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

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-17ß-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.

Cancer Therapy by Silver Nanoparticles: Fiction or Reality?

As an emerging new class, metal nanoparticles and especially silver nanoparticles hold great potential in the field of cancer biology. Due to cancer-specific targeting, the consequently attenuated side-effects and the massive anti-cancer features render nanoparticle therapeutics desirable platforms for clinically relevant drug development. In this review, we highlight those characteristics of silver nanoparticle-based therapeutic concepts that are unique, exploitable, and achievable, as well as those that represent the critical hurdle in their advancement to clinical utilization. The collection of findings presented here will describe the features that distinguish silver nanoparticles from other anti-cancer agents and display the realistic opportunities and implications in oncotherapeutic innovations to find out whether cancer therapy by silver nanoparticles is fiction or reality.

Synthesis and conversion of primary and secondary 2-aminoestradiols into A-ring-integrated benzoxazolone hybrids and their in vitro anticancer activity.

Hybrid systems are often endowed with completely different and improved properties compared to their parent compounds. In order to extend the chemical space toward sterane-based molecular hybrids, a number of estradiol-derived benzoxazol-2-ones with combined aromatic rings were synthesized via the corresponding 2-aminophenol intermediates. 2-Aminoestradiol was first prepared from estrone by a two-step nitration/reduction sequence under mild reaction conditions. Subsequent reductive aminations with different arylaldehydes furnished secondary 2-aminoestradiol derivatives in good yields. The proton dissociation processes of the aminoestradiols were investigated in aqueous solution by UV-visible spectrophotometric titrations to reveal their actual chemical forms at physiological pH. The determined pK 1 and pK 2 values are attributed to the +NH3 or +NH2R and OH moieties, and both varied by the different R substituents of the amino group. Primary and secondary 2-aminoestradiols were next reacted with carbonyldiimidazole as a phosgene equivalent to introduce a carbonyl group with simultaneous ring-closure to give A-ring-fused oxazolone derivatives in high yields. The novel aminoestradiols and benzoxazolones were subjected to in vitro cytotoxicity analysis and were found to exert cancer cell specific activity.