Synthesis of the vitamin E amino acid esters with an enhanced anticancer activity and in silico screening for new antineoplastic drugs
Authorized Users Only
2016
Authors
Gagić, ŽarkoIvković, Branka
Srdić-Rajić, Tatjana
Vučićević, Jelica
Nikolić, Katarina
Agbaba, Danica
Article (Published version)
Metadata
Show full item recordAbstract
Tocopherols and tocotrienols belong to the family of vitamin E (VE) with the well-known antioxidant properties. For certain alpha-tocopherol and gamma-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 alpha-tocopherol (4a-d) and gamma-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: 20.6 mu M, 28.6 mu M and 19 mu M for the MCF-7, MDA-MB-231 and A549 cells, respectively), while compound 4a inhibited proliferation of the M...CF-7 (IC50 = 8.6 mu M) and A549 cells (IC50 = 8.6 mu M). Ester 4d exerted strong antiproliferative activity against the estrogenunresponsive, multi-drug resistant MDA-MB-231 breast cancer cell line, with IC50 value of 9.2 mu M. Compared with the strong activity of compounds 4a, 4d and 6a, commercial alpha-tocopheryl succinate and gamma-tocotrienol showed only a limited activity against all three cell lines, with IC50 values >50 mu M. 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.
Source:
European Journal of Pharmaceutical Sciences, 2016, 88, 59-69Publisher:
- Elsevier Science BV, Amsterdam
Funding / projects:
- Synthesis, Quantitative Structure and Activity Relationship, Physico-Chemical Characterisation and Analysis of Pharmacologically Active Substances (RS-MESTD-Basic Research (BR or ON)-172033)
DOI: 10.1016/j.ejps.2016.04.008
ISSN: 0928-0987
PubMed: 27063330
WoS: 000376655200006
Scopus: 2-s2.0-84963542076
Collections
Institution/Community
PharmacyTY - JOUR AU - Gagić, Žarko AU - Ivković, Branka AU - Srdić-Rajić, Tatjana AU - Vučićević, Jelica AU - Nikolić, Katarina AU - Agbaba, Danica PY - 2016 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2532 AB - Tocopherols and tocotrienols belong to the family of vitamin E (VE) with the well-known antioxidant properties. For certain alpha-tocopherol and gamma-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 alpha-tocopherol (4a-d) and gamma-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: 20.6 mu M, 28.6 mu M and 19 mu M for the MCF-7, MDA-MB-231 and A549 cells, respectively), while compound 4a inhibited proliferation of the MCF-7 (IC50 = 8.6 mu M) and A549 cells (IC50 = 8.6 mu M). Ester 4d exerted strong antiproliferative activity against the estrogenunresponsive, multi-drug resistant MDA-MB-231 breast cancer cell line, with IC50 value of 9.2 mu M. Compared with the strong activity of compounds 4a, 4d and 6a, commercial alpha-tocopheryl succinate and gamma-tocotrienol showed only a limited activity against all three cell lines, with IC50 values >50 mu M. 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. PB - Elsevier Science BV, Amsterdam T2 - European Journal of Pharmaceutical Sciences T1 - Synthesis of the vitamin E amino acid esters with an enhanced anticancer activity and in silico screening for new antineoplastic drugs VL - 88 SP - 59 EP - 69 DO - 10.1016/j.ejps.2016.04.008 ER -
@article{ author = "Gagić, Žarko and Ivković, Branka and Srdić-Rajić, Tatjana and Vučićević, Jelica and Nikolić, Katarina and Agbaba, Danica", year = "2016", abstract = "Tocopherols and tocotrienols belong to the family of vitamin E (VE) with the well-known antioxidant properties. For certain alpha-tocopherol and gamma-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 alpha-tocopherol (4a-d) and gamma-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: 20.6 mu M, 28.6 mu M and 19 mu M for the MCF-7, MDA-MB-231 and A549 cells, respectively), while compound 4a inhibited proliferation of the MCF-7 (IC50 = 8.6 mu M) and A549 cells (IC50 = 8.6 mu M). Ester 4d exerted strong antiproliferative activity against the estrogenunresponsive, multi-drug resistant MDA-MB-231 breast cancer cell line, with IC50 value of 9.2 mu M. Compared with the strong activity of compounds 4a, 4d and 6a, commercial alpha-tocopheryl succinate and gamma-tocotrienol showed only a limited activity against all three cell lines, with IC50 values >50 mu M. 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.", publisher = "Elsevier Science BV, Amsterdam", journal = "European Journal of Pharmaceutical Sciences", title = "Synthesis of the vitamin E amino acid esters with an enhanced anticancer activity and in silico screening for new antineoplastic drugs", volume = "88", pages = "59-69", doi = "10.1016/j.ejps.2016.04.008" }
Gagić, Ž., Ivković, B., Srdić-Rajić, T., Vučićević, J., Nikolić, K.,& Agbaba, D.. (2016). Synthesis of the vitamin E amino acid esters with an enhanced anticancer activity and in silico screening for new antineoplastic drugs. in European Journal of Pharmaceutical Sciences Elsevier Science BV, Amsterdam., 88, 59-69. https://doi.org/10.1016/j.ejps.2016.04.008
Gagić Ž, Ivković B, Srdić-Rajić T, Vučićević J, Nikolić K, Agbaba D. Synthesis of the vitamin E amino acid esters with an enhanced anticancer activity and in silico screening for new antineoplastic drugs. in European Journal of Pharmaceutical Sciences. 2016;88:59-69. doi:10.1016/j.ejps.2016.04.008 .
Gagić, Žarko, Ivković, Branka, Srdić-Rajić, Tatjana, Vučićević, Jelica, Nikolić, Katarina, Agbaba, Danica, "Synthesis of the vitamin E amino acid esters with an enhanced anticancer activity and in silico screening for new antineoplastic drugs" in European Journal of Pharmaceutical Sciences, 88 (2016):59-69, https://doi.org/10.1016/j.ejps.2016.04.008 . .