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Synthesis, antitumor activity and structure-activity studies of novel pyridoxine-based bioisosteric analogs of estradiol

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dc.contributor.author Pugachev M.V.
dc.contributor.author Pavelyev R.S.
dc.contributor.author Nguyen T.N.T.
dc.contributor.author Gabbasova R.R.
dc.contributor.author Bulatov T.M.
dc.contributor.author Iksanova A.G.
dc.contributor.author Aljondi B.
dc.contributor.author Bondar O.V.
dc.contributor.author Grishaev D.Y.
dc.contributor.author Yamaleeva Z.R.
dc.contributor.author Kataeva O.N.
dc.contributor.author Nikishova T.V.
dc.contributor.author Balakin K.V.
dc.contributor.author Shtyrlin Y.G.
dc.date.accessioned 2022-02-09T20:34:53Z
dc.date.available 2022-02-09T20:34:53Z
dc.date.issued 2021
dc.identifier.issn 0968-0896
dc.identifier.uri https://dspace.kpfu.ru/xmlui/handle/net/169173
dc.description.abstract A new efficient approach to the synthesis of 6-alkenyl substituted pyridoxine derivatives has been developed. A series of 31 novel alkenyl pyridoxine derivatives, stilbene-based bioisosteric analogs of estradiol, were synthesized. In vitro cytotoxicity of the obtained compounds against MCF-7 (ER+) breast cancer tumor cells was studied using the MTT assay. The most active compounds with IC50, MCF-7 < 10 μM were also tested for cytotoxicity in vitro against MDA-MB-231 (ER-) breast adenocarcinoma cells and conditionally normal human skin fibroblasts (HSF). The patterns of structure-antitumor activity relationships of the obtained compounds were analyzed. The most active compounds were found to contain a six-membered ketal ring, a methyl group in position 5, a 3,4-dimethoxystyryl fragment in positions 2 or 6 of the pyridoxine ring, and a trans-configuration of the double bond. Using the most active compound 5a as a representative cytotoxic agent, we have demonstrated that it has high specificity and antiproliferative activity against MCF-7 (ER+) tumor cells (IC50 < 5 μM), and a higher therapeutic index compared to the reference compound raloxifene (48 versus 5.8). Compound 5a decreased the mitochondrial membrane potential and increased the level of reactive oxygen species in MCF-7 cells, but not MDA-MB-231 cells. Compound 5a did not affect the distribution of cell cycle phases and induced apoptosis in MCF-7 cells, but not MDA-MB-231. Unlike compound 5a, raloxifene decreased mitochondrial potential, increased the ROS level, and induced apoptosis in both MCF-7 and MDA-MB-231 cells, which indicated a lack of selectivity for cells with estrogen receptor expression. It was also shown that compound 5a reduced the level of ERα expression in cells to a lesser extent than raloxifene and, unlike the latter, did not activate the PI3K/Akt signaling pathway.
dc.relation.ispartofseries Bioorganic and Medicinal Chemistry
dc.subject Antitumor activity
dc.subject Bioisosteric analogs of estradiol
dc.subject Drug discovery
dc.subject Pyridoxine
dc.subject Vitamin B6
dc.title Synthesis, antitumor activity and structure-activity studies of novel pyridoxine-based bioisosteric analogs of estradiol
dc.type Article
dc.relation.ispartofseries-volume 30
dc.collection Публикации сотрудников КФУ
dc.source.id SCOPUS09680896-2021-30-SID85098159166

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  • Публикации сотрудников КФУ Scopus [24551]
    Коллекция содержит публикации сотрудников Казанского федерального (до 2010 года Казанского государственного) университета, проиндексированные в БД Scopus, начиная с 1970г.

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