title: Synthesis of the vitamin E amino acid esters with an enhanced anticancer activity and in silico screening for new antineoplastic drugs.
abstract: Tocopherols and tocotrienols belong to the family of vitamin E (VE) with the well-known antioxidant properties. For certain α-tocopherol and γ-tocotrienol derivatives used as the lead compounds in this study, antitumor activities against various cancer cell types have been reported. In the course of the last decade, structural analogs of VE (esters, ethers and amides) with an enhanced antiproliferative and proapoptotic activity against various cancer cells were synthesized. Within the framework of this study, seven amino acid esters of α-tocopherol (4a-d) and γ-tocotrienol (6a-c) were prepared using the EDC/DMAP reaction conditions and their ability to inhibit proliferation of the MCF-7 and MDA-MB-231 breast cancer cells and the A549 lung cancer cells was evaluated. Compound 6a showed an activity against all three cell lines (IC50: 20.6μM, 28.6μM and 19μM for the MCF-7, MDA-MB-231 and A549 cells, respectively), while compound 4a inhibited proliferation of the MCF-7 (IC50=8.6μM) and A549 cells (IC50=8.6μM). Ester 4d exerted strong antiproliferative activity against the estrogen-unresponsive, multi-drug resistant MDA-MB-231 breast cancer cell line, with IC50 value of 9.2μM. Compared with the strong activity of compounds 4a, 4d and 6a, commercial α-tocopheryl succinate and γ-tocotrienol showed only a limited activity against all three cell lines, with IC50 values >50μM. Investigation of the cell cycle phase distribution and the cell death induction confirmed an apoptosis of the MDA-MB-231 cells treated with 4d, as well as a synergistic effect of 4d with the known anticancer drug doxorubicin. This result suggests a possibility of a combined therapy of breast cancer in order to improve the therapeutic response and to lower the toxicity associated with a high dose of doxorubicin. The stability study of 4d in human plasma showed that ca. 83% initial concentration of this compound remains in plasma in the course of six hours incubation. The ligand based virtual screening of the ChEMBL database identified new compounds with a potential antiproliferative activity on MCF-7 and on multi-drug resistant MDA-MB 231 breast cancer cells.
authors.affiliation: University of Banja Luka, Faculty of Medicine, Department of Pharmacy, Save Mrkalja 14, 78000 Banja Luka, Bosnia and Herzegovina. Electronic address: zarko.gagic@unibl.rs.
authors.forename: Zarko
authors.initials: Z
authors.lastname: Gagic
authors.affiliation: University of Belgrade, Faculty of Pharmacy, Institute of Pharmaceutical Chemistry, Vojvode Stepe 450, 11000 Belgrade, Serbia.
authors.forename: Branka
authors.initials: B
authors.lastname: Ivkovic
authors.affiliation: Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Srdic-Rajic
authors.affiliation: University of Belgrade, Faculty of Pharmacy, Institute of Pharmaceutical Chemistry, Vojvode Stepe 450, 11000 Belgrade, Serbia.
authors.forename: Jelica
authors.initials: J
authors.lastname: Vucicevic
authors.affiliation: University of Belgrade, Faculty of Pharmacy, Institute of Pharmaceutical Chemistry, Vojvode Stepe 450, 11000 Belgrade, Serbia.
authors.forename: Katarina
authors.initials: K
authors.lastname: Nikolic
authors.affiliation: University of Belgrade, Faculty of Pharmacy, Institute of Pharmaceutical Chemistry, Vojvode Stepe 450, 11000 Belgrade, Serbia.
authors.forename: Danica
authors.initials: D
authors.lastname: Agbaba
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D014810:Vitamin E
keywords: Anticancer; Esters; Screening; Synthesis; Vitamin E