Identification of a new tamoxifen-xanthene hybrid as pro-apoptotic anticancer agent |
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| Affiliation: | 1. Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d’Augusto 237, 47921 Rimini, Italy;2. Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy;3. Department of Biomolecular Sciences, University of Urbino Carlo Bo, Via I Maggetti 26, 61029 Urbino (PU), Italy;4. Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Irnerio 48, 40126 Bologna, Italy;1. Department of Chemistry & Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh, 160014, India;2. M. L. S. M. College, Sunder Nagar, Himachal Pradesh, India;1. Biology Department, Faculty of Science, King Khalid University, 9004 Abha, Saudi Arabia;2. Chemistry Department, Faculty of Science, Damanhour University, Egypt;3. Chemistry department, College of Alwajh, Tabuk University, Saudi Arabia;4. Cell Culture Lab, Egyptian Organization for Biological Products and Vaccines (VACSERA Holding Company), Giza 12311, Egypt;5. Faculty of Science, Zoology Department, Suez University, 43533 Suez, Egypt;6. Faculty of Science, Chemistry Department, Suez University, 43533 Suez, Egypt;7. Institut für Anorganische Chemie und Strukturchemie, Heinrich-Heine Universität Düsseldorf, 40204 Düsseldorf, Germany;1. Department of Organic Chemistry, Faculty of Chemistry, Urmia University, 57159, Urmia, Iran;2. Department of Chemistry, Faculty of Science, Shahid Beheshti University, Tehran, Iran;3. Joints, Bones and Connective Tissue Research Center, Golestan University of Medical Science, Gorgan, Iran |
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| Abstract: | Breast cancer is the most diagnosed type of cancer among women for which an exhaustive cure has not been discovered yet. Nowadays, tamoxifen still represents the gold standard for breast cancer therapy; it acts on both estrogen receptor-positive and estrogen receptor-negative breast cancers. Unfortunately, its toxicity and the related chemoresistance undermine its antitumor potential. In this paper, new tamoxifen-based derivatives with a rigid structural motif in their structure were designed, synthesized, and evaluated to assess their antitumor behavior. All the tested compounds affected estrogen receptor-positive tumor (MCF-7) cell growth, even with different extents, among which, the most active ones proved also to induce mitochondria-mediated apoptosis through activation of PARP cleavage, decrease in Bax/Bcl-2 ratio and increase in Bim gene expression levels. Here we found that the compound 1, carrying a rigid xanthene core, turned out to be the most promising of the set showing an activity profile comparable to that of tamoxifen. Furthermore, a more favorable genotoxic profile than tamoxifen made compound 1 a promising candidate for further studies. |
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| Keywords: | apoptosis Bax, Bcl-2, breast cancer genotoxicity γ-H2A.X phosphorylation, PARP cleavage, tamoxifen triphenylethylene xanthene scaffold ER" },{" #name" :" keyword" ," $" :{" id" :" k0040" }," $$" :[{" #name" :" text" ," _" :" estrogen receptor FCC" },{" #name" :" keyword" ," $" :{" id" :" k0050" }," $$" :[{" #name" :" text" ," _" :" flash column chromatography i.m." },{" #name" :" keyword" ," $" :{" id" :" k0060" }," $$" :[{" #name" :" text" ," _" :" isomers mixture PARP" },{" #name" :" keyword" ," $" :{" id" :" k0070" }," $$" :[{" #name" :" text" ," _" :" poly (ADP-ribose) polymerase-1 SERM" },{" #name" :" keyword" ," $" :{" id" :" k0080" }," $$" :[{" #name" :" text" ," _" :" selective estrogen receptor modulator TAM" },{" #name" :" keyword" ," $" :{" id" :" k0090" }," $$" :[{" #name" :" text" ," _" :" tamoxifen |
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