title: Differential Effect of Wortmannolone Derivatives on MDA-MB-231 Breast Cancer Cells.
abstract: The survival rate of women diagnosed with triple-negative breast-cancer (TNBC) remains low. Hence, this study aimed at the chemical and biological optimization of furanosteroid derivatives for the treatment of this type of malignancy using TNBC cells.
  
  
  
  Semi-synthetic analogs of wortmannolone (1-6) that negatively affected the aberrant pathways in tumor cells were evaluated in hormone-independent breast cancer cells using western blot and cell-cycle analysis.
  
  
  
  Wortmannolone derivatization generated NF-ĸB inhibitors as new lead structures for further development. Compound (3) was found to be the most significantly active lead.
  
  
  
  Structure-activity analysis in the present study showed that acetylation of the hydroxyl groups and substitution on C3 and C17 of wortmannolone enhanced biological activity. Alpha-substitution of the acetyl group in C3 on ring A (compound3) resulted in ROS inducing effect; however, presence of an acetyl group in β-position of C3 displayed the highest NF-ĸB p65 inhibitory activity (0.60 μM).
authors.affiliation: Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, OH, U.S.A.|Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, U.S.A.
authors.forename: Ulyana Munoz
authors.initials: UM
authors.lastname: Acuña
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, U.S.A.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Curley
authors.affiliation: Department of Biotechnology, Quaid-i-Azam University, Islamabad, Pakistan.|Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, Hilo, HI, U.S.A.
authors.forename: Nighat
authors.initials: N
authors.lastname: Fatima
authors.affiliation: Department of Microbiology, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Safia
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, Hilo, HI, U.S.A.
authors.forename: Leng Chee
authors.initials: LC
authors.lastname: Chang
authors.affiliation: Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, OH, U.S.A. carcache-de-blan.1@osu.edu.|Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, U.S.A.
authors.forename: Esperanza J Carcache
authors.initials: EJ
authors.lastname: DE Blanco
mesh_terms: D000730:Androstadienes / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007166:Immunosuppressive Agents / Q000737:chemistry*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D000077191:Wortmannin
keywords: Furanosteroids; K-Ras; NF-ĸB p65; ROS; breast cancer cells; wortmannolone