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-17 beta-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 poly-merase 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.
