Design, synthesis, in-vitro thymidine phosphorylase inhibition, in-vivo antiangiogenic and in-silico studies of C-6 substituted dihydropyrimidines

Fatima Iftikhar; Farhana Yaqoob; Nida Tabassum; Muhammad Saeed Jan; Abdul Sadiq; Saba Tahir; Tahira Batool; Basit Niaz; Farzana Latif Ansari; Muhammad Iqbal Choudhary; Umer Rashid

doi:10.1016/j.bioorg.2018.05.026

Design, synthesis, in-vitro thymidine phosphorylase inhibition, in-vivo antiangiogenic and in-silico studies of C-6 substituted dihydropyrimidines

Bioorg Chem. 2018 Oct:80:99-111. doi: 10.1016/j.bioorg.2018.05.026. Epub 2018 Jun 1.

Authors

Affiliations

¹ Department of Chemistry, Hazara University, Mansehra 21120, Pakistan.
² Department of Pharmacology, Rawalpindi Medical University, Rawalpindi 463000, Pakistan.
³ Department of Pharmacy, University of Malakand, Chakdara 18000, Dir (L), Pakistan.
⁴ Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus 22060, Pakistan.
⁵ H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Department of Biotechnology, University of Azad Jammu & Kashmir Bagh, Pakistan.
⁶ Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.
⁷ H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
⁸ Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus 22060, Pakistan. Electronic address: umerrashid@ciit.net.pk.

PMID: 29894893
DOI: 10.1016/j.bioorg.2018.05.026

Abstract

Thymidine phosphorylase (TP) is an angiogenic enzyme. It plays an important role in angiogenesis, tumour growth, invasion and metastasis. In current research work, we study the effect of structural modification of dihydropyrimidine-2-ones (DHPM-2-ones) on TP inhibition. A series of eighteen new derivatives of 3,4-dihydropyrimidone-2-one were designed and synthesized through the structural modification at C-6 position. All these new derivatives were then assessed for in-vitro inhibition of thymidine phosphorylase (TP) from E. coli. Oxadiazole derivatives 4a-e exhibited excellent TP-inhibition at low micromolar concentration levels better than standard drug 7-deazaxanthine (7-DX). Among all these compounds, 4b was found to be the most potent with IC₅₀ = 1.09 ± 0.004 μM. Anti-angiogenesis potential of representative compounds were also studied in a chorioallantoic membrane (CAM) assay. Here again, compound 4b was found to be the potent anti-angiogenesis compound in a CAM assay. Docking studies were also performed with Molecular Operating Environment (MOE) to further analyse the mode of inhibition of these compounds. Binding mode analysis of the most active inhibitors showed that these are well accommodated into the binding site of enzyme though stable hydrogen bonding and hydrophobic interactions.

Keywords: Antiangiogenesis; Chorioallantoic membrane assay; Dihydropyrimine-2-ones; Thymidine phosphorylase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inhibitors / chemical synthesis*
Angiogenesis Inhibitors / metabolism
Angiogenesis Inhibitors / pharmacology
Animals
Binding Sites
Catalytic Domain
Chickens
Drug Design*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology
Escherichia coli / enzymology
Escherichia coli Proteins / antagonists & inhibitors
Escherichia coli Proteins / metabolism*
Inhibitory Concentration 50
Molecular Docking Simulation
Neovascularization, Physiologic / drug effects
Pyrimidines / chemistry*
Pyrimidines / metabolism
Pyrimidines / pharmacology
Structure-Activity Relationship
Thymidine Phosphorylase / antagonists & inhibitors
Thymidine Phosphorylase / metabolism*

Substances

Angiogenesis Inhibitors
Enzyme Inhibitors
Escherichia coli Proteins
Pyrimidines
Thymidine Phosphorylase