Efficient Access to Domain-Integrated Estradiol-Flavone Hybrids Via the Corresponding Chalcones and Their in Vitro Anticancer Potential † ‡

Abstract

Structural modification of the phenolic A-ring of estrogens at C-2 and/or C-3 significantly reduces or eliminates the hormonal effects of the compounds, thus the incorporation of other pharmacophores into these positions can provide biologically active derivatives suitable for new indications, without possessing unwanted side effects. As part of this work, A-ring integration of estradiol with chalcones and flavones was carried out in the hope of obtaining novel molecular hybrids with anticancer action. The syntheses were performed from 2-acetylestradiol-17β-acetate which was first reacted with various (hetero)aromatic aldehydes in a pyrrolidine-catalyzed reaction in DMSO. The chalcones thus obtained were then subjected to oxidative cyclization with I2 in DMSO to afford estradiol-flavone hybrids in good yields. All newly synthesized derivatives were tested in vitro for cytotoxicity on human malignant cell lines of diverse origins as well as on a non-cancerous cell line, and the results demonstrated that estradiol-flavone hybrids containing a structure-integrated flavone moiety were the most active and cancer cell-selective agents. The minimal inhibitory concentration values (IC50) were calculated for selected compounds and their apoptosis inducing capacity was verified by RT-qPCR (real time quantitative polymerase chain reaction). The results suggest an important structure−activity relationship regarding estradiol-flavone hybrids that could form a promising synthetic platform and rationale for future drug developments.

Note:
Funding Information: This research was supported by the New National Excellence Program of the Ministry for Innovation and Technology from the National Research, Development, and Innovation Fund (ÚNKP-21-5-SZTE-592 to M.K, ÚNKP-21-2-SZTE-356 to F.I.N) and the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/00878/19/8 to M.K.). This research work was conducted with the support of the National Scientists Academy under the sponsorship of the Hungarian Ministry of Innovation and Technology (FEIF/433-4/2020-ITM to F.I.N.). Financial support by EC H2020 project “METROFOOD-PP” (grant agreement No 871083) is gratefully acknowledged.

Declaration of Interests: There are no conflicts to declare.

Keywords: steroid, molecular hybridization, chalcone, flavone, antiproliferative activity