title: Target β-catenin/CD44/Nanog axis in colon cancer cells by certain N'-(2-oxoindolin-3-ylidene)-2-(benzyloxy)benzohydrazides.
abstract: Cell surface molecule CD44 plays a major role in regulation of cancer stem cells CSCs on both phenotypic and functional level, however chemical inhibition approach of CD44 to targets CSCs is poorly studied. Herein, we report the discovery of certain N'-(2-oxoindolin-3-ylidene)-2-(benzyloxy)benzohydrazides as a novel inhibitor of CD44. Molecular docking study showed interference of the scaffold of these compounds with β-catenin/TCF-4 complex, building a direct relationship between CD44 inhibition and observed well-fitted binding domain. Compound 11a, most potent member elicits inhibition effect on TCF/LEF reporter activity conformed the involvement of Wnt pathway inhibition as a mechanism of action. Furthermore, the treatment by the mentioned compound leads to inhibition of embryonic transcriptional factor Nanog but not Sox2 or Oct-4 suggested specific targeted effect. Moreover, the cytotoxicity and cell cycle effect of this series seems to be dependent on CD44 expression.
authors.affiliation: Kayyali Chair, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt. Electronic address: dhna_2001@hotmail.com.
authors.forename: Awwad A
authors.initials: AA
authors.lastname: Radwan
authors.affiliation: Department of Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Saudi Arabia.
authors.forename: F
authors.initials: F
authors.lastname: Al-Mohanna
authors.affiliation: Kayyali Chair, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Fares K
authors.initials: FK
authors.lastname: Alanazi
authors.affiliation: Stem Cell Therapy & Tissue Re-engineering Program, King Faisal Specialized Hospital and Research Center, MBC-03, PO Box 3354, Riyadh 11211, Saudi Arabia.
authors.forename: P S
authors.initials: PS
authors.lastname: Manogaran
authors.affiliation: Stem Cell Therapy & Tissue Re-engineering Program, King Faisal Specialized Hospital and Research Center, MBC-03, PO Box 3354, Riyadh 11211, Saudi Arabia; Department of Pharmacology & Toxicology, Collage of Pharmacy, King Saud University, Saudi Arabia. Electronic address: aaldhfyan@kfshrc.edu.sa.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Al-Dhfyan
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D000071317:Nanog Homeobox Protein; D015398:Signal Transduction / Q000187:drug effects*; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; D006834:Hydrazines; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D051153:Wnt Proteins; D051176:beta Catenin
keywords: Benzohydrazides; Docking; Synthesis; β-Catenin