title: Discovery, optimization, and pharmacophore modeling of oleanolic acid and analogues as breast cancer cell migration and invasion inhibitors through targeting Brk/Paxillin/Rac1 axis.
abstract: Bioassay-guided fractionation of Terminalia bentzoe L. leaves methanol extract identified the known triterpene oleanolic acid (1) as its major breast cancer cell migration inhibitor. Further chemical optimization afforded five new (9-12 and 15) and seven known (4-8, 13, and 14) semisynthetic analogues. All compounds were tested for their ability to inhibit human breast cancer MDA-MB-231 cells migration, proliferation, and invasion. The results revealed that 3-O-[N-(3'-chlorobenzenesulfonyl)-carbamoyl]-oleanolic acid (11) and 3-O-[N-(5'-fluorobenzenesulfonyl)-carbamoyl]-oleanolic acid (12) were the most active hits at low μM concentration. Western blot analysis indicated the activity of 1, 11, and 12 might be related, at least in part, to the suppression of Brk/Paxillin/Rac1 signaling pathway. Pharmacophore modeling study was conducted to better understand the common structural binding epitopes important for the antimigratory activity. The sulfonyl carbamoyl moiety with an optimal bulkiness electron-deficient phenyl ring is associated with improved activity. This study is the first to discover the antimigratory and anti-invasive activities of oleanolic acid and analogues through targeting the Brk/Paxillin/Rac1 axis.
authors: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, 71201, USA; Department of Pharmacognosy, Faculty of Pharmacy, Helwan University, Helwan, Cairo, 11795, Egypt.
authors: Heba E
authors: HE
authors: Elsayed
authors: Mohamed R
authors: MR
authors: Akl
authors: Hassan Y
authors: HY
authors: Ebrahim
authors: Asmaa A
authors: AA
authors: Sallam
authors: Eman G
authors: EG
authors: Haggag
authors: Amel M
authors: AM
authors: Kamal
authors: Khalid A
authors: KA
authors: El Sayed
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D055808:Drug Discovery; D005260:Female; D006801:Humans; D008958:Models, Molecular; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control*; D009363:Neoplasm Proteins / Q000378:metabolism; D009828:Oleanolic Acid / Q000737:chemistry* / Q000494:pharmacology*; D051419:Paxillin / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D029766:Terminalia / Q000737:chemistry; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D009363:Neoplasm Proteins; D051419:Paxillin; C107953:RAC1 protein, human; D009828:Oleanolic Acid; D011505:Protein-Tyrosine Kinases; C088375:PTK6 protein, human; D020830:rac1 GTP-Binding Protein
keywords: Brk/Paxillin/Rac1 axis; Combretaceae; Terminalia bentzoe L; bioassay-guided; breast cancer; oleanolic acid