Efficient access to domain-integrated estradiol-flavone hybrids via the corresponding chalcones and their in vitro anticancer potential

• Published in: Steroids Vol. 187; p. 109099
• Main Authors: Molnár, Barnabás, Gopisetty, Mohana K., Nagy, Ferenc István, Adamecz, Dóra Izabella, Kása, Zsolt, Kiricsi, Mónika, Frank, Éva
• Format: Journal Article
• Language: English
• Published: NEW YORK Elsevier Inc 01.11.2022; Elsevier
• Subjects: Antiproliferative activity; Biochemistry & Molecular Biology; Chalcone; Endocrinology & Metabolism; Flavone; Life Sciences & Biomedicine; Molecular hybridization; Science & Technology; Steroid; Steroid; Molecular hybridization; Antiproliferative activity; Flavone; Chalcone; DESIGN; STEROIDS; SYSTEMS; PROLIFERATION; 2-METHOXYESTRADIOL; DERIVATIVES; CYTOTOXICITY
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2022.109099

[Display omitted] •Novel estradiol-chalcone and estradiol-flavone hybrids were synthesized.•Framework integration was achieved via molecular hybridization.•Pharmalogical screening was carried out to determine their antiproliferative activity.•Compounds 3c, 3d and 3e exhibit prominent cytotoxic activity on cancerous cell lines. 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 (3c, 3d and 3e) 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.