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

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.

journal_name

Bioorg Med Chem

authors

Pugachev MV,Pavelyev RS,Nguyen TNT,Gabbasova RR,Bulatov TM,Iksanova AG,Aljondi B,Bondar OV,Grishaev DY,Yamaleeva ZR,Kataeva ON,Nikishova TV,Balakin KV,Shtyrlin YG

doi

10.1016/j.bmc.2020.115957

subject

Has Abstract

pub_date

2021-01-15 00:00:00

pages

115957

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(20)30787-2

journal_volume

30

pub_type

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