Skip to main content

Advertisement

SpringerLink
Log in

Structure-based design and synthesis of acyclic and substituted heterocyclic phosphonates linearly linked to thiazolobenzimidazoles as potent hydrophilic antineoplastic agents

  • Original Paper
  • Published:
Chemical Papers Aims and scope Submit manuscript

Abstract

As a contribution to our investigations to develop multidisciplinary entities of substituted heterocycle phosphor esters, in this paper, we prepared a series of thiazolobenzimidazoles incorporating phosphor esters of potential anticancer properties. Phosphoryl reagents were applied on E-3-(N,N-dimethylamino)-1-(3-methythiazolo[3,2-a]benzoimidazol-2-yl)prop-2-en-1-one and 1-(3-methylthiazolo[3,2-a]benzimidazol-2-yl)ethanone. The reactions proceeded under mild conditions to give an ensemble of 14 new phosphonates in good yields (68–74%). The stereoselective chemistry was studied by a series of heteronuclear 13C[1H]-nOe experiments. Based on the prediction studies in the early stage using PASS algorithm 14, the synthesized phosphonates were evaluated as antitumor candidates at a dose of 10 µmol/mL against human breast and human colon tumor (4 cultured cell lines each). Three products showed significant antineoplastic potency in relative to the standard drug, adriamycin. Permeability of the lead molecules was determined and the structure–activity relationship (SAR) was discussed to suggest a pro-drug chromophore. Furthermore, there was good coincidence of experimental data of antitumor properties and prediction results.

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

Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abdel-Aziz HA, Hamdy NA, Farag AM, Fakhr IMI (2008) Synthesis of some novel pyrazolo[1,5-a]pyrimidine, 1,2,4-triazolo[1,5-a]pyrimidine, pyrido[2,3-d]pyrimidine, pyrazolo[5,1-c]-1,2,4-triazine and 1,2,4-triazolo[5,1-c]-1,2,4-triazine derivatives incorporating a thiazolo[3,2-a]benzimidazole moiety. J Heterocycl Chem 45:1033–1037. doi:10.1002/jhet.5570450413

    Article  CAS  Google Scholar 

  • Abdel-Aziz HA, Saleh TS, El-Zahabi HSA (2010) Facile synthesis and in vitro antitumor activity of some pyrazolo[3,4-b]pyridines and pyrazolo[1,5-a] pyrimidines linked to a thiazolo[3,2-a]benzimidazole moiety. Arch Pharm Chem Life Sci 343:24–30. doi:10.1002/ardp.200900082

    CAS  Google Scholar 

  • Abdou WM, Bekheit MS (2016) One pot three-component synthesis of peptidomimics for investigation of antibacterial and antineoplastic properties. Arab J Chem. doi:10.1016/j.arabjc.2015.04.014

    Google Scholar 

  • Abdou WM, Kamel AA, Khidre RE, Geronikaki A, Ekonomopoulou MT (2012) 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. doi:10.1111/j.1747-0285.2012.01327

    Article  CAS  Google Scholar 

  • Abdou WM, Kamel AA, Khidre MD (2015) Design, synthesis, and antioxidant/antidiabetic activity of nucleic acid-bases bearing fused N, S-heterocycle phosphor esters. J Heterocycl Chem 52:1654–1662. doi:10.1002/jhet.2260

    Article  CAS  Google Scholar 

  • Abdou WM, Bekheit MS, Barghash RF (2016a) Microwave-assisted synthesis and diabetic/antioxidant assessments of 1,3,2-benzothiazaphosphole-3(2H)carbo-thioamide-, and diazaphosphole-3(2H)dicarbothioamide 2-oxide derivatives. Monatsh Chem 147:1797–1808. doi:10.1007/s00706-016-1721-y

    Article  CAS  Google Scholar 

  • Abdou WM, Ganoub NA, Ismail MAH, Sabry E, Barghash RF, Geronikaki A (2016b) Elaborating efficient protocols for synthesis of α- and β-aminomethylenebisphosphonate derivatives: Antiosteoarthritic/antiinflammatory assessments and docking studies. Arab J Chem. doi:10.1016/j.arabjc.2016.02.019

    Google Scholar 

  • Abdou WM, Ganoub NA, Sabry E (2016c) Spiro- and substituted hexylthiophene-triazaphospholes and phosphoramidates as potent antineoplastic agents: synthesis, biological evaluation and SAR studies. Monatsh Chem 147:619–626. doi:10.1007/s00706-015-1542-4

    Article  CAS  Google Scholar 

  • Abdou WM, Shaddy AA, Khidre MD (2016d) Efficient approaches for the synthesis of substituted thiazolo[3,2-a]-benzimidazole-phosphonates and -phosphinic diamide derivatives. Chem Select 1:6106–6110. doi:10.1002/slct.201601310

    CAS  Google Scholar 

  • Barghash RF, Abdou WM (2016) Pathophysiology of metastatic bone disease and the role of the second generation of bisphosphonates: from basic science to medicine. Curr Pharm Des 22:1546–1557. doi:10.2174/1381612822666160122093810

    Article  CAS  Google Scholar 

  • Bender PE, Hill D, Offen PH, Razgaitis K, Lavanchy P, Stringer OD, Sutton BM, Giswold DE, Dimertino M (1985) 5,6-Diaryl-2,3-dihydroimidazo[2,1-b]thiazoles: a new class of immunoregulatory antiinflammatory agents. J Med Chem 28:1169–1177. doi:10.1021/jm00147a008

    Article  CAS  Google Scholar 

  • Boyd MR, Paull KD (1995) Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen. Drug Dev Res 34:91–109. doi:10.1002/ddr.430340203

    Article  CAS  Google Scholar 

  • Coleman RE (2001) Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 27:165–176. doi:10.1053/ctrv.2000.0210

    Article  CAS  Google Scholar 

  • Coppola GM, Hardtmann GE, Pfister OR (1976) Chemistry of 2H-3,1-benzoxazine-2,4-(1H)-dione (isatoic anhydride). 2. Reactions with thiopseudoureas and carbanions. J Org Chem 41:825–831. doi:10.1021/jo00867a017

    Article  CAS  Google Scholar 

  • D’Amico JJ, Campbell RH, Guinn EC (1964) Derivatives of 3-Methylthiazolo[3,2-a]benzimidazole. J Org Chem 29:865–869. doi:10.1021/jo01027a024

    Article  Google Scholar 

  • Dijoseph JF, Palumbo GJ, Crossley R, Santili AA, Nielsen ST (1991) Gastric antisecretory activity of an acid stable H+/K+ATPase inhibitor, WY-26,769. Drug Dev Res 23:57–64. doi:10.1002/ddr.430230106

    Article  CAS  Google Scholar 

  • Dillman RO, Ryan KP, Dillman JB, Shawler DL, Maguire R (1992) WY 18,251 (Tilomisole), an analog of levamisole: tolerability, and immune modulating effects in cancer patients. Mol Biotherap 4:10–14

    CAS  Google Scholar 

  • Farag AM, Dawood KM, Abdel-Aziz HA, Hamdy NA, Fakhr IMI (2011) Synthesis of some new azole, pyrimidine, pyran, and benzo/naphtho[b]furan derivatives incorporating thiazolo[3,2-a]benzimidazole moiety. J Heterocycl Chem 48:355–360. doi:10.1002/jhet.584

    Article  CAS  Google Scholar 

  • Ferlay J, Bray F, Parkin DM, Pisani P (Eds.) Globocan (2000) Cancer incidence, mortality and prevalence worldwide. (2001) version 1.0. IARC Cancer Base No. 5. Lyon, IARC Press

  • Geronikaki A, Lagunin A, Poroikov V, Filimonov D, Hadjipavlou-Litina D, Vicini P (2002) Computer aided prediction of biological activity spectra: evaluating versus known and predicting of new activities for thiazole derivatives. SAR QSAR Environ Res 13:457–471. doi:10.1080/10629360290014322

    Article  CAS  Google Scholar 

  • Goel RK, Kumar V, Mahajan MP (2005) Quinazolines revisited: search for novel anxiolytic and GABAergic agents. Bioorg Med Chem Lett 15:2145–2148. doi:10.1016/j.bmcl.2005.02.023

    Article  CAS  Google Scholar 

  • Gooodrich KH, Alvarez X, Holcombe RF (1993) Effect of levamisole on major histocompatibility complex class I expression in colorectal and breast carcinoma cell lines. Cancer 72:225–230

    Article  Google Scholar 

  • Harrison MR, Holen KD, Liu G (2009) Beyond taxanes: a review of novel agents that target mitotic tubulin and microtubules, kinases, and kinesins. Clin Adv Hematol Oncol 7:54–64

    Google Scholar 

  • Hopkins AL, Groom CR, Alex A (2004) Ligand efficiency: a useful metric for lead selection. Drug Discov Today 9:430–431. doi:10.1016/S1359-6446(04)03069-7

    Article  Google Scholar 

  • Ibrahim AS, Khaled HM, Mikhail NNH, Baraka H, Kamel H (2014) Cancer Incidence in Egypt: results of the national population-based cancer registry program. J Cancer Epidemiol 2014:1–18. doi:10.1155/2014/437971

    Article  Google Scholar 

  • Kafarski P, Lejczak B (2001) Aminophosphonic acids of potential medical importance. Curr Med Chem Anti Canc Agents 1:301–312. doi:10.2174/1568011013354543

    Article  CAS  Google Scholar 

  • Kamel AA, Geronikaki A, Abdou WM (2012) Inhibitory effect of novel S. N-bisphosphonates on some carcinoma cell lines, osteoarthritis, and chronic inflammation. Eur J Med Chem 51:239–249. doi:10.1016/j.ejmech.2012.02.047

    Article  CAS  Google Scholar 

  • Kingston DG, Newman DJ (2007) Taxoids: cancer-fighting compounds from nature. Curr Opin Drug Discov Devel 10:130–144 PMID: 17436548

    CAS  Google Scholar 

  • Lagunin AA, Gomazkov OA, Filimonov DA, Gureeva TA, Dilakyan EA, Kugaevskaya EV, Elisseeva YE, Solovyeva NI, Poroikov VV (2003) Computer-aided selection of potential antihypertensive compounds with dual mechanism of action. J Med Chem 46:3326–3332. doi:10.1021/jm021089h

    Article  CAS  Google Scholar 

  • Lee YY, Derakhshan MH (2013) Environmental and lifestyle risk factors of gastric cancer. Arch Iran Med 16:358–365

    Google Scholar 

  • Leeson PD, Springthorpe B (2007) The influence of drug-like concepts on decision-making in medicinal chemistry. Nat Rev Drug Discov 6:881–890. doi:10.1038/nrd2445

    Article  CAS  Google Scholar 

  • Majoural JP, Bertrand G (Eds.) (2002) New aspects in phosphorus chemistry. Springer, Heidelberg March J 1985. Advanced organic chemistry, Wiley, third ed. pp 800–802

  • Neidlein R, Hahn DU, Kramer W, Krieger C (1998) Synthesis and chemical reactions of new phosphono-phosphino substituted γ-thiapyrones. Heterocycles 47:221–262. doi:10.3987/COM-97-S(N)9

    Article  CAS  Google Scholar 

  • Palinko I, Kukovecz A, Torok B, Kortvelyesi T (2000) On the mechanism of a modified Perkin condensation leading to a-phenylcinnamic acid stereoisomers—experiments and molecular modelling. Monatsh Chem 131:1097–1104. doi:10.1007/s007060070043

    Article  CAS  Google Scholar 

  • Patia S, Schowartz A (1960) Notes- condensation of triethyl phosphonoacetate with aromatic aldehydes. J Org Chem 25:1232–1237. doi:10.1021/jo01077a604

    Article  Google Scholar 

  • Poroikov VV, Filimonov DA (2002) How to acquire new biological activities in old compounds by computer prediction. J Comput Aided Mol Des 16:819–824

    Article  CAS  Google Scholar 

  • Poroikov VV, Filimonov DA, Borodina YuV, Lagunin AA, Kos A (2000) Robustness of biological activity spectra predicting by computer program PASS for noncongeneric sets of chemical compounds. J Chem Inf Comput Sci 40:1349–1355. doi:10.1021/ci000383k

    Article  CAS  Google Scholar 

  • Püsküllü MO, Yıldız S, Göker H (2010) Synthesis and antistaphylococcal activity of N-substituted-1H-benzimidazole-sulphonamides. Ach Pharm Life Sci 343:31–39. doi:10.1002/ardp.200900199

    Google Scholar 

  • Rainsford KD (1989) Effects of anti-inflammatory drugs on interleukin 1-induced cartilage proteoglycan resorption in vitro: inhibition by aurothiophosphines but no influence from perturbed eicosanoid metabolism. J Pharm Pharmacol 41:112–117. doi:10.1111/j.2042-7158.1989.tb06404.x

    Article  CAS  Google Scholar 

  • Runowicz CD (2006) Clarifying cancer mortality rates. Science 313:171–172. doi:10.1126/science.313.5784.171c

    Article  CAS  Google Scholar 

  • Santis CD, Ma J, Bryan L, Jemal A (2014) Breast cancer statistics, 2013. CA Cancer J Clin 64:52–62. doi:10.3322/caac.21203

    Article  Google Scholar 

  • Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 82:1107–1112. doi:10.1093/jnci/82.13.1107

    Article  CAS  Google Scholar 

  • Surveillance, Epidemiology, and End Results (SEER) Program (2013) SEER* Stat Database: Incidence-SEER 9 Regs Research Data, Nov. 2012 Sub (1973-2010) < Katrina/Rita Population Adjustment > -Linked To County Attributes-Total US, 1969–2011 Counties. Bethesda, MD: National Cancer Institute, Division of Cancer Control and Population Sciences, Surveillance Research Program, Surveillance Systems Branch; 2013. Released April 2013 based on the November 2012 submission

  • Troev K (2006) Chemistry and application of H-phosphonates, 1st edn. Elsevier, Amsterdam

    Google Scholar 

  • Varmus H (2006) The new era in cancer research. Science 312:1162–1165. doi:10.1126/science.1126758

    Article  CAS  Google Scholar 

  • Westheimer FH (1987) Why nature chose phosphates. Science 235:1173–1178. doi:10.1126/science.2434996

    Article  CAS  Google Scholar 

  • World Cancer Report (2014) World Health Organization, 2014. Chapter 5.4. ISBN 9283204298

  • Website: http://www.ibmc.msk.ru/PASS

  • Yacum MD (1994) The use of immunomodulators in early rheumatoid arthritis. Semin Arthritis Rheum 23:44–49. PMID: 7939731

    Article  Google Scholar 

Download references

Acknowledgements

Authors would like to thank the National Research Centre, Dokki, Cairo Egypt (project# 11010340) for financial support. Authors are also thankful to the National Cancer Institute, NY, USA for carrying out the antitumor screening and taking care of getting the culture cell lines.

Author information

Authors and Affiliations

  1. Chemical Industries Division, National Research Centre, Elbehouth St., Dokki, Cairo, 12311, Egypt

    Wafaa M. Abdou, Abeer A. Shaddy & Azza A. Kamel

Authors
  1. Wafaa M. Abdou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abeer A. Shaddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Azza A. Kamel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wafaa M. Abdou.

Additional information

Dedicated to one of the greatest contributors to Biophosphorus Chemistry–Prof. Richard Neidlein (Late, 2012), Heidelberg University, Germany.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (RAR 298 kb)

Supplementary material 2 (RAR 285 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abdou, W.M., Shaddy, A.A. & Kamel, A.A. Structure-based design and synthesis of acyclic and substituted heterocyclic phosphonates linearly linked to thiazolobenzimidazoles as potent hydrophilic antineoplastic agents. Chem. Pap. 71, 1961–1973 (2017). https://doi.org/10.1007/s11696-017-0190-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11696-017-0190-z

Keywords

Search

Navigation