Ulyana Munoz Acuña1,2, Robert W Curley2, Nighat Fatima3,4, Safia Ahmed5, Leng Chee Chang4, Esperanza J Carcache DE Blanco6,2. 1. Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, OH, U.S.A. 2. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, U.S.A. 3. Department of Biotechnology, Quaid-i-Azam University, Islamabad, Pakistan. 4. Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, Hilo, HI, U.S.A. 5. Department of Microbiology, Quaid-i-Azam University, Islamabad, Pakistan. 6. Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, OH, U.S.A. carcache-de-blan.1@osu.edu.
Abstract
BACKGROUND/AIM: 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. MATERIALS AND METHODS: 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. RESULTS: Wortmannolone derivatization generated NF-ĸB inhibitors as new lead structures for further development. Compound (3) was found to be the most significantly active lead. CONCLUSION: 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 (compound 3) 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). Copyright
BACKGROUND/AIM: 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. MATERIALS AND METHODS: 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. RESULTS:Wortmannolone derivatization generated NF-ĸB inhibitors as new lead structures for further development. Compound (3) was found to be the most significantly active lead. CONCLUSION: 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 (compound 3) 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). Copyright
Authors: Patrícia S Guerreiro; Ana Sofia Fernandes; João G Costa; Matilde Castro; Joana P Miranda; Nuno G Oliveira Journal: Mutat Res Date: 2013-08-16 Impact factor: 2.433
Authors: Mary Kaileh; Wim Vanden Berghe; Arne Heyerick; Julie Horion; Jacques Piette; Claude Libert; Denis De Keukeleire; Tamer Essawi; Guy Haegeman Journal: J Biol Chem Date: 2006-12-06 Impact factor: 5.157
Authors: P Christian Schulze; Jun Yoshioka; Tomosaburo Takahashi; Zhiheng He; George L King; Richard T Lee Journal: J Biol Chem Date: 2004-05-05 Impact factor: 5.157