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

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

  • Bioorg Med Chem. 2021 Jan 15:30:115957. doi: 10.1016/j.bmc.2020.115957.
Mikhail V Pugachev 1,  Roman S Pavelyev 1,  Thang N T Nguyen 1,  Raylya R Gabbasova 1,  Timur M Bulatov 1,  Alfiya G Iksanova 1,  Bashar Aljondi 1,  Oksana V Bondar 1,  Denis Yu Grishaev 1,  Zilya R Yamaleeva 2,  Olga N Kataeva 2,  Tatyana V Nikishova 1,  Konstantin V Balakin 1,  Yurii G Shtyrlin 3
Affiliations

Affiliations

  • 1 Kazan (Volga Region) Federal University, Kremlyovskaya 18, Kazan 420008, Russia.
  • 2 A.E. Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov str. 8, Kazan 420088, Russia.
  • 3 Kazan (Volga Region) Federal University, Kremlyovskaya 18, Kazan 420008, Russia. Electronic address: yurii.shtyrlin@kpfu.ru.
PMID: 33373820 DOI: 10.1016/j.bmc.2020.115957
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.

Keywords

Antitumor activity; Bioisosteric analogs of estradiol; Drug discovery; Pyridoxine; Vitamin B6.

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