsants. Acta Pol Pharm 66:161–167PubMedGoogle Scholar
  34. Taori K, Paul VJ, Luesch H (2008) Structure and activity of largazole, a potent antiproliferative agent from the Floridian marine cyanobacterium symploca sp. J Am Chem Soc 130:1806–1807. CrossRefPubMedGoogle Scholar
  35. Wang L, Kamath A, Daz H, Li L, Bukowski JF (2001) Antibacterial effect of human Vγ2 Vδ2 T cells in vivo. J Clin Invest 108:1349–1357. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Wardle NJ, Bligh SWA, Hudson HR (2005) Organophosphorus chemistry: therapeutic intervention in mechanisms of viral and cellular replication. Curr Org Chem 9:1803–1828. CrossRefGoogle Scholar
  37. Westheimer FH (1987) Why nature chose phosphates. Science 235:1173–1178. CrossRefPubMedGoogle Scholar
  38. Wyngaert TVD, Huizing MT, Fossion E, Vermorken JB (2009) Bisphosphonates in oncology: rising stars or fallen heroes. Oncologist 14:181–191. CrossRefPubMedGoogle Scholar
  39. Yoneda T, Sasak A, Dustan C, William PJ, Bauss F, Clerck YAD, Mundy GR (1997) Inhibition of osteolytic bone metastasis of breast cancer by combined treatment with the bisphosphonate ibandronate and tissue inhibitor of the matrix metalloproteinase-2. J Clin Invest 99:2509–2517. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Institute of Chemistry, Slovak Academy of Sciences 2018

Authors and Affiliations

  1. 1.Chemical Industries DivisionNational Research CentreDokkiEgypt

Personalised recommendations