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  3. Synthesis, evaluation of thymidine phosphorylase and angiogenic inhibitory potential of ciprofloxacin analogues: Repositioning of ciprofloxacin from antibiotic to future anticancer drugs

Synthesis, evaluation of thymidine phosphorylase and angiogenic inhibitory potential of ciprofloxacin analogues: Repositioning of ciprofloxacin from antibiotic to future anticancer drugs

  • Bioorg Chem. 2020 Jul;100:103876. doi: 10.1016/j.bioorg.2020.103876.
Sohail Anjum Shahzad 1,  Ayesha Sarfraz 2,  Muhammad Yar 3,  Zulfiqar Ali Khan 4,  Syed Ali Raza Naqvi 4,  Sadia Naz 5,  Nazeer Ahmad Khan 2,  Umar Farooq 6,  Razia Batool 7,  Muhammad Ali 8
Affiliations

Affiliations

  • 1 Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan. Electronic address: sashahzad@cuiatd.edu.pk.
  • 2 Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan.
  • 3 Interdisciplinary Research Center in Biomedical Materials, COMSATS University Islamabad, Lahore Campus, Lahore 54000, Pakistan. Electronic address: drmyar@cuilahore.edu.pk.
  • 4 Department of Chemistry, Government College University, Faisalabad 38000, Pakistan.
  • 5 Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan; Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China.
  • 6 Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan. Electronic address: umarf@cuiatd.edu.pk.
  • 7 Interdisciplinary Research Center in Biomedical Materials, COMSATS University Islamabad, Lahore Campus, Lahore 54000, Pakistan.
  • 8 Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 611, Oman.
PMID: 32388426 DOI: 10.1016/j.bioorg.2020.103876
Abstract

Over expression of thymidine phosphorylase (TP) in various human tumors compared to normal healthy tissue is associated with progression of Cancer and proliferation. The 2-deoxy-d-ribose is the final product of thymidine phosphorylase (TP) catalyzed reaction. Both TP and 2-deoxy-d-ribose are known to promote unwanted angiogenesis in cancerous cells. Discovery of potent inhibitors of thymidine phosphorylase (TP) can offer appropriate approach in Cancer treatment. A series of ciprofloxacin 2, 3a-3c, 4a-4d, 5a-5b, 6 and 7 has been synthesized and characterized using spectroscopic techniques. Afterwards, inhibitory potential of synthesized ciprofloxacin 2, 3a-3c, 4a-4d, 5a-5b, 6 and 7 against thymidine phosphorylase Enzyme was assessed. Out of these twelve analogs of ciprofloxacin nine analogues 3a-3c, 4a-4c, 5a-5b and 6 showed good inhibitory activity against thymidine phosphorylase. Inhibitory activity as presented by their IC50 values was found in the range of 39.71 ± 1.13 to 161.89 ± 0.95 μM. The 7-deazaxanthine was used as a standard inhibitor with IC50 = 37.82 ± 0.93 μM. Furthermore, the chick chorionic allantoic membrane (CAM) assay was used to investigate anti-angiogenic activity of the most active ciprofloxacin-based inhibitor 3b. To enlighten the important binding interactions of ciprofloxacin derivatives with target Enzyme, the structure activity relationship and molecular docking studies of chosen ciprofloxacin analogues was discussed. Docking studies revealed key π-π stacking, π-cation and hydrogen bonding interactions of ciprofloxacin analogues with active site residues of thymidine phosphorylase Enzyme.

Keywords

Antiangiogenic activity; Ciprofloxacin; Thymidine phosphorylase inhibitors.

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