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Computer-aided design, synthesis, and biological studies of anticological nitrogen-containing tetraphosphonic acids against melanoma

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Abstract

As a part of our quest to develop new bioactive bisphosphonic acids, we synthesized a series of bis(α-aminobisphosphonic acids) in good yields (66–78%) as new entities for treating malignant melanoma. The reaction of the Schiff bases, 1,4-pheneylenediimines with the Horner–Emmons–Wadsworth reagent, tetraethyl methylene-1,1-bisphosphonate in DMF/LiOH (aq) solution led exclusively to a meso form of nitrogen-containing tetraphosphonates (NTPs) (bis(α-aminobisphosphonates)). Next, hydrolysis of the ester moieties of the tetraphosphonate products yielded the corresponding tetraphosphonic acids, which treated with MeOH/KOH (aq, 20%) to give the respective NTP-tetrapotassium salts. Prior to synthesis, the suggested structures (and others) were applied to the computer-assisted molecular modeling, PASS program to investigate their prospective biological properties. Cytotoxic properties were later evaluated against five malignant melanoma cell lines that originated from different categories of malignant melanoma primary stage (I/II), histologically advanced stage (III/IV), and metastasized malignancy. Almost all tested compounds showed antitumor activity though on different levels. Three NTP salts were found to have activity in the range of GI50 0.650–5.73 μM vs. control reference GI50: 1.745–6.50 μM. Structure activity relationship is also discussed.

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Acknowledgements

The authors would 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.

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Authors and Affiliations

  1. Chemical Industries Research Division, National Research Centre, Elbuhouth St., Dokki, Cairo, 12622, Egypt

    Mohamed S. Bekheit, Reham F. Barghash & Wafaa M. Abdou

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  1. Mohamed S. Bekheit
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  2. Reham F. Barghash
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  3. Wafaa M. Abdou
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Correspondence to Wafaa M. Abdou.

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Bekheit, M.S., Barghash, R.F. & Abdou, W.M. Computer-aided design, synthesis, and biological studies of anticological nitrogen-containing tetraphosphonic acids against melanoma. Monatsh Chem 149, 1481–1491 (2018). https://doi.org/10.1007/s00706-018-2196-9

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  • DOI: https://doi.org/10.1007/s00706-018-2196-9

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