title: Reprofiling of full-length phosphonated carbocyclic 2'-oxa-3'-aza-nucleosides toward antiproliferative agents: Synthesis, antiproliferative activity, and molecular docking study.
abstract: A series of phosphonated carbocyclic 2'-oxa-3'-aza-nucleosides were synthesized via 1,3 dipolar cycloaddition and evaluated for their in vitro antiproliferative activity against the growth of cancer cell lines (MCF-7, A2780, HCT116) and normal non-transformed fibroblast (MRC5) using MTT assay. Synthesized compounds exhibited antiproliferative activity in the micromolar range. Compounds 11b showed the highest activity against MCF-7 cells (IC50of 0.2344 μm). Cell cycle analysis was performed for compound 11b on MCF7 cells showing arrest of cells in the S phase. Molecular docking of synthesized compounds confirmed high affinity of these compounds to two different receptors for anticancer nucleosides on dCK, namely the 1P5Z and 2ZIA, showing scores higher than the cognate ligand for all tested compounds. All synthesized compounds were evaluated according to the Lipinski, Veber, and Opera rules, and all of them passed the evaluation showing excellent features, superior to reference drugs. In addition, ADME for all the synthesized compounds was predicted through a theoretical kinetic study using the discovery studio 3.1 software.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Majdi M
authors.identifier: http://orcid.org/0000-0002-9912-1456
authors.initials: MM
authors.lastname: Bkhaitan
authors.affiliation: Science and Technology Unit (STU), Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Agha Zeeshan
authors.initials: AZ
authors.lastname: Mirza
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Ashraf N
authors.initials: AN
authors.lastname: Abdalla
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Hina
authors.initials: H
authors.lastname: Shamshad
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.
authors.forename: Zaheer
authors.initials: Z
authors.lastname: Ul-Haq
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alarjah
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Piperno
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001372:Aza Compounds; D009705:Nucleosides; D063065:Organophosphonates
keywords: ADME; antiproliferative; deoxycytidine kinase; isoxazolidine nucleosides; molecular docking; phosphonated nucleosides