Resveratrol is a plant-derived phytoalexin found in grapes, red wine and many other plants used in Asian folk medicine. It is extensively studied for pleiotropic biological activity. The most crucial are anticancer and chemopreventive properties. Resveratrol has also been reported to be an antioxidant and phytoestrogen. The phytoestrogenic activity of resveratrol was assayed in different in vitro and in vivo models. Although these works brought some, on the first look, conflicting results, it is commonly accepted that resveratrol interacts with estrogen receptors and functions as a mixed agonist/antagonist. It is widely accepted that the hydroxyl groups are crucial for resveratrol’s cytotoxic and antioxidative activity and are responsible for binding estrogen receptors. In this work, we assayed 11 resveratrol analogues, seven barring methoxy groups and six hydroxylated analogues in different combinations at positions 3, 4, 5 and 3′,4′,5′. For this purpose, recombined estrogen receptors and estrogen-dependent MCF-7 and Ishikawa cells were used. Our study was supported by in silico docking studies. We have shown that, resveratrol and 3,4,4′5′-tetrahydroxystilbene, 3,3′,4,5,5′-pentahydroxystilbene and 3,3′,4,4′,5,5′-hexahydroxystilbene may act as selective estrogen receptor modulators.

Although curcumin is a well-known natural polyphenol with many biological activities, its clinical application has been limited by low aqueous solubility and stability. Therefore, curcumin derivatives have been proposed to overcome these limitations and increase anticancer activity. This study tested curcumin derivatives with modified feruloyl moieties (2a and 2a-B) and the β-diketo moiety (2a-B) to better understand their anticancer mechanism against human bladder cancer cells. The anticancer activity of 2a and 2a-B was determined using MTT (hypoxic conditions) and LDH (normoxic conditions) assays. An ELISA-based protein panel was used to find the potential molecular targets, while flow cytometric, colorimetric, fluorescent, and luminescent assays were used to investigate the cell death mechanism. It was shown that compound 2a exerted a more potent cytotoxic effect under hypoxic conditions, while compound 2a-B demonstrated a comparable effect in normoxic and hypoxic conditions. The potential molecular targets modified by 2a and 2a-B depending on oxygen concentration were also proposed. Both compounds alter cell cycle progression by blocking the cell cycle in the G2/M phase and decreasing the percentage of cells in the G0/G1 phase. Compound 2a-B led to phosphatidylserine translocation, increased caspase 3/7 activity, and decreased mitochondrial membrane potential, suggesting a mitochondrial apoptosis pathway. We found that the Akt signaling pathway may modulate the activity of compound 2a-B, as evidenced by enhanced cytotoxic activity in combination with MK-2206, an Akt 1/2/3 inhibitor. Thus, our results provide new insights into the anticancer activity of compounds 2a and 2a-B; however, further studies are needed to better understand their therapeutic potential.

Curcumin is a versatile natural compound that has been extensively studied for its potential activity in cancer models. However, its clinical development faces challenges, including poor water solubility, chemical instability under physiological conditions, rapid metabolism, and limited systemic bioavailability. These issues have driven efforts to modify the curcumin structure to enhance stability, pharmacokinetics, and target interaction, while preserving or improving its antiproliferative effects. This review highlights key medicinal chemistry strategies for creating analogs beyond curcumin, including (i) monocarbonyl variants that replace the β-diketone group to improve stability, (ii) aromatic ring modifications that adjust electronic properties, lipophilicity, and cellular entry, (iii) prodrug designs that conceal phenolic groups to increase solubility or permeability, and (iv) hybrid molecules and conjugates for dual targeting or better delivery. Additionally, we discuss metal–curcumin(oid) complexes as promising options to modify stability, redox activity, and biological effects in cancer models. We also propose a basic evaluation toolkit to support more consistent comparisons among analogs, emphasizing the need to report chemical stability, microsomal metabolism, selectivity, and in vivo exposure, alongside in vitro viability/proliferation readouts and, where available, orthogonal cytotoxicity endpoints. Rather than treating beyond-curcumin chemistry as a catalog of potency-improving modifications, this review frames the major scaffold classes in terms of developability, evidentiary burden, and translational pragmatism. Overall, successful translation will depend less on isolated IC50 gains and more on standardized profiling and alignment of mechanism claims with achievable exposure.